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Folestad E, Mehlem A, Ning FC, Oosterveld T, Palombo I, Singh J, Olauson H, Witasp A, Thorell A, Stenvinkel P, Ebefors K, Nyström J, Eriksson U, Falkevall A. Vascular endothelial growth factor B-mediated fatty acid flux in the adipose-kidney axis contributes to lipotoxicity in diabetic kidney disease. Kidney Int 2025; 107:492-507. [PMID: 39689809 DOI: 10.1016/j.kint.2024.11.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 11/11/2024] [Accepted: 11/18/2024] [Indexed: 12/19/2024]
Abstract
A common observation in diabetic kidney disease is lipid accumulation, but the mechanism(s) underlying this pathology is unknown. Inhibition of Vascular endothelial growth factor B (VEGF-B) signaling was shown to prevent glomerular lipid accumulation and ameliorated diabetic kidney disease in experimental models. Here, we examined kidney biopsies from patients with Type 2 (84%) and Type 1 diabetes (16%), combined with data mining of RNA-seq dataset analyses in patients with diabetic kidney disease. In glomeruli, mesangial cell-derived VEGF-B expression was increased, and glomerular lipid accumulation positively correlated with impaired kidney function. Tubular lipid accumulation also associated with kidney dysfunction but was independent of tubular-derived VEGF-B expression. In vitro, the uptake of the fatty acid analogue, BODIPY-FA, was quantified. VEGF-B treatment increased BODIPY-FA uptake in endothelial cells, whilst pre-incubation with neutralizing antibodies against VEGF-B and its receptor VEGFR1 abolished this uptake. Transcriptome analyses of kidney and white adipose tissue from diabetic macaques showed that VEGF-B expression was higher in white adipose tissue than in kidney, and expression of VEGF-B was increased in white adipose tissue from patients with diabetic kidney disease. Analyses in diabetic transgenic mice demonstrated that expression of VEGF-B in adipocytes determined the lipolytic activity, dyslipidemia, kidney lipid accumulation and the development of diabetic kidney disease. Overall, VEGF-B is a regulator of kidney lipotoxicity in diabetic kidney disease, by controlling white adipose tissue lipolysis as well as endothelial fatty acid transport in glomeruli. Our data propose that assessment of kidney lipid accumulation, and VEGF-B expression can serve as biomarkers for early diabetic kidney disease.
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Affiliation(s)
- Erika Folestad
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annika Mehlem
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Frank Chenfei Ning
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Timo Oosterveld
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Isolde Palombo
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jaskaran Singh
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Olauson
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Witasp
- Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Anders Thorell
- Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Surgery and Anaesthesiology, Ersta Hospital, Stockholm, Sweden
| | - Peter Stenvinkel
- Division of Renal Medicine, Department of Clinical Sciences, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Kerstin Ebefors
- Lundberg Laboratory for Kidney Research, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jenny Nyström
- Lundberg Laboratory for Kidney Research, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Eriksson
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Annelie Falkevall
- Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
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Tramontano D, D'Erasmo L, Larouche M, Brisson D, Lauzière A, Di Costanzo A, Bini S, Minicocci I, Covino S, Baratta F, Pasquali M, Cerbelli B, Gaudet D, Arca M. The vicious circle of chronic kidney disease and hypertriglyceridemia: What is first, the hen or the egg? Atherosclerosis 2025; 403:119146. [PMID: 40056689 DOI: 10.1016/j.atherosclerosis.2025.119146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/10/2025]
Abstract
Chronic kidney disease (CKD) is documented to cause alterations in lipid metabolism, and this was considered a potent driver of increased cardiovascular risk. Among the diverse alteration of lipid traits in CKD, research endeavours have predominantly concentrated on low-density lipoproteins (LDL) in view of the potent pro-atherogenic role of these lipoprotein particles and the demonstration of protective cardiovascular effect of reducing LDL. However, few studies have focused on the metabolism of triglyceride-rich lipoproteins and even fewer on their role in causing kidney damage. Therefore, the comprehensive description of the impact of hypertriglyceridemia (HTG) in CKD pathophysiology remains largely undetermined. This reflects the difficulty of disentangling the independent role of triglycerides (TG) in the complex, bidirectional relationship between TG and kidney disease. Abnormal neutral lipid accumulation in the intrarenal vasculature and renal cells eventually due to HTG may also promote glomerular injury, throughout mechanisms including oxidative stress, mitochondrial dysfunction and proinflammatory responses. While epidemiological and experimental evidence suggests a potential role of TG in kidney damage, the causal mechanisms and their clinical relevance remain unclear, representing a significant area for future investigation. This review aims to highlight the intricate interplay between TG metabolism and kidney disease, shedding light on the mechanisms through which HTG may influence kidney functionality.
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Affiliation(s)
- Daniele Tramontano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy.
| | - Miriam Larouche
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Diane Brisson
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Alex Lauzière
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Ilenia Minicocci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Stella Covino
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Francesco Baratta
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Marzia Pasquali
- Department of Internal Medicine and Medical Specialities, Nephrology Unit, University Policlinico Umberto I Hospital, Rome, Italy
| | - Bruna Cerbelli
- Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome, Rome, Italy
| | - Daniela Gaudet
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
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Sun Y, Li B, Song B, Xia Y, Ye Z, Lin F, Zhou X, Li W, Rao T, Cheng F. UHRF1 promotes calcium oxalate-induced renal fibrosis by renal lipid deposition via bridging AMPK dephosphorylation. Cell Biol Toxicol 2025; 41:39. [PMID: 39899077 PMCID: PMC11790803 DOI: 10.1007/s10565-025-09991-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/17/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Nephrolithiasis, a common urinary system disorder, exhibits high morbidity and recurrence rates, correlating with renal dysfunction and the increased risk of chronic kidney disease. Nonetheless, the precise role of disrupted cellular metabolism in renal injury induced by calcium oxalate (CaOx) crystal deposition is unclear. The purpose of this study is to investigate the involvement of the ubiquitin-like protein containing PHD and RING finger structural domain 1 (UHRF1) in CaOx-induced renal fibrosis and its impacts on cellular lipid metabolism. METHODS Various approaches, including snRNA-seq, transcriptome RNA-seq, immunohistochemistry, and western blot analyses, were employed to assess UHRF1 expression in kidneys of nephrolithiasis patients, hyperoxaluric mice, and CaOx-induced renal tubular epithelial cells. Subsequently, knockdown of UHRF1 in mice and cells corroborated its effect of UHRF1 on fibrosis, ectopic lipid deposition (ELD) and fatty acid oxidation (FAO). Rescue experiments using AICAR, ND-630 and Compound-C were performed in UHRF1-knockdown cells to explore the involvement of the AMPK pathway. Then we confirmed the bridging molecule and its regulatory pathway in vitro. Experimental results were finally confirmed using AICAR and chemically modified si-UHRF1 in vivo of hyperoxaluria mice model. RESULTS Mechanistically, UHRF1 was found to hinder the activation of the AMPK/ACC1 pathway during CaOx-induced renal fibrosis, which was mitigated by employing AICAR, an AMPK agonist. As a nuclear protein, UHRF1 facilitates nuclear translocation of AMPK and act as a molecular link targeting the protein phosphatase PP2A to dephosphorylate AMPK and inhibit its activity. CONCLUSION This study revealed that UHRF1 promotes CaOx -induced renal fibrosis by enhancing lipid accumulation and suppressing FAO via inhibiting the AMPK pathway. These findings underscore the feasible therapeutic implications of targeting UHRF1 to prevent renal fibrosis due to stones.
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Affiliation(s)
- Yushi Sun
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Bojun Li
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Baofeng Song
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Yuqi Xia
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Zehua Ye
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Fangyou Lin
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Xiangjun Zhou
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China
| | - Wei Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People's Republic of China.
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Wang Z, Gao H, Ma X, Zhu D, Zhao L, Xiao W. Adrenic acid: A promising biomarker and therapeutic target (Review). Int J Mol Med 2025; 55:20. [PMID: 39575474 PMCID: PMC11611323 DOI: 10.3892/ijmm.2024.5461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/06/2024] [Indexed: 01/05/2025] Open
Abstract
Adrenic acid is a 22‑carbon unsaturated fatty acid that is widely present in the adrenal gland, liver, brain, kidney and vascular system that plays a regulatory role in various pathophysiological processes, such as inflammatory reactions, lipid metabolism, oxidative stress, vascular function, and cell death. Adrenic acid is a potential biomarker for various ailments, including metabolic, neurodegenerative and cardiovascular diseases and cancer. In addition, adrenic acid is influenced by the pharmacological properties of several natural products, such as astragaloside IV, evodiamine, quercetin, kaempferol, Berberine‑baicalin and prebiotics, so it is a promising new target for clinical treatment and drug development. However, the molecular mechanisms by which adrenic acid exerts are unclear. The present study systematically reviewed the biosynthesis and metabolism of adrenic acid, focusing on intrinsic mechanisms that influence the progression of metabolic, cardiovascular and neurological disease. These mechanisms regulate several key processes, including immuno‑inflammatory response, oxidative stress, vascular function and cell death. In addition, the present study explored the potential clinical translational value of adrenic acid as a biomarker and therapeutic target. To the best of our knowledge, the present study is first systematic summary of the mechanisms of action of adrenic acid across a range of diseases. The present study provides understanding of the wide range of metabolic activities of adrenic acid and a basis for further exploring the pathogenesis and therapeutic targets of various diseases.
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Affiliation(s)
- Ze Wang
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Haoyang Gao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Xiaotong Ma
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Danlin Zhu
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
| | - Linlin Zhao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
- School of Physical Education, Shanghai Normal University, Shanghai 200234, P.R. China
| | - Weihua Xiao
- Shanghai Key Laboratory of Human Performance, Shanghai University of Sport, Shanghai 200438, P.R. China
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Meulders B, Marei WFA, Loier L, Leroy JLMR. Lipotoxicity and Oocyte Quality in Mammals: Pathogenesis, Consequences, and Reversibility. Annu Rev Anim Biosci 2025; 13:233-254. [PMID: 39565833 DOI: 10.1146/annurev-animal-111523-102249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Metabolic stress conditions are often characterized by upregulated lipolysis and subsequently increased serum free fatty acid (FFA) concentrations, leading to the uptake of FFAs by non-adipose tissues and impairment of their function. This phenomenon is known as lipotoxicity. The increased serum FFA concentrations are reflected in the ovarian follicular fluid, which can have harmful effects on oocyte development. Several studies using in vitro and in vivo mammalian models showed that altered oocyte metabolism, increased oxidative stress, and mitochondrial dysfunction are crucial mechanisms underlying this detrimental impact. Ultimately, this can impair offspring health through the persistence of defective mitochondria in the embryo, hampering epigenetic reprogramming and early development. In vitro and in vivo treatments to enhance oocyte mitochondrial function are increasingly being developed. This can help to improve pregnancy rates and safeguard offspring health in metabolically compromised individuals.
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Affiliation(s)
- Ben Meulders
- Gamete Research Centre, Laboratory of Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium; , , ,
| | - Waleed F A Marei
- Department of Theriogenology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
- Gamete Research Centre, Laboratory of Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium; , , ,
| | - Lien Loier
- Gamete Research Centre, Laboratory of Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium; , , ,
| | - Jo L M R Leroy
- Gamete Research Centre, Laboratory of Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium; , , ,
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Alhermi A, Perks H, Nigi V, Altahoo N, Atkin SL, Butler AE. The Role of the Liver in the Pathophysiology of PCOS: A Literature Review. Biomolecules 2025; 15:51. [PMID: 39858445 PMCID: PMC11764088 DOI: 10.3390/biom15010051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder found in women of reproductive age and is characterized by both metabolic and reproductive dysfunction. Women with PCOS commonly have insulin resistance, increased susceptibility to type 2 diabetes mellitus, dyslipidemia, hyperinsulinemia, increased cardiovascular risk, hepatic steatosis, infertility, and an overall reduction in physical and psychological well-being. Several previous studies have shown a causal association between PCOS and hepatic disorders, such as chronic liver disease (CLD) and nonalcoholic fatty liver disease (NAFLD), where PCOS was identified as contributing to the hepatic features. Whilst it is recognized that PCOS may contribute to hepatic dysfunction, there is also evidence that the liver may contribute to the features of PCOS. The purpose of this review is to discuss the current understanding regarding hepatic involvement in PCOS pathophysiology, the inflammatory markers and hepatokines involved in the development of PCOS, and the role of genetics in the occurrence of PCOS. This review illustrates that PCOS and NAFLD are both common disorders and that there is both genetic and metabolic linkage between the disorders. As such, whilst PCOS may contribute to NAFLD development, the converse may also be the case, with a potential bidirectional relationship between PCOS and liver disease.
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Affiliation(s)
- Abrar Alhermi
- School of Medicine, Royal College of Surgeons of Ireland, Busaiteen, Adliya P.O. Box 15503, Bahrain; (A.A.); (H.P.); (V.N.); (N.A.)
| | - Heather Perks
- School of Medicine, Royal College of Surgeons of Ireland, Busaiteen, Adliya P.O. Box 15503, Bahrain; (A.A.); (H.P.); (V.N.); (N.A.)
| | - Varsha Nigi
- School of Medicine, Royal College of Surgeons of Ireland, Busaiteen, Adliya P.O. Box 15503, Bahrain; (A.A.); (H.P.); (V.N.); (N.A.)
| | - Noor Altahoo
- School of Medicine, Royal College of Surgeons of Ireland, Busaiteen, Adliya P.O. Box 15503, Bahrain; (A.A.); (H.P.); (V.N.); (N.A.)
| | - Stephen L. Atkin
- Research Department, Royal College of Surgeons of Ireland, Busaiteen, Adliya P.O. Box 15503, Bahrain;
| | - Alexandra E. Butler
- Research Department, Royal College of Surgeons of Ireland, Busaiteen, Adliya P.O. Box 15503, Bahrain;
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Xi Y, Yang M, Deng Z, Xiong X, Wei L, Cai J, Tang C, Sun L. ACSL5 promotes lipid deposition and lipoapoptosis in proximal tubular epithelial cells of diabetic kidney disease. Mol Cell Endocrinol 2025; 595:112418. [PMID: 39557186 DOI: 10.1016/j.mce.2024.112418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/07/2024] [Accepted: 11/15/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Lipoapoptosis in Proximal tubular epithelial cells (PTCs) are substantial in the etiology of diabetic kidney disease (DKD), yet the underlying mechanisms warrant further investigation. Acyl-CoA synthetase long-chain family member 5 (ACSL5) facilitates the formation of acyl-CoA, however, the precise role of ACSL5 in lipoapoptosis of PTCs in DKD remains inconclusive. METHODS Transcriptomic data analysis identified the hub gene Acsl5 associated with lipid metabolism in DKD. The expression of ACSL5 was examined in high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mice and high glucose/palmitic acid (HGPA)-induced mouse proximal tubular epithelial cell (BUMPT). Oil Red O staining, free fatty acids (FFA) ELISA assay, Western Blot, and morphological changes were employed to assess lipid deposition and lipoapoptosis. Furthermore, knockdown and overexpression of ACSL5 were conducted in BUMPT cells, followed by morphological assessment, Oil Red O staining, FFA ELISA assay and Western Blot analysis. Using the ChEA3 database, we predicted that STAT3 may transcriptionally regulate ACSL5. Subsequently, we knocked down STAT3 and evaluated Acsl5 expression via RT-qPCR. Additionally, we investigated whether STAT3 modulates the impact of ACSL5 on lipoapoptosis through Western Blot analysis. RESULTS We demonstrated, for the first time, a notable upregulation of ACSL5 expression in PTCs in HFD/STZ-induced diabetic mice, accompanied by increased the expression of FATP2, lipid accumulation and heightened lipoapoptosis. In HGPA-treated BUMPT cells, ACSL5 knockdown reduced the expression of FATP2, lipid deposition and lipoapoptosis, whereas its overexpression elevated the expression of FATP2 and exacerbated these effects. These findings strongly suggest that ACSL5 may exacerbate lipoapoptosis in PTCs within a diabetic milieu. From a molecular mechanism perspective, ACSL5 expression decreased after Stat3 knockdown. Concurrent knockdown of Stat3 and overexpression of Acsl5 led to a mitigation of lipoapoptosis compared to sole Acsl5 overexpression. Furthermore, STAT3 promotes the activation of ACSL5 promoter under HGPA conditions. CONCLUSIONS In summary, our research identified ACSL5 as an important contributor exacerbating lipoapoptosis in the renal proximal tubules within diabetic environments. In addition, we found that ACSL5 is transcriptionally regulated by STAT3.
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Affiliation(s)
- Yiyun Xi
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China; Department of Nephrology & Immunology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Zebin Deng
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaofeng Xiong
- Department of Ultrasound Diagnosis, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ling Wei
- Department of Rehabilitation, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Juan Cai
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chengyuan Tang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
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Kim C, Gabriel KR, Boone D, Brown MR, Oppenheimer K, Kost-Alimova M, Pablo JLB, Greka A. FAF2 is a bifunctional regulator of peroxisomal homeostasis and saturated lipid responses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.12.628015. [PMID: 39763943 PMCID: PMC11702540 DOI: 10.1101/2024.12.12.628015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Exposure to saturated fatty acids (SFAs), such as palmitic acid, can lead to cellular metabolic dysfunction known as lipotoxicity. Although canonical adaptive metabolic processes like lipid storage or desaturation are known cellular responses to saturated fat exposure, the link between SFA metabolism and organellar biology remains an area of active inquiry. We performed a genome-wide CRISPR knockout screen in human epithelial cells to identify modulators of SFA toxicity. The screen revealed peroxisomal proteins, especially those that impact ether lipid synthesis, as important regulators of lipotoxicity. We identified Fas-associated factor family member 2 (FAF2) as a critical bifunctional co-regulator of peroxisomal and fatty acid biology. We further uncovered a new biological function for the ubiquitin-regulatory X (UBX) and UAS thioredoxin-like domains of FAF2, demonstrating their requirement for peroxisomal protein abundance and SFA-induced cellular stress. Our work highlights the role of FAF2 in regulating peroxisomal abundance and function, and the peroxisome as a key organelle in the cellular response to SFAs.
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Affiliation(s)
- Choah Kim
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Harvard Medical School, Boston, MA 02115, USA
- Department of Medicine, Mass General Brigham, Boston, MA 02115, USA
| | - Katlyn R. Gabriel
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- Department of Medicine, Mass General Brigham, Boston, MA 02115, USA
| | - Dylan Boone
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | | | - Katherine Oppenheimer
- Harvard Medical School, Boston, MA 02115, USA
- Department of Medicine, Mass General Brigham, Boston, MA 02115, USA
| | | | | | - Anna Greka
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Harvard Medical School, Boston, MA 02115, USA
- Department of Medicine, Mass General Brigham, Boston, MA 02115, USA
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9
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Warmuzińska N, Łuczykowski K, Stryjak I, Wojtal E, Woderska-Jasińska A, Masztalerz M, Włodarczyk Z, Bojko B. Metabolomic and Lipidomic Profiling for Pre-Transplant Assessment of Delayed Graft Function Risk Using Chemical Biopsy with Microextraction Probes. Int J Mol Sci 2024; 25:13502. [PMID: 39769265 PMCID: PMC11728147 DOI: 10.3390/ijms252413502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
Organ shortage remains a significant challenge in transplantology, prompting efforts to maximize the use of available organs and expand the donor pool, including through extended criteria donors (ECDs). However, ECD kidney recipients often face poorer outcomes, including a higher incidence of delayed graft function (DGF), which is linked to worse graft performance, reduced long-term survival, and an increased need for interventions like dialysis. This underscores the urgent need for strategies to improve early DGF risk assessment and optimize post-transplant management for high-risk patients. This study conducted multi-time point metabolomic and lipidomic analyses of donor kidney tissue and recipient plasma to identify compounds predicting DGF risk and assess the translational potential of solid-phase microextraction (SPME) for graft evaluation and early complication detection. The SPME-based chemical biopsy enabled a direct kidney analysis, while thin-film microextraction facilitated high-throughput plasma preparation. Following high-performance liquid chromatography coupled with a mass spectrometry analysis, the random forest algorithm was applied to identify compounds with predictive potential for assessing DGF risk before transplantation. Additionally, a comparison of metabolomic and lipidomic profiles of recipient plasma during the early post-operative days identified metabolites that distinguish between DGF and non-DGF patients. The selected compounds primarily included amino acids and their derivatives, nucleotides, organic acids, peptides, and lipids, particularly phospholipids and triacylglycerols. In conclusion, this study highlights the significant translational potential of chemical biopsies and plasma metabolite analyses for risk assessments and the non-invasive monitoring of DGF. The identified metabolites provide a foundation for developing a comprehensive DGF assessment and monitoring method, with potential integration into routine clinical practice.
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Affiliation(s)
- Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
| | - Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
| | - Iga Stryjak
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
| | - Emilia Wojtal
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Aleksandra Woderska-Jasińska
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Marek Masztalerz
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Zbigniew Włodarczyk
- Department of Transplantology and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Antoni Jurasz University Hospital No. 1 in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089 Bydgoszcz, Poland
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10
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Khoi CS, Lin TY, Chiang CK. Targeting Insulin Resistance, Reactive Oxygen Species, Inflammation, Programmed Cell Death, ER Stress, and Mitochondrial Dysfunction for the Therapeutic Prevention of Free Fatty Acid-Induced Vascular Endothelial Lipotoxicity. Antioxidants (Basel) 2024; 13:1486. [PMID: 39765815 PMCID: PMC11673094 DOI: 10.3390/antiox13121486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/11/2025] Open
Abstract
Excessive intake of free fatty acids (FFAs), especially saturated fatty acids, can lead to atherosclerosis and increase the incidence of cardiovascular diseases. FFAs also contribute to obesity, hyperlipidemia, and nonalcoholic fatty liver disease. Palmitic acid (PA) is human plasma's most abundant saturated fatty acid. It is often used to study the toxicity caused by free fatty acids in different organs, including vascular lipotoxicity. Fatty acid overload induces endothelial dysfunction through various molecular mechanisms. Endothelial dysfunction alters vascular homeostasis by reducing vasodilation and increasing proinflammatory and prothrombotic states. It is also linked to atherosclerosis, which leads to coronary artery disease, peripheral artery disease, and stroke. In this review, we summarize the latest studies, revealing the molecular mechanism of free fatty acid-induced vascular dysfunction, targeting insulin resistance, reactive oxygen species, inflammation, programmed cell death, ER stress, and mitochondrial dysfunction. Meanwhile, this review provides new strategies and perspectives for preventing and reducing the impact of cardiovascular diseases on human health through the relevant targeting molecular mechanism.
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Affiliation(s)
- Chong-Sun Khoi
- Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 220216, Taiwan;
- Graduate School of Biotechnology and Bioengineering, College of Engineering, Yuan Ze University, Taoyuan City 320315, Taiwan
| | - Tzu-Yu Lin
- Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 220216, Taiwan;
- Department of Mechanical Engineering, College of Engineering, Yuan Ze University, Taoyuan City 320315, Taiwan
| | - Chih-Kang Chiang
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei City 10617, Taiwan
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei City 10617, Taiwan
- Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei City 100229, Taiwan
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11
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Zhang X, Wu W, Li Y, Peng Z. Exploring the role and therapeutic potential of lipid metabolism in acute kidney injury. Ren Fail 2024; 46:2403652. [PMID: 39319697 PMCID: PMC11425701 DOI: 10.1080/0886022x.2024.2403652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/06/2024] [Accepted: 09/06/2024] [Indexed: 09/26/2024] Open
Abstract
Acute kidney injury (AKI) is a prevalent condition, yet no specific treatment is available. Extensive research has revealed the pivotal role of lipid-related alterations in AKI. Lipid metabolism plays an essential role in the sustenance of the kidneys. In addition to their energy-supplying function, lipids contribute to the formation of renal biomembranes and the establishment of the renal microenvironment. Moreover, lipids or their metabolites actively participate in signal transduction, which governs various vital biological processes, such as proliferation, differentiation, apoptosis, autophagy, and epithelial-mesenchymal transition. While previous studies have focused predominantly on abnormalities in lipid metabolism in chronic kidney disease, this review focuses on lipid metabolism anomalies in AKI. We explore the significance of lipid metabolism products as potential biomarkers for the early diagnosis and classification of AKI. Additionally, this review assesses current preclinical investigations on the modulation of lipid metabolism in the progression of AKI. Finally, on the basis of existing research, this review proposes future directions, highlights challenges, and presents novel targets and innovative ideas for the treatment of and intervention in AKI.
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Affiliation(s)
- Xiaoyu Zhang
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
| | - Wen Wu
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
- Department of Critical Care Medicine, Yichang Central People's Hospital, Yichang, China
| | - Yiming Li
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
| | - Zhiyong Peng
- Department of Critical Care Medicine, Zhongnan Hospital, Wuhan University, Wuhan, China
- Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
- Department of Critical Care Medicine, Center of Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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12
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Chen X, Zhu S, Huang C, Liu J, Wang J, Cui S. Bioinformatic analyses reveal lysosomal-associated protein transmembrane 5 as a potential therapeutic target in lipotoxicity-induced injury in diabetic kidney disease. Ren Fail 2024; 46:2359638. [PMID: 38832484 PMCID: PMC11151807 DOI: 10.1080/0886022x.2024.2359638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 05/20/2024] [Indexed: 06/05/2024] Open
Abstract
Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.
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Affiliation(s)
- Xin Chen
- Department of Endocrinology, Jiangnan University Medical Center, Affiliated Wuxi Clinical College of Nantong University, Wuxi No.2 People’s Hospital, Wuxi, P. R. China
- School of Medicine, Nanjing Medical University, Nanjing, P. R. China
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, P. R. China
| | - Ciyou Huang
- Department of Endocrinology, Jiangnan University Medical Center, Affiliated Wuxi Clinical College of Nantong University, Wuxi No.2 People’s Hospital, Wuxi, P. R. China
| | - Jiayi Liu
- Department of Endocrinology, Jiangnan University Medical Center, Affiliated Wuxi Clinical College of Nantong University, Wuxi No.2 People’s Hospital, Wuxi, P. R. China
| | - Jinbang Wang
- Subei People’s Hospital of Jiangsu Province, Clinical Medical School of Yangzhou University, Yangzhou, Jiangsu, P. R. China
| | - Siyuan Cui
- Department of Endocrinology, Jiangnan University Medical Center, Affiliated Wuxi Clinical College of Nantong University, Wuxi No.2 People’s Hospital, Wuxi, P. R. China
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13
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Wang J, Shen Y, Chen H, Guan J, Li Z, Liu X, Guo S, Wang L, Yan B, Jin C, Li H, Guo T, Sun Y, Zhang W, Zhang Z, Tian Y, Tian Z. Non-lethal sonodynamic therapy inhibits high glucose and palmitate-induced macrophage inflammasome activation through mtROS-DRP1-mitophagy pathway. FASEB J 2024; 38:e70178. [PMID: 39556373 DOI: 10.1096/fj.202402008r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/18/2024] [Accepted: 11/01/2024] [Indexed: 11/19/2024]
Abstract
Obesity plays a crucial role in the development and progression of type 2 diabetes mellitus (T2DM) by causing excessive release of free fatty acid from adipose tissue, which in turn leads to systemic infiltration of macrophages. In individuals with T2DM, the infiltration of macrophages into pancreatic islets results in islet inflammation that impairs beta cell function, as evidenced by increased apoptosis and decreased glucose-stimulated insulin secretion. The present study aimed to investigate the effects of non-lethal sonodynamic therapy (NL-SDT) on bone marrow-derived macrophages (BMDMs) exposed to high glucose and palmitic acid (HG/PA). These findings indicate that NL-SDT facilitates the expression of DRP1 through the transient production of mitochondrial ROS, which subsequently promotes mitophagy. This mitophagy was shown to limit the activation of the NLRP3 inflammasome and the secretion of IL-1β in BMDMs exposed to HG/PA. In co-culture experiments, beta cells exhibited significant dysfunction when interacting with HG/PA-treated BMDMs. However, this dysfunction was markedly alleviated when the BMDMs had undergone NL-SDT treatment. Moreover, NL-SDT was found to lower blood glucose levels and elevate serum insulin concentrations in db/db mice. Furthermore, NL-SDT effectively reduced the infiltration of F4/80-positive macrophages and the expression of CASP1 within islets. These findings provide fundamental insights into the mechanisms through which NL-SDT may serve as a promising approach for the treatment of T2DM.
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Affiliation(s)
- Jiayu Wang
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Yicheng Shen
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Heyu Chen
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Jinwei Guan
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Zhitao Li
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Xianna Liu
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Shuyuan Guo
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
- Department of Cardiology, 1st Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, P. R. China
| | - Linxin Wang
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
- Department of Cardiology, 1st Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, P. R. China
| | - Baoyue Yan
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Chenrun Jin
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - He Li
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Tian Guo
- Medical College of Jining Medical University, Jining, P. R. China
| | - Yun Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Weihua Zhang
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
| | - Zhiguo Zhang
- School of Physics, Harbin Institute of Technology, Harbin, P. R. China
- School of Instrumentation Science and Engineering, Harbin Institute of Technology, Harbin, P. R. China
| | - Ye Tian
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
- Department of Cardiology, 1st Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, P. R. China
| | - Zhen Tian
- Department of Pathophysiology, Harbin Medical University, Harbin, P. R. China
- Key Laboratory of Acoustic, Optical, Electrical and Magnetic Diagnostics and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, P. R. China
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Han L, Chen X, Wan D, Xie M, Ouyang S. One anastomosis gastric bypass ameliorates diabetic nephropathy via regulating the GLP-1-mediated Sirt1/AMPK/PGC1α pathway. Clin Exp Nephrol 2024; 28:1051-1061. [PMID: 38782822 DOI: 10.1007/s10157-024-02516-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Diabetic nephropathy (DN), a complication of diabetes, is the most leading cause of end-stage renal disease. Bariatric surgery functions on the remission of diabetes and diabetes-related complications. One anastomosis gastric bypass (OAGB), one of popular bariatric surgery, can improve diabetes and its complications by regulating the glucagon-like peptide-1 (GLP-1) level. Meanwhile, GLP-1 can alleviate renal damage in high-fat-diet-induced obese rats. However, the effect of OAGB on renal injury remains uncertain in DN. METHODS A diabetes model was elicited in rats via HFD feeding and STZ injection. The role and mechanism of OAGB were addressed in DN rats by the body and kidney weight and blood glucose supervision, oral glucose tolerance test (OGTT), enzyme-linked immunosorbent assay (ELISA), biochemistry detection, histopathological analysis, and western blot assays. RESULTS OAGB surgery reversed the increase in body weight and glucose tolerance indicators in diabetes rats. Also, OAGB operation neutralized the DN-induced average kidney weight, kidney weight/body weight, and renal injury indexes accompanied with reduced glomerular hypertrophy, alleviated mesangial dilation and decreased tubular and periglomerular collagen deposition. In addition, OAGB introduction reduced the DN-induced renal triglyceride and renal cholesterol with the regulation of fatty acids-related proteins expression. Mechanically, OAGB administration rescued the DN-induced expression of Sirt1/AMPK/PGC1α pathway mediated by GLP-1. Pharmacological block of GLP-1 receptor inverted the effect of OAGB operation on body weight, glucose tolerance, renal tissue damage, and fibrosis and lipids accumulation in DN rats. CONCLUSION OAGB improved renal damage and fibrosis and lipids accumulation in DN rats by GLP-1-mediated Sirt1/AMPK/PGC1α pathway.
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Affiliation(s)
- Lang Han
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, No. 149, Dalian Road, Huichuan, Zunyi, 563000, Guizhou, China
| | - Xiaojiao Chen
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, No. 149, Dalian Road, Huichuan, Zunyi, 563000, Guizhou, China
| | - Dianwei Wan
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, No. 149, Dalian Road, Huichuan, Zunyi, 563000, Guizhou, China
| | - Min Xie
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, No. 149, Dalian Road, Huichuan, Zunyi, 563000, Guizhou, China
| | - Shurui Ouyang
- Department of General Surgery, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, No. 149, Dalian Road, Huichuan, Zunyi, 563000, Guizhou, China.
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Liu X, Peng Y, Wu S, Huang X, Gao L, Deng R, Lu J. Identification of serum metabolites associated with aristolochic acid nephropathy severity and insights into the underlying mechanism. Toxicol Lett 2024; 400:24-34. [PMID: 39098565 DOI: 10.1016/j.toxlet.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/25/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024]
Abstract
Aristolochic acid nephropathy (AAN) is a rapidly progressive kidney disease caused by medical or environmental exposure to aristolochic acids (AAs). This study aimed to identify serum metabolites associated with the severity of acute AAN and investigate the underlying mechanisms. Male C57BL/6 mice were treated with vehicle and 3 doses of aristolochic acid I (AAI) (1.25, 2.5, and 5 mg/kg/d) for 5 days by intraperitoneal injection. The results showed that AAI dose-dependently increased blood urea nitrogen (BUN) and serum creatinine (Scr) levels and renal pathological damage. Non-targeted metabolomics revealed that differences in serum metabolite profiles from controls increased with increasing AAI doses. Compared with the control group, 56 differentially expressed metabolites (DEMs) that could be affected by all 3 doses of AAI were obtained. We further identified 13 DEMs whose abundance significantly correlated with Scr and BUN levels and had good predictive values for diagnosing AAI exposure. Among the 13 DEMs, lipids and lipid-like molecules constituted the majority. Western blotting found that AAI suppressed renal fatty acid oxidation (FAO)-related enzymes expression. In conclusion, these findings provided evidence for developing biomarkers for monitoring AAs exposure and AAN diagnosis and indicated activation of FAO as a potential direction for the treatment of AAN.
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Affiliation(s)
- Xinhui Liu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China.
| | - Yu Peng
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China; The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China
| | - Shanshan Wu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China; The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China
| | - Xi Huang
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China; The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China
| | - Liwen Gao
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China; The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China
| | - Ruyu Deng
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China; Shenzhen Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Shenzhen, Guangdong 518033, China
| | - Jiandong Lu
- Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, China
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16
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Jiang X, Wang H, Nie K, Gao Y, Chen S, Tang Y, Wang Z, Su H, Dong H. Targeting lipid droplets and lipid droplet-associated proteins: a new perspective on natural compounds against metabolic diseases. Chin Med 2024; 19:120. [PMID: 39232826 PMCID: PMC11373146 DOI: 10.1186/s13020-024-00988-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/22/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND Lipid droplet (LD) is a metabolically active organelle, which changes dynamically with the metabolic state and energy requirements of cells. Proteins that either insert into the LD phospholipid monolayer or are present in the cytoplasm, playing a crucial role in lipid homeostasis and signaling regulation, are known as LD-associated proteins. METHODS The keywords "lipid droplets" and "metabolic diseases" were used to obtain literature on LD metabolism and pathological mechanism. After searching databases including Scopus, OVID, Web of Science, and PubMed from 2013 to 2024 using terms like "lipid droplets", "lipid droplet-associated proteins", "fatty liver disease", "diabetes", "diabetic kidney disease", "obesity", "atherosclerosis", "hyperlipidemia", "natural drug monomers" and "natural compounds", the most common natural compounds were identified in about 954 articles. Eventually, a total of 91 studies of 10 natural compounds reporting in vitro or in vivo studies were refined and summarized. RESULTS The most frequently used natural compounds include Berberine, Mangostin, Capsaicin, Caffeine, Genistein, Epigallocatechin-3-gallate, Chlorogenic acid, Betaine, Ginsenoside, Resveratrol. These natural compounds interact with LD-associated proteins and help ameliorate abnormal LDs in various metabolic diseases. CONCLUSION Natural compounds involved in the regulation of LDs and LD-associated proteins hold promise for treating metabolic diseases. Further research into these interactions may lead to new therapeutic applications.
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Affiliation(s)
- Xinyue Jiang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongzhan Wang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kexin Nie
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Gao
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shen Chen
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yueheng Tang
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Su
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Wang Y, Liu T, Liu W, Zhao H, Li P. Research hotspots and future trends in lipid metabolism in chronic kidney disease: a bibliometric and visualization analysis from 2004 to 2023. Front Pharmacol 2024; 15:1401939. [PMID: 39290864 PMCID: PMC11405329 DOI: 10.3389/fphar.2024.1401939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Background Disorders of lipid metabolism play a key role in the initiation and progression of chronic kidney disease (CKD). Recently, research on lipid metabolism in CKD has rapidly increased worldwide. However, comprehensive bibliometric analyses in this field are lacking. Therefore, this study aimed to evaluate publications in the field of lipid metabolism in CKD over the past 20 years based on bibliometric analysis methods to understand the important achievements, popular research topics, and emerging thematic trends. Methods Literature on lipid metabolism in CKD, published between 2004 and 2023, was retrieved from the Web of Science Core Collection. The VOSviewer (v.1.6.19), CiteSpace (v.6.3 R1), R language (v.4.3.2), and Bibliometrix (v.4.1.4) packages (https://www.bibliometrix.org) were used for the bibliometric analysis and visualization. Annual output, author, country, institution, journal, cited literature, co-cited literature, and keywords were also included. The citation frequency and H-index were used to evaluate quality and influence. Results In total, 1,285 publications in the field of lipid metabolism in CKD were identified in this study. A total of 7,615 authors from 1,885 institutions in 69 countries and regions published articles in 466 journals. Among them, China was the most productive (368 articles), and the United States had the most citations (17,880 times) and the highest H-index (75). Vaziri Nosratola D, Levi Moshe, Fornoni Alessia, Zhao Yingyong, and Merscher Sandra emerged as core authors. Levi Moshe (2,247 times) and Vaziri Nosratola D (1,969 times) were also authors of the top two most cited publications. The International Journal of Molecular Sciences and Kidney International are the most published and cited journals in this field, respectively. Cardiovascular disease (CVD) and diabetic kidney disease (DKD) have attracted significant attention in the field of lipid metabolism. Oxidative stress, inflammation, insulin resistance, autophagy, and cell death are the key research topics in this field. Conclusion Through bibliometric analysis, the current status and global trends in lipid metabolism in CKD were demonstrated. CVD and DKD are closely associated with the lipid metabolism of patients with CKD. Future studies should focus on effective CKD treatments using lipid-lowering targets.
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Affiliation(s)
- Ying Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Tongtong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Weijing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hailing Zhao
- China-Japan Friendship Hospital, Institute of Medical Science, Beijing, China
| | - Ping Li
- China-Japan Friendship Hospital, Institute of Medical Science, Beijing, China
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Pengrattanachot N, Thongnak L, Promsan S, Phengpol N, Sutthasupha P, Tocharus J, Lungkaphin A. Fructooligosaccharides Ameliorate Renal Injury and Dysfunction Through the Modulation of Gut Dysbiosis, Inhibition of Renal Inflammation, Oxidative Stress, Fibrosis, and Improve Organic Anion Transporter 3 Function in an Obese Rat Model. Mol Nutr Food Res 2024; 68:e2400191. [PMID: 39021322 DOI: 10.1002/mnfr.202400191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 06/11/2024] [Indexed: 07/20/2024]
Abstract
SCOPE High-fat diet (HFD) consumption causes obesity and gut dysbiosis which induces kidney injury. It has been reported that prebiotics improve gut dysbiosis and insulin sensitivity and decelerate the progression of kidney disease. This study investigates the impact of fructooligosaccharides (FOS) on renoprotection and the prevention of gut dysbiosis and intestinal barrier injury in obese rats. METHODS AND RESULTS Wistar rats are treated with HFD for 16 weeks. Then, the HFD fed rats (HF) are given FOS 1 g day-1 (HFFOS1), 2 g day-1 (HFFOS2), or metformin 30 mg kg-1 day-1 (HFMET), by intragastric feeding for 8 weeks. Blood, urine, feces, kidney, and intestine are collected to determine the metabolic changes, gut dysbiosis, and the expression of proteins involved in kidney and intestinal injury. FOS can attenuate insulin resistance and hypercholesterolemia concomitant with the inhibition of renal inflammation, oxidative stress, fibrosis, and apoptosis, which are related to the deceleration of the overexpression of renal Toll-like receptor 4 (TLR4) and NADPH oxidase (NOX4). Moreover, FOS shows a greater efficacy than metformin in the reduction of the intestinal injury and loss of tight junction proteins induced by HFD. CONCLUSION FOS may be used as a supplement for therapeutic purposes in an obese condition to improve intestinal integrity and prevent renal complications.
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Affiliation(s)
| | - Laongdao Thongnak
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Sasivimon Promsan
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nichakorn Phengpol
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Prempree Sutthasupha
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Functional Foods for Health and Disease, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Functional Food Research Center for Well-being, Multidisciplinary Research Institute Chiang Mai University, Chiang Mai, Thailand
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Functional Foods for Health and Disease, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Functional Food Research Center for Well-being, Multidisciplinary Research Institute Chiang Mai University, Chiang Mai, Thailand
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Lonardo A, Weiskirchen R. From Hypothalamic Obesity to Metabolic Dysfunction-Associated Steatotic Liver Disease: Physiology Meets the Clinics via Metabolomics. Metabolites 2024; 14:408. [PMID: 39195504 DOI: 10.3390/metabo14080408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/23/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Metabolic health is tightly regulated by neuro-hormonal control, and systemic metabolic dysfunction may arise from altered function of the hypothalamic-anterior pituitary axis (HAPA). Ancient experimental observations of hypothalamic obesity (HO) and liver cirrhosis occurring among animals subjected to hypothalamic injury can now be explained using the more recent concepts of lipotoxicity and metabolic dysfunction-associated steatotic liver disease (MASLD). Lipotoxicity, the range of abnormalities resulting from the harmful effects of fatty acids accumulated in organs outside of adipose tissue, is the common pathogenic factor underlying closely related conditions like hypothalamic syndrome, HO, and MASLD. The hormonal deficits and the array of metabolic and metabolomic disturbances that occur in cases of HO are discussed, along with the cellular and molecular mechanisms that lead, within the MASLD spectrum, from uncomplicated steatotic liver disease to steatohepatitis and cirrhosis. Emphasis is placed on knowledge gaps and how they can be addressed through novel studies. Future investigations should adopt precision medicine approaches by precisely defining the hormonal imbalances and metabolic dysfunctions involved in each individual patient with HO, thus paving the way for tailored management of MASLD that develops in the context of altered HAPA.
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Affiliation(s)
- Amedeo Lonardo
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria of Modena (-2023), 41126 Modena, Italy
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH), University Hospital Aachen, D-52074 Aachen, Germany
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20
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Poindessous V, Lazareth H, Crambert G, Cheval L, Sampaio JL, Pallet N. STAT3 drives the expression of ACSL4 in acute kidney injury. iScience 2024; 27:109737. [PMID: 38799564 PMCID: PMC11126884 DOI: 10.1016/j.isci.2024.109737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/27/2024] [Accepted: 04/10/2024] [Indexed: 05/29/2024] Open
Abstract
Long-chain acyl-CoA synthetase family 4 (ACSL4) metabolizes long-chain polyunsaturated fatty acids (PUFAs), enriching cell membranes with phospholipids susceptible to peroxidation and drive ferroptosis. The role of ACSL4 and ferroptosis upon endoplasmic-reticulum (ER)-stress-induced acute kidney injury (AKI) is unknown. We used lipidomic, molecular, and cellular biology approaches along with a mouse model of AKI induced by ER stress to investigate the role of ACSL4 regulation in membrane lipidome remodeling in the injured tubular epithelium. Tubular epithelial cells (TECs) activate ACSL4 in response to STAT3 signaling. In this context, TEC membrane lipidome is remodeled toward PUFA-enriched triglycerides instead of PUFA-bearing phospholipids. TECs expressing ACSL4 in this setting are not vulnerable to ferroptosis. Thus, ACSL4 activity in TECs is driven by STAT3 signaling, but ACSL4 alone is not enough to sensitize ferroptosis, highlighting the significance of the biological context associated with the study model.
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Affiliation(s)
- Virginie Poindessous
- Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, Paris, France
| | - Helene Lazareth
- Centre de Recherche des Cordeliers, INSERM U1138, Université Paris Cité, Paris, France
- Université Paris-Cité, Paris, France
- Laboratory of Renal Physiology and Tubulopathies, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France
| | - Gilles Crambert
- EMR 8228 Metabolism and Renal Physiology Unit, CNRS, Paris, France
- CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, Paris, France
| | - Lydie Cheval
- EMR 8228 Metabolism and Renal Physiology Unit, CNRS, Paris, France
- CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, Paris, France
| | - Julio L. Sampaio
- CurieCoreTech Metabolomics and Lipidomics Technology Platform, Institut Curie, Paris, France
| | - Nicolas Pallet
- Laboratory of Renal Physiology and Tubulopathies, Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France
- Department of Clinical Chemistry, Assistance Publique Hôpitaux de Paris, Georges Pompidou European Hospital, Paris, France
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21
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An TF, Zhang ZP, Xue JT, Luo WM, Li Y, Fang ZZ, Zong GW. Interpretable machine learning identifies metabolites associated with glomerular filtration rate in type 2 diabetes patients. Front Endocrinol (Lausanne) 2024; 15:1279034. [PMID: 38915893 PMCID: PMC11194401 DOI: 10.3389/fendo.2024.1279034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 01/17/2024] [Indexed: 06/26/2024] Open
Abstract
Objective The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients. Methods We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model. Results For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1μmol/L, Cit higher than 26 μmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR. Conclusion Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.
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Affiliation(s)
- Tian-Feng An
- Department of Toxicology and Health Inspection and Quarantine, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhi-Peng Zhang
- Department of Toxicology and Health Inspection and Quarantine, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Jun-Tang Xue
- Department of Surgery, Peking University Third Hospital, Beijing, China
| | - Wei-Ming Luo
- Department of Toxicology and Health Inspection and Quarantine, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Yang Li
- Department of Toxicology and Health Inspection and Quarantine, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhong-Ze Fang
- Department of Toxicology and Health Inspection and Quarantine, School of Public Health, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China
| | - Guo-Wei Zong
- Department of Mathematics, School of Public Health, Tianjin Medical University, Tianjin, China
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22
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Yeo WJ, Surapaneni AL, Hasson DC, Schmidt IM, Sekula P, Köttgen A, Eckardt KU, Rebholz CM, Yu B, Waikar SS, Rhee EP, Schrauben SJ, Feldman HI, Vasan RS, Kimmel PL, Coresh J, Grams ME, Schlosser P. Serum and Urine Metabolites and Kidney Function. J Am Soc Nephrol 2024; 35:00001751-990000000-00343. [PMID: 38844075 PMCID: PMC11387034 DOI: 10.1681/asn.0000000000000403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 05/29/2024] [Indexed: 07/05/2024] Open
Abstract
Key Points We provide an atlas of cross-sectional and longitudinal serum and urine metabolite associations with eGFR and urine albumin-creatinine ratio in an older community-based cohort. Metabolic profiling in serum and urine provides distinct and complementary insights into disease. Background Metabolites represent a read-out of cellular processes underlying states of health and disease. Methods We evaluated cross-sectional and longitudinal associations between 1255 serum and 1398 urine known and unknown (denoted with “X” in name) metabolites (Metabolon HD4, 721 detected in both biofluids) and kidney function in 1612 participants of the Atherosclerosis Risk in Communities study. All analyses were adjusted for clinical and demographic covariates, including for baseline eGFR and urine albumin-creatinine ratio (UACR) in longitudinal analyses. Results At visit 5 of the Atherosclerosis Risk in Communities study, the mean age of participants was 76 years (SD 6); 56% were women, mean eGFR was 62 ml/min per 1.73 m2 (SD 20), and median UACR level was 13 mg/g (interquartile range, 25). In cross-sectional analysis, 675 serum and 542 urine metabolites were associated with eGFR (Bonferroni-corrected P < 4.0E-5 for serum analyses and P < 3.6E-5 for urine analyses), including 248 metabolites shared across biofluids. Fewer metabolites (75 serum and 91 urine metabolites, including seven metabolites shared across biofluids) were cross-sectionally associated with albuminuria. Guanidinosuccinate; N2,N2-dimethylguanosine; hydroxy-N6,N6,N6-trimethyllysine; X-13844; and X-25422 were significantly associated with both eGFR and albuminuria. Over a mean follow-up of 6.6 years, serum mannose (hazard ratio [HR], 2.3 [1.6–3.2], P = 2.7E-5) and urine X-12117 (HR, 1.7 [1.3–2.2], P = 1.9E-5) were risk factors of UACR doubling, whereas urine sebacate (HR, 0.86 [0.80–0.92], P = 1.9E-5) was inversely associated. Compared with clinical characteristics alone, including the top five endogenous metabolites in serum and urine associated with longitudinal outcomes improved the outcome prediction (area under the receiver operating characteristic curves for eGFR decline: clinical model=0.79, clinical+metabolites model=0.87, P = 8.1E-6; for UACR doubling: clinical model=0.66, clinical+metabolites model=0.73, P = 2.9E-5). Conclusions Metabolomic profiling in different biofluids provided distinct and potentially complementary insights into the biology and prognosis of kidney diseases.
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Affiliation(s)
- Wan-Jin Yeo
- Division of Precision Medicine, Department of Medicine, NYU Langone Health, New York, New York
| | - Aditya L. Surapaneni
- Division of Precision Medicine, Department of Medicine, NYU Langone Health, New York, New York
| | - Denise C. Hasson
- Division of Pediatric Critical Care Medicine, Hassenfeld Children's Hospital, NYU Langone Health, New York, New York
| | - Insa M. Schmidt
- Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts
| | - Peggy Sekula
- Department of Data Driven Medicine, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Anna Köttgen
- Department of Data Driven Medicine, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany
- Department of Nephrology and Medical Intensive Care, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Casey M. Rebholz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Sushrut S. Waikar
- Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts
| | - Eugene P. Rhee
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Sarah J. Schrauben
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Harold I. Feldman
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ramachandran S. Vasan
- School of Public Health, University of Texas Health San Antonio, San Antonio, Texas
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston Medical Center and Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts
| | - Paul L. Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Optimal Aging Institute, Departments of Population Health and Medicine, NYU Langone Health, New York, New York
- Department of Population Health, NYU Langone Medical Center, New York, New York
| | - Morgan E. Grams
- Division of Precision Medicine, Department of Medicine, NYU Langone Health, New York, New York
- Department of Population Health, NYU Langone Medical Center, New York, New York
| | - Pascal Schlosser
- Department of Data Driven Medicine, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
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Fang Z, Liu R, Xie J, He JC. Molecular mechanism of renal lipid accumulation in diabetic kidney disease. J Cell Mol Med 2024; 28:e18364. [PMID: 38837668 PMCID: PMC11151220 DOI: 10.1111/jcmm.18364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/10/2024] [Accepted: 04/16/2024] [Indexed: 06/07/2024] Open
Abstract
Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.
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Affiliation(s)
- Zhengying Fang
- Department of Nephrology, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Barbara T. Murphy Division of Nephrology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Ruijie Liu
- Barbara T. Murphy Division of Nephrology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Jingyuan Xie
- Department of Nephrology, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - John Cijiang He
- Barbara T. Murphy Division of Nephrology, Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Renal SectionJames J Peters Veterans Affair Medical CenterBronxNew YorkUSA
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24
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Wang X, Chang HC, Gu X, Han W, Mao S, Lu L, Jiang S, Ding H, Han S, Qu X, Bao Z. Renal lipid accumulation and aging linked to tubular cells injury via ANGPTL4. Mech Ageing Dev 2024; 219:111932. [PMID: 38580082 DOI: 10.1016/j.mad.2024.111932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 04/02/2024] [Indexed: 04/07/2024]
Abstract
Renal tubular epithelial cells are vulnerable to stress-induced damage, including excessive lipid accumulation and aging, with ANGPTL4 potentially playing a crucial bridging role between these factors. In this study, RNA-sequencing was used to identify a marked increase in ANGPTL4 expression in kidneys of diet-induced obese and aging mice. Overexpression and knockout of ANGPTL4 in renal tubular epithelial cells (HK-2) was used to investigate the underlying mechanism. Subsequently, ANGPTL4 expression in plasma and kidney tissues of normal young controls and elderly individuals was analyzed using ELISA and immunohistochemical techniques. RNA sequencing results showed that ANGPTL4 expression was significantly upregulated in the kidney tissue of diet-induced obesity and aging mice. In vitro experiments demonstrated that overexpression of ANGPTL4 in HK-2 cells led to increased lipid deposition and senescence. Conversely, the absence of ANGPTL4 appears to alleviate the impact of free fatty acids (FFA) on aging in HK-2 cells. Additionally, aging HK-2 cells exhibited elevated ANGPTL4 expression, and stress response markers associated with cell cycle arrest. Furthermore, our clinical evidence revealed dysregulation of ANGPTL4 expression in serum and kidney tissue samples obtained from elderly individuals compared to young subjects. Our study findings indicate a potential association between ANGPTL4 and age-related metabolic disorders, as well as injury to renal tubular epithelial cells. This suggests that targeting ANGPTL4 could be a viable strategy for the clinical treatment of renal aging.
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Affiliation(s)
- Xiaojun Wang
- Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Hung-Chen Chang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Xuchao Gu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Wanlin Han
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shihang Mao
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, China
| | - Lili Lu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Traditional Chinese Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Shuai Jiang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Haiyong Ding
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Urologic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Shisheng Han
- Department of Nephrology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xinkai Qu
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Zhijun Bao
- Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
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Nie H, Yang H, Cheng L, Yu J. Identification of Lipotoxicity-Related Biomarkers in Diabetic Nephropathy Based on Bioinformatic Analysis. J Diabetes Res 2024; 2024:5550812. [PMID: 38774257 PMCID: PMC11108700 DOI: 10.1155/2024/5550812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/10/2024] [Accepted: 04/20/2024] [Indexed: 05/24/2024] Open
Abstract
Objective: This study is aimed at investigating diagnostic biomarkers associated with lipotoxicity and the molecular mechanisms underlying diabetic nephropathy (DN). Methods: The GSE96804 dataset from the Gene Expression Omnibus (GEO) database was utilized to identify differentially expressed genes (DEGs) in DN patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the DEGs. A protein-protein interaction (PPI) network was established to identify key genes linked to lipotoxicity in DN. Immune infiltration analysis was employed to identify immune cells with differential expression in DN and to assess the correlation between these immune cells and lipotoxicity-related hub genes. The findings were validated using the external dataset GSE104954. ROC analysis was performed to assess the diagnostic performance of the hub genes. The Gene set enrichment analysis (GSEA) enrichment method was utilized to analyze the key genes associated with lipotoxicity as mentioned above. Result: In this study, a total of 544 DEGs were identified. Among them, extracellular matrix (ECM), fatty acid metabolism, AGE-RAGE, and PI3K-Akt signaling pathways were significantly enriched. Combining the PPI network and lipotoxicity-related genes (LRGS), LUM and ALB were identified as lipotoxicity-related diagnostic biomarkers for DN. ROC analysis showed that the AUC values for LUM and ALB were 0.882 and 0.885, respectively. The AUC values for LUM and ALB validated in external datasets were 0.98 and 0.82, respectively. Immune infiltration analysis revealed significant changes in various immune cells during disease progression. Macrophages M2, mast cells activated, and neutrophils were significantly associated with all lipotoxicity-related hub genes. These key genes were enriched in fatty acid metabolism and extracellular matrix-related pathways. Conclusion: The identified lipotoxicity-related hub genes provide a deeper understanding of the development mechanisms of DN, potentially offering new theoretical foundations for the development of diagnostic biomarkers and therapeutic targets related to lipotoxicity in DN.
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Affiliation(s)
- Han Nie
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
| | - Huan Yang
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
| | - Lidan Cheng
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
| | - Jianxin Yu
- Department of Endocrinology, Affiliated Hospital of Jiujiang University, No. 57, East Road, Xunyang District, Jiujiang, Jiangxi, China 332000
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26
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Stryjak I, Warmuzińska N, Łuczykowski K, Jaroch K, Urbanellis P, Selzner M, Bojko B. Metabolomic and lipidomic landscape of porcine kidney associated with kidney perfusion in heart beating donors and donors after cardiac death. Transl Res 2024; 267:79-90. [PMID: 38052298 DOI: 10.1016/j.trsl.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 10/23/2023] [Accepted: 12/01/2023] [Indexed: 12/07/2023]
Abstract
Transplant centers are currently facing a lack of tools to ensure adequate evaluation of the quality of the available organs, as well as a significant shortage of kidney donors. Therefore, efforts are being made to facilitate the effective use of available organs and expand the donor pool, particularly with expanded criteria donors. Fulfilling a need, we aim to present an innovative analytical method based on solid-phase microextraction (SPME) - chemical biopsy. In order to track changes affecting the organ throughout the entire transplant procedure, porcine kidneys were subjected to multiple samplings at various time points. The application of small-diameter SPME probes assured the minimal invasiveness of the procedure. Porcine model kidney autotransplantation was executed for the purpose of simulating two types of donor scenarios: donors with a beating heart (HBD) and donors after cardiac death (DCD). All renal grafts were exposed to continuous normothermic ex vivo perfusion. Following metabolomic and lipidomic profiling using high-performance liquid chromatography coupled to a mass spectrometer, we observed differences in the profiles of HBD and DCD kidneys. The alterations were predominantly related to energy and glucose metabolism, and differences in the levels of essential amino acids, purine nucleosides, lysophosphocholines, phosphoethanolamines, and triacylglycerols were noticed. Our results indicate the potential of implementing chemical biopsy in the evaluation of graft quality and monitoring of renal function during perfusion.
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Affiliation(s)
- Iga Stryjak
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Natalia Warmuzińska
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Kamil Łuczykowski
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Karol Jaroch
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
| | - Peter Urbanellis
- Ajmera Transplant Center, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada
| | - Markus Selzner
- Ajmera Transplant Center, Department of Surgery, Toronto General Hospital, University Health Network, Toronto, ON, Canada; Department of Medicine, Toronto General Hospital, Toronto, ON, Canada
| | - Barbara Bojko
- Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
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Oh JE, Yu SR, Yoo JY, Shin KA. Relationship Between Asymptomatic Hyperuricemia and the Hypertriglyceridemic-Waist Phenotype in Korean Adults: A Cross-Sectional Study. Diabetes Metab Syndr Obes 2024; 17:1727-1738. [PMID: 38645653 PMCID: PMC11032133 DOI: 10.2147/dmso.s444084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 04/01/2024] [Indexed: 04/23/2024] Open
Abstract
Purpose Visceral fat accumulation can negatively affect uric acid metabolism in healthy adults. The hypertriglyceridemic-waist (HTGW) phenotype is a predictor of diabetes and cardiometabolic risk. This study aimed to investigate the association between the HTGW phenotype and asymptomatic hyperuricemia in Korean adults. Patients and Methods The study included 23,240 adults, aged 20-80 years who underwent comprehensive health examinations at a general hospital in Gyeonggi Province, Korea, from January 2020 to December 2022. The HTGW phenotype was defined as the simultaneous presence of elevated serum triglyceride (TG) levels and increased waist circumference (WC). The diagnostic capability of the HTGW phenotype for hyperuricemia and its association with the condition were assessed using the receiver operating characteristic (ROC) curve and logistic regression analysis. Results The prevalence of hyperuricemia in the HTGW phenotype was 3.44 times higher than that in the normal TG normal waist (NTNW) phenotype. Compared with those in the NTNW group, the hazard ratios for developing hyperuricemia in the HTGW group were 2.887 (2.566-3.249, P <0.001) for men and 7.341 (5.139-10.487, P <0.001) for women, and these values remained significant after adjusting for potential confounders. The stratified analysis revealed that the HTGW phenotype, coupled with diabetes, had the highest probability of developing asymptomatic hyperuricemia (2.55 times). ROC curve analysis revealed that the area under the curve values of the WC*TG index for hyperuricemia diagnosis were 0.702, 0.627, and 0.685 for all participants, men, and women, respectively. Conclusion Among Korean adults, the HTGW phenotype was closely related to hyperuricemia in both men and women and showed a particularly strong association in patients with diabetes. It may be used in combination with an indicator that can complement its accuracy for identifying individuals at high risk of hyperuricemia.
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Affiliation(s)
- Ji-Eun Oh
- Department of Biomedical Laboratory Science, Far East University, Eumseong, Republic of Korea
| | - Sung Ryul Yu
- Department of Clinical Laboratory Science, Semyung University, Jecheon, Republic of Korea
| | - Jung-Yoon Yoo
- Department of Biomedical Laboratory Science, Yonsei University MIRAE Campus, Wonju-si, Republic of Korea
| | - Kyung-A Shin
- Department of Clinical Laboratory Science, Shinsung University, Dangjin, Republic of Korea
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Mantovani A, Csermely A, Cappelli D, Taverna A, Sani E, Shtembari E, Pagani M, Targher G. Higher circulating levels of non-esterified fatty acids are associated with faster kidney function decline in post-menopausal women with type 2 diabetes: a pilot prospective study. Acta Diabetol 2024; 61:281-288. [PMID: 37853295 DOI: 10.1007/s00592-023-02198-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 10/04/2023] [Indexed: 10/20/2023]
Abstract
AIMS Currently, there is little and inconsistent evidence regarding the possible adverse effects of circulating levels of non-esterified fatty acids (NEFA) on kidney function decline in patients with type 2 diabetes mellitus (T2DM). METHODS We followed for a median of 4.6 years 85 post-menopausal women with non-insulin-treated T2DM and preserved kidney function at baseline. Serum NEFA concentrations were measured using an enzymatic colorimetric method. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS Enrolled patients had a baseline mean eGFRCKD-EPI of 83 ± 12 mL/min/1.73 m2 and a median serum NEFA concentration of 662 uEq/L (interquartile range 524-842 uEq/L). During the follow-up period, 13 patients developed kidney function decline at follow-up (defined as an eGFRCKD-EPI decline ≥ 30% from baseline). In Cox proportional hazards regression analyses, higher serum NEFA levels were significantly associated with an increased risk of developing kidney function decline (adjusted-hazard ratio 3.67, 95% CI 1.64-8.22, p < 0.001; for each 1-SD increment, i.e., 262 uEq/L), even after adjustment for waist circumference, hemoglobin A1c, C-reactive protein, HOMA-estimated insulin resistance, hypertension, dyslipidemia, microalbuminuria, baseline eGFRCKD-EPI, as well as temporal changes in HbA1c levels or the use of renin-angiotensin system inhibitors over the follow-up. CONCLUSIONS The findings of this exploratory prospective study show that in post-menopausal women with T2DM and preserved kidney function at baseline, higher circulating levels of NEFA were strongly associated with a faster kidney function decline, even after adjustment for established renal risk factors and potential confounders.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy.
| | - Alessandro Csermely
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Davide Cappelli
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Antonio Taverna
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Elena Sani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Emigela Shtembari
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Micol Pagani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy
- IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
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Eritja À, Caus M, Belmonte T, de Gonzalo-Calvo D, García-Carrasco A, Martinez A, Martínez M, Bozic M. microRNA Expression Profile in Obesity-Induced Kidney Disease Driven by High-Fat Diet in Mice. Nutrients 2024; 16:691. [PMID: 38474819 DOI: 10.3390/nu16050691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Obesity is one of the main causes of chronic kidney disease; however, the precise molecular mechanisms leading to the onset of kidney injury and dysfunction in obesity-associated nephropathy remain unclear. The present study aimed to unveil the kidney microRNA (miRNA) expression profile in a model of obesity-induced kidney disease in C57BL/6J mice using next-generation sequencing (NGS) analysis. High-fat diet (HFD)-induced obesity led to notable structural alterations in tubular and glomerular regions of the kidney, increased renal expression of proinflammatory and profibrotic genes, as well as an elevated renal expression of genes involved in cellular lipid metabolism. The miRNA sequencing analysis identified a set of nine miRNAs differentially expressed in the kidney upon HFD feeding, with miR-5099, miR-551b-3p, miR-223-3p, miR-146a-3p and miR-21a-3p showing the most significant differential expression between standard diet (STD) and HFD mice. A validation analysis showed that the expression levels of miR-5099, miR-551b-3p and miR-146a-3p were consistent with NGS results, while Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that these three validated miRNAs modulated target genes involved in metabolic and adipocytokine pathways, fatty acid and lipid metabolism, and inflammatory, senescence and profibrotic pathways. Our results suggest that differentially expressed miRNAs play pivotal roles in the intricate pathophysiology of obesity-associated kidney disease and could potentially create novel treatment strategies to counteract the deleterious effects of obesity on kidney function.
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Affiliation(s)
- Àuria Eritja
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain
| | - Maite Caus
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain
| | - Thalia Belmonte
- Translational Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova-Santa Maria, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain
| | - David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova-Santa Maria, Biomedical Research Institute of Lleida (IRBLleida), 25198 Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Alicia García-Carrasco
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain
| | - Ana Martinez
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain
| | - Montserrat Martínez
- Biostatistics Unit (Biostat), Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain
| | - Milica Bozic
- Vascular and Renal Translational Research Group, Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLleida), 25196 Lleida, Spain
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Wang L, Xie Y, Xiao B, He X, Ying G, Zha H, Yang C, Jin X, Li G, Ping L, Wang J, Weng Q. Isorhamnetin alleviates cisplatin-induced acute kidney injury via enhancing fatty acid oxidation. Free Radic Biol Med 2024; 212:22-33. [PMID: 38101584 DOI: 10.1016/j.freeradbiomed.2023.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/03/2023] [Accepted: 12/11/2023] [Indexed: 12/17/2023]
Abstract
Cisplatin is an effective chemotherapy drug widely used in the treatment of various solid tumors. However, the clinical usage of cisplatin is limited by its nephrotoxicity. Isorhamnetin, a natural flavanol compound, displays remarkable pharmacological effects, including anti-inflammatory and anti-oxidation. In this study, we aimed to investigate the potential of isorhamnetin in alleviating acute kidney injury induced by cisplatin. In vitro study showed that isorhamnetin significantly suppressed the cytotoxic effects of cisplatin on human tubular epithelial cells. Furthermore, isorhamnetin exerted significantly inhibitory effects on cisplatin-induced apoptosis and inflammatory response. In acute kidney injury mice induced by a single intraperitoneal injection with 20 mg/kg cisplatin, oral administration of isorhamnetin two days before or 2 h after cisplatin injection effectively ameliorated renal function and renal tubule injury. Transcriptomics RNA-seq analysis of the mice kidney tissues suggested that isorhamnetin treatment may protect against cisplatin-induced nephrotoxicity via PGC-1α mediated fatty acid oxidation. Isorhamnetin achieved significant enhancements in the lipid clearance, ATP level, as well as the expression of PGC-1α and its downstream target genes PPARα and CPT1A, which were otherwise impaired by cisplatin. In addition, the protection effects of isorhamnetin against cisplatin-induced nephrotoxicity were abolished by a PGC-1α inhibitor, SR-18292. In conclusion, our findings indicate that isorhamnetin could protect against cisplatin-induced acute kidney injury by inducing PGC-1α-dependent reprogramming of fatty acid oxidation, which highlights the clinical potential of isorhamnetin as a therapeutic approach for the management of cisplatin-induced nephrotoxicity.
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Affiliation(s)
- Lingkun Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Yaochen Xie
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Boneng Xiao
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xuelin He
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Department of Nephrology, Beilun People's Hospital, Ningbo, 315826, China
| | - Guanghui Ying
- Department of Nephrology, Beilun People's Hospital, Ningbo, 315826, China
| | - Huiyan Zha
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Chen Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Xuejin Jin
- Department of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, China
| | - Guilin Li
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Li Ping
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China
| | - Jincheng Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Research Institute of Zhejiang University-Taizhou, Taizhou, 318000, China; Beijing Life Science Academy, Beijing, 102200, China.
| | - Qinjie Weng
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310007, China; Research Institute of Zhejiang University-Taizhou, Taizhou, 318000, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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31
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Guan M, Wu L, Cheng Y, Qi D, Chen J, Song H, Hu H, Wan Q. Defining the threshold: triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio's non-linear impact on tubular atrophy in primary membranous nephropathy. Front Endocrinol (Lausanne) 2024; 15:1322646. [PMID: 38327562 PMCID: PMC10847559 DOI: 10.3389/fendo.2024.1322646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 01/03/2024] [Indexed: 02/09/2024] Open
Abstract
Background Hyperlipidemia is common in primary membranous nephropathy (PMN) patients, and tubular atrophy (TA) is an unfavorable prognostic factor. However, the correlation between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and TA is controversial. Therefore, our study aimed to investigate the association between the TG/HDL-C ratio and TA in PMN patients. Methods We conducted a cross-sectional study and collected data from 363 PMN patients at Shenzhen Second People's Hospital from January 2008 to April 2023. The primary objective was to evaluate the independent correlation between the TG/HDL-C ratio and TA using binary logistic regression model. We used a generalized additive model along with smooth curve fitting and multiple sensitivity analyses to explore the relationship between these variables. Additionally, subgroup analyses were conducted to delve deeper into the results. Results Of the 363 PMN patients, 75 had TA (20.66%). The study population had a mean age of 46.598 ± 14.462 years, with 217 (59.78%) being male. After adjusting for sex, age, BMI, hypertension, history of diabetes, smoking, alcohol consumption, UPRO, eGFR, HB, FPG, and ALB, we found that the TG/HDL-C ratio was an independent risk factor for TA in PMN patients (OR=1.29, 95% CI: 1.04, 1.61, P=0.0213). A non-linear correlation was observed between the TG/HDL-C ratio and TA, with an inflection point at 4.25. The odds ratios (OR) on the left and right sides of this inflection point were 1.56 (95% CI: 1.17, 2.07) and 0.25 (95% CI: 0.04, 1.54), respectively. Sensitivity analysis confirmed these results. Subgroup analysis showed a consistent association between the TG/HDL-C ratio and TA, implying that factors such as gender, BMI, age, UPRO, ALB, hypertension and severe nephrotic syndrome had negligible effects on the link between the TG/HDL-C ratio and TA. Conclusion Our study demonstrates a non-linear positive correlation between the TG/HDL-C ratio and the risk of TA in PMN patients, independent of other factors. Specifically, the association is more pronounced when the ratio falls below 4.25. Based on our findings, it would be advisable to decrease the TG/HDL-C ratio below the inflection point in PMN patients as part of treatment strategies.
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Affiliation(s)
- Mijie Guan
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Liling Wu
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Yuan Cheng
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Dongli Qi
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Jia Chen
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Haiying Song
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Haofei Hu
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
| | - Qijun Wan
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China
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Lopes-Virella MF, Hammad SM, Baker NL, Klein RL, Hunt KJ. Circulating Lipoprotein Sphingolipids in Chronic Kidney Disease with and without Diabetes. Biomedicines 2024; 12:190. [PMID: 38255295 PMCID: PMC10813484 DOI: 10.3390/biomedicines12010190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Abnormalities of sphingolipid metabolism play an important role in diabetes. We compared sphingolipid levels in plasma and in isolated lipoproteins between healthy control subjects and two groups of patients, one with chronic kidney disease without diabetes (ND-CKD), and the other with type 2 diabetes and macroalbuminuria (D-MA). Ceramides, sphingomyelins, and sphingoid bases and their phosphates in LDL were higher in ND-CKD and in D-MA patients compared to controls. However, ceramides and sphingoid bases in HDL2 and HDL3 were lower in ND-CKD and in D-MA patients than in controls. Sphingomyelins in HDL2 and HDL3 were lower in D-MA patients than in controls but were normal in ND-CKD patients. Compared to controls, lactosylceramides in LDL and VLDL were higher in ND-CKD patients but not in D-MA patients. However, lactosylceramides in HDL2 and HDL3 were lower in both ND-CKD and D-MA patients than in controls. Plasma hexosylceramides in ND-CKD patients were increased and sphingoid bases decreased in both ND-CKD and D-MA patients. However, hexosylceramides in LDL, HDL2, and HDL3 were higher in ND-CKD patients than in controls. In D-MA patients, only C16:0 hexosylceramide in LDL was higher than in controls. The data suggest that sphingolipid measurement in lipoproteins, rather than in whole plasma, is crucial to decipher the role of sphingolipids in kidney disease.
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Affiliation(s)
- Maria F. Lopes-Virella
- Department of Medicine, Division of Diabetes, Endocrinology and Medical Genetics, Medical University of South Carolina, Charleston, SC 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA;
| | - Samar M. Hammad
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Nathaniel L. Baker
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA;
| | - Richard L. Klein
- Department of Medicine, Division of Diabetes, Endocrinology and Medical Genetics, Medical University of South Carolina, Charleston, SC 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA;
| | - Kelly J. Hunt
- Ralph H. Johnson VA Medical Center, Charleston, SC 29401, USA;
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA;
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Sourris KC, Ding Y, Maxwell SS, Al-Sharea A, Kantharidis P, Mohan M, Rosado CJ, Penfold SA, Haase C, Xu Y, Forbes JM, Crawford S, Ramm G, Harcourt BE, Jandeleit-Dahm K, Advani A, Murphy AJ, Timmermann DB, Karihaloo A, Knudsen LB, El-Osta A, Drucker DJ, Cooper ME, Coughlan MT. Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation. Kidney Int 2024; 105:132-149. [PMID: 38069998 DOI: 10.1016/j.kint.2023.09.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 09/16/2023] [Accepted: 09/25/2023] [Indexed: 01/07/2024]
Abstract
Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease. Mice with deletion of the GLP-1 receptor displayed an abnormal kidney phenotype that was accelerated by diabetes and improved with co-deletion of RAGE in vivo. Activation of the GLP-1 receptor pathway with liraglutide, an anti-diabetic treatment, downregulated kidney RAGE, reduced the expansion of bone marrow myeloid progenitors, promoted M2-like macrophage polarization and lessened markers of kidney damage in diabetic mice. Single cell transcriptomics revealed that liraglutide induced distinct transcriptional changes in kidney endothelial, proximal tubular, podocyte and macrophage cells, which were dominated by pathways involved in nutrient transport and utilization, redox sensing and the resolution of inflammation. The kidney-protective action of liraglutide was corroborated in a non-diabetic model of chronic kidney disease, the subtotal nephrectomised rat. Thus, our findings identify a novel glucose-independent kidney-protective action of GLP-1-based therapies in diabetic kidney disease and provide a valuable resource for exploring the cell-specific kidney transcriptional response ensuing from pharmacological GLP-1R agonism.
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Affiliation(s)
- Karly C Sourris
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia; Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
| | - Yi Ding
- Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia; Diabetes Complications Research, Novo Nordisk, Måløv, Denmark
| | - Scott S Maxwell
- Epigenetics in Human Health and Disease Program, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Annas Al-Sharea
- Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Phillip Kantharidis
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Carlos J Rosado
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Sally A Penfold
- Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Claus Haase
- Diabetes Complications Research, Novo Nordisk, Måløv, Denmark
| | - Yangsong Xu
- Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Josephine M Forbes
- Mater Research Institute, the University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Simon Crawford
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, Victoria, Australia
| | - Georg Ramm
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Clayton, Victoria, Australia
| | - Brooke E Harcourt
- Murdoch Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Karin Jandeleit-Dahm
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michaels Hospital, Toronto, Ontario, Canada
| | - Andrew J Murphy
- Haematopoiesis and Leukocyte Biology, Division of Immunometabolism, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | | | - Anil Karihaloo
- Novo Nordisk Research Center Seattle, Inc., Seattle, Washington, USA
| | | | - Assam El-Osta
- Epigenetics in Human Health and Disease Program, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mark E Cooper
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Monash University, Central Clinical School, Alfred Research Alliance, Melbourne, Victoria, Australia; Diabetes Complications Division, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University Parkville Campus, Parkville, Victoria, Australia.
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Yazıcı D, Demir SÇ, Sezer H. Insulin Resistance, Obesity, and Lipotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:391-430. [PMID: 39287860 DOI: 10.1007/978-3-031-63657-8_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.
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Affiliation(s)
- Dilek Yazıcı
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey.
| | - Selin Çakmak Demir
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
| | - Havva Sezer
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
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Carullo N, Zicarelli M, Michael A, Faga T, Battaglia Y, Pisani A, Perticone M, Costa D, Ielapi N, Coppolino G, Bolignano D, Serra R, Andreucci M. Childhood Obesity: Insight into Kidney Involvement. Int J Mol Sci 2023; 24:17400. [PMID: 38139229 PMCID: PMC10743690 DOI: 10.3390/ijms242417400] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
This review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of providing pediatricians and nephrologists with the most current data on this topic. The prevalence of childhood obesity and chronic kidney disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While the impact of obesity in children with CKD is less pronounced than in adults, recent studies suggest a similar trend in the child population. This is likely due to the significant association between obesity and the two leading causes of end-stage renal disease (ESRD): diabetes mellitus (DM) and hypertension. Obesity is a complex, systemic disease that reflects interactions between environmental and genetic factors. A key mechanism of kidney damage is related to metabolic syndrome and insulin resistance. Therefore, we can speculate about an adipose tissue-kidney axis in which neurohormonal and immunological mechanisms exacerbate complications resulting from obesity. Adipose tissue, now recognized as an endocrine organ, secretes cytokines called adipokines that may induce adaptive or maladaptive responses in renal cells, leading to kidney fibrosis. The impact of obesity on kidney transplant-related outcomes for both donors and recipients is also significant, making stringent preventive measures critical in the pre- and post-transplant phases. The challenge lies in identifying renal involvement as early as possible, as it is often completely asymptomatic and not detectable through common markers of kidney function. Ongoing research into innovative technologies, such as proteomics and metabolomics, aims to identify new biomarkers and is constantly evolving. Many aspects of pediatric disease progression in the population of children with obesity still require clarification. However, the latest scientific evidence in the field of nephrology offers glimpses into various new perspectives, such as genetic factors, comorbidities, and novel biomarkers. Investigating these aspects early could potentially improve the prognosis of these young patients through new diagnostic and therapeutic strategies. Hence, the aim of this review is to provide a comprehensive exploration of the pathogenetic mechanisms and prevalent pathological patterns of kidney damage observed in children with obesity.
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Affiliation(s)
- Nazareno Carullo
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (N.C.); (M.Z.); (A.M.); (T.F.); (G.C.)
| | - Mariateresa Zicarelli
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (N.C.); (M.Z.); (A.M.); (T.F.); (G.C.)
| | - Ashour Michael
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (N.C.); (M.Z.); (A.M.); (T.F.); (G.C.)
| | - Teresa Faga
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (N.C.); (M.Z.); (A.M.); (T.F.); (G.C.)
| | - Yuri Battaglia
- Department of Medicine, University of Verona, 37129 Verona, Italy;
| | - Antonio Pisani
- Department of Public Health, University Federico II of Naples, 80131 Naples, Italy;
| | - Maria Perticone
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (D.C.); (D.B.)
| | - Davide Costa
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (D.C.); (D.B.)
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy;
| | - Nicola Ielapi
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy;
- Department of Public Health and Infectious Disease, “Sapienza” University of Rome, 00185 Rome, Italy
| | - Giuseppe Coppolino
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (N.C.); (M.Z.); (A.M.); (T.F.); (G.C.)
| | - Davide Bolignano
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (D.C.); (D.B.)
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.P.); (D.C.); (D.B.)
- Interuniversity Center of Phlebolymphology (CIFL), “Magna Graecia” University, 88100 Catanzaro, Italy;
| | - Michele Andreucci
- Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (N.C.); (M.Z.); (A.M.); (T.F.); (G.C.)
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李 卉, 张 历, 黄 蓉, 任 倩, 郭 帆, 石 敏, 杨 乐, 于 洋, 马 良, 付 平. [Sichuan Dark Tea-Based Medicated Dietary Formula Improves Obesity-Induced Renal Lipid Metabolism Disorder in Mice by Remodeling Gut Microbiota and Short-Chain Fatty Acid Metabolism]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2023; 54:1112-1120. [PMID: 38162058 PMCID: PMC10752792 DOI: 10.12182/20231160208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Indexed: 01/03/2024]
Abstract
Objective To investigate the renoprotective effects of a Sichuan dark tea-based medicated dietary formula (alternatively referred to as Qing, or clarity in Chinese) on mice with diet-induced obesity (DIO) and to explore the specific mechanisms involved. Methods Male C57BL/6 mice were randomly assigned to three groups, a control group, a DIO group, and a Qing treatment group, or the Qing group, with 8 mice in each group. The mice in the control group were given normal maintenance feed and purified water, and the other two groups were fed a high-fat diet for 12 weeks to establish the DIO model. After that, high-fat diet continued in the DIO group, while the Qing group was given Qing at the same time for 12 weeks, during which period the weight of the mice was monitored and recorded every week. The mice were sacrificed after 12 weeks. Serum samples were collected and the levels of triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin were measured to evaluate liver function. In addition, renal lipids were extracted to determine the levels of TG and TC in the kidney and periodic acid-Schiff (PAS) and oil red O stainings were performed to evaluate kidney pathological injury. Western blot was performed to determine the phosphorylated AMPK (pAMPK)/AMPK ratio in the kidney tissue. RT-qPCR and Western blot were used to determine the expression of proteins related to fatty acid oxidation, including acetyl-CoA carboxylase 1 (ACC1), carnitine acyltransferase 1 (CTP1), peroxisome proliferators-activated receptor γ (PPARγ), peroxisome proliferators-activated receptor-1 α (PPAR1α), sterol-regulatory element binding proteins (SREBP-1), and key proteins related to lipid synthesis, including fatty acid synthase (FASN) and stearoyl-coenzyme A desaturase 1 (stearoyl-CoA desaturase) in the kidney tissue. 16SrRNA and metabolomics were applied to analyze the gut microbiota in the intestinal contents and its metabolites. Results Compared with those of the control group, the levels of liver mass (P=0.0003), serum ALT (P<0.0001) and AST (P=0.0001), and kidney TC (P=0.0191) and TG (P=0.0101) of the DIO group were significantly increased and there was lipid deposition in the kidney. Compared with those of the DIO group, mice in the Qing group showed effective reduction in liver mass (P=0.0316) and improvements in the abnormal serum levels of AST (P=0.0012) and ALT (P=0.0027) and kidney TC (P=0.0200) and TG (P=0.0499). In addition, mice in the Qing group showed significant improvement in lipid deposition in the kidney. Qing group showed increased pAMPK/AMPK ratio in comparison with that of the DIO group. In comparison with those of the control group, mice in the DIO group had upregulated expression of lipid synthesis-related genes and proteins (SREBP-1, FASN, and SCD1). As for the fatty acid oxidation-related genes and proteins, DIO mice showed upregulated expression of ACC1 and downregulated expression of CPT1A, PPARγ, and PGC1α in comparison with those of the control group. In the Qing goup, improvements in regard to all these changes were observed. The Qing group demonstrated improvement in the disrupted homeostasis of the gut microbiota. Short-chain fatty acids in the cecal contents, especially isovaleric acid and propionic acid, were also restored. Conclusion Sichuan dark tea-based medicated dietary formula may improve renal lipid metabolism by regulating gut microbiota and the levels of intestinal short-chain fatty acids, thereby protecting obesity-related kidney injury. Isovaleric acid and propionic acid may be the metabolites key to its regulation of gut microbiota.
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Affiliation(s)
- 卉 李
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 历涵 张
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 蓉双 黄
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 倩 任
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 帆 郭
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 敏 石
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 乐天 杨
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 洋 于
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 良 马
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - 平 付
- 四川大学华西医院 肾脏内科 肾脏病研究所 （成都 610041）Kidney Research Institute, Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China
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Braga PC, Bernardino RL, Guerra-Carvalho B, Carrageta DF, Oliveira PF, Rodrigues AS, Alves MG. The progression from mild to severe hyperglycemia coupled with insulin resistance causes mitochondrial dysfunction and alters the metabolic secretome of epithelial kidney cells. Exp Cell Res 2023; 431:113744. [PMID: 37648074 DOI: 10.1016/j.yexcr.2023.113744] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 09/01/2023]
Abstract
Diabetic nephropathy (DN) and insulin resistance (IR) in kidney cells are considered main causes for end-stage renal failure. However, it is unclear how IR affects early stages of the disease. Here, we investigate the impact of mild (11 mM) and severe (22 mM) hyperglycemia, with and without induced IR, on cellular metabolism and mitochondrial bioenergetics in a human kidney cell line (HK-2). IR in HK-2 cells was induced with palmitic acid and cellular cytotoxicity was studied. We evaluated the impact of mild and severe hyperglycemia with and without IR on the metabolic secretome of the cells, their live-cell mitochondria function, mitochondrial membrane potential, and mitochondrial complex activities. Furthermore, we measured fatty acid oxidation and lipid accumulation. Cells cultured under mild hyperglycemic conditions exhibited increased mitochondrial bioenergetic parameters, such as basal respiration, ATP-linked production, maximal respiration capacity, and spare respiration capacity. However, these parameters decreased when cells were cultured under higher glucose concentrations when IR was induced. Our data suggests that progression from mild to severe hyperglycemia induces a metabolic shift, where gluconeogenic amino acids play a crucial role in supplying the energy requirements of HK-2. To our knowledge, this is the first study to evaluate the progression from mild to severe hyperglycemia allied to IR in human kidney cells. This work highlights that this progression leads to mitochondrial dysfunction and alters the metabolic profile of kidney cells. These results identify possible targets for early intervention in DN.
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Affiliation(s)
- Patrícia C Braga
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; ITR- Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; Laboratory of Physiology, Department of Imuno-physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
| | - Raquel L Bernardino
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; ITR- Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.
| | - Bárbara Guerra-Carvalho
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; ITR- Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; Laboratory of Physiology, Department of Imuno-physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Portugal.
| | - David F Carrageta
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; ITR- Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; Laboratory of Physiology, Department of Imuno-physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
| | - Pedro F Oliveira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Portugal.
| | - Anabela S Rodrigues
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; ITR- Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; Department of Nephrology, Santo António Hospital, CHUdSA, Porto, Portugal.
| | - Marco G Alves
- Institute of Biomedicine - iBiMED and Department of Medical Sciences, University of Aveiro, 3810-193, Aveiro, Portugal.
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Hammad SM, Lopes-Virella MF. Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications. Int J Mol Sci 2023; 24:14015. [PMID: 37762318 PMCID: PMC10531201 DOI: 10.3390/ijms241814015] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Sphingolipids play an important role in the development of diabetes, both type 1 and type 2 diabetes, as well as in the development of both micro- and macro-vascular complications. Several reviews have been published concerning the role of sphingolipids in diabetes but most of the emphasis has been on the possible mechanisms by which sphingolipids, mainly ceramides, contribute to the development of diabetes. Research on circulating levels of the different classes of sphingolipids in serum and in lipoproteins and their importance as biomarkers to predict not only the development of diabetes but also of its complications has only recently emerged and it is still in its infancy. This review summarizes the previously published literature concerning sphingolipid-mediated mechanisms involved in the development of diabetes and its complications, focusing on how circulating plasma sphingolipid levels and the relative content carried by the different lipoproteins may impact their role as possible biomarkers both in the development of diabetes and mainly in the development of diabetic complications. Further studies in this field may open new therapeutic avenues to prevent or arrest/reduce both the development of diabetes and progression of its complications.
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Affiliation(s)
- Samar M. Hammad
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Maria F. Lopes-Virella
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC 29425, USA
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Dalga D, Verissimo T, de Seigneux S. Gluconeogenesis in the kidney: in health and in chronic kidney disease. Clin Kidney J 2023; 16:1249-1257. [PMID: 37529654 PMCID: PMC10387387 DOI: 10.1093/ckj/sfad046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Indexed: 08/03/2023] Open
Abstract
Chronic kidney disease (CKD) is a global health issue with increasing prevalence. Despite large improvements in current therapies, slowing CKD progression remains a challenge. A better understanding of renal pathophysiology is needed to offer new therapeutic targets. The role of metabolism alterations and mitochondrial dysfunction in tubular cells is increasingly recognized in CKD progression. In proximal tubular cells, CKD progression is associated with a switch from fatty acid oxidation to glycolysis. Glucose synthesis through gluconeogenesis is one of the principal physiological functions of the kidney. Loss of tubular gluconeogenesis in a stage-dependent manner is a key feature of CKD and contributes to systemic and possibly local metabolic complications. The local consequences observed may be related to an accumulation of precursors, such as glycogen, but also to the various physiological functions of the gluconeogenesis enzymes. The basic features of metabolism in proximal tubular cells and their modifications during CKD will be reviewed. The metabolic modifications and their influence on kidney disease will be described, as well as the local and systemic consequences. Finally, therapeutic interventions will be discussed.
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Affiliation(s)
- Delal Dalga
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Thomas Verissimo
- Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
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Kumar M, Gaivin RJ, Khan S, Fedorov Y, Adams DJ, Zhao W, Lee HY, Dai X, Dealwis CG, Schelling JR. Definition of fatty acid transport protein-2 (FATP2) structure facilitates identification of small molecule inhibitors for the treatment of diabetic complications. Int J Biol Macromol 2023; 244:125328. [PMID: 37307967 PMCID: PMC10527240 DOI: 10.1016/j.ijbiomac.2023.125328] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/14/2023]
Abstract
Diabetes is a major public health problem due to morbidity and mortality associated with end organ complications. Uptake of fatty acids by Fatty Acid Transport Protein-2 (FATP2) contributes to hyperglycemia, diabetic kidney and liver disease pathogenesis. Because FATP2 structure is unknown, a homology model was constructed, validated by AlphaFold2 prediction and site-directed mutagenesis, and then used to conduct a virtual drug discovery screen. In silico similarity searches to two low-micromolar IC50 FATP2 inhibitors, followed by docking and pharmacokinetics predictions, narrowed a diverse 800,000 compound library to 23 hits. These candidates were further evaluated for inhibition of FATP2-dependent fatty acid uptake and apoptosis in cells. Two compounds demonstrated nanomolar IC50, and were further characterized by molecular dynamic simulations. The results highlight the feasibility of combining a homology model with in silico and in vitro screening, to economically identify high affinity inhibitors of FATP2, as potential treatment for diabetes and its complications.
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Affiliation(s)
- Mukesh Kumar
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Robert J Gaivin
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Shenaz Khan
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Yuriy Fedorov
- Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Drew J Adams
- Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Weiyang Zhao
- Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Hsueh-Yun Lee
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
| | - Xinghong Dai
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Chris G Dealwis
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, United States of America; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, United States of America
| | - Jeffrey R Schelling
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, United States of America; Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, United States of America.
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Pereira PG, Alves LL, Ciambarella BT, Rabelo K, Nascimento ALR, Moraes ACN, Bernardi A, Guimarães FV, Carvalho GM, da Silva JFR, de Carvalho JJ. Capybara Oil Improves Renal Pathophysiology and Inflammation in Obese Mice. Nutrients 2023; 15:2925. [PMID: 37447251 DOI: 10.3390/nu15132925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/06/2023] [Accepted: 01/10/2023] [Indexed: 07/15/2023] Open
Abstract
Obesity is an inflammatory disease associated with secondary diseases such as kidney disease, which can cause lipotoxicity, inflammation and loss of organ function. Polyunsaturated fatty acids act in the production of lipid mediators and have anti-inflammatory characteristics. In this work, the objective was to evaluate renal histopathology in obese mice and the effects of treatment with capybara oil (CO) (5000 mg/kg/day for 4 weeks). Parameters such as body mass, lipid profile, systolic blood pressure, urinary creatinine and protein excretion, structure and ultrastructure of the renal cortex, fibrosis, tissue inflammation and oxidative stress were analyzed. CO treatment in obese mice showed improvement in the lipid profile and reduction in systolic blood pressure levels, in addition to beneficial remodeling of the renal cortex. Our data demonstrated that CO decreased inflammation, oxidative stress and renal fibrosis, as evidenced by quantifying the expression of TNF-α, IL-10, CAT, SOD, α-SMA and TGF-β. Although treatment with CO did not show improvement in renal function, ultrastructural analysis showed that the treatment was effective in restoring podocytes and pedicels, with restructuring of the glomerular filtration barrier. These results demonstrate, for the first time, that treatment with CO is effective in reducing kidney damage, being considered a promising treatment for obesity.
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Affiliation(s)
- Priscila G Pereira
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Luciana L Alves
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Bianca T Ciambarella
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Kíssila Rabelo
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Ana Lúcia R Nascimento
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Alan Cesar N Moraes
- Electron Microscopy Laboratory of Biology Institute, University of Federal Fluminense, Rio de Janeiro 21040-900, RJ, Brazil
| | - Andressa Bernardi
- Inflammation Laboratory, Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil
| | | | - Gabriela M Carvalho
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Jemima F R da Silva
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
| | - Jorge J de Carvalho
- Ultrastructure and Tissue Biology Laboratory, Institute of Biology, Rio de Janeiro State University, Boulevard Vinte e Oito de Setembro, 87 Fundos, 3° Andar Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil
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Li Z, Ouyang H, Zhu J. Traditional Chinese medicines and natural products targeting immune cells in the treatment of metabolic-related fatty liver disease. Front Pharmacol 2023; 14:1195146. [PMID: 37361209 PMCID: PMC10289001 DOI: 10.3389/fphar.2023.1195146] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
MAFLD stands for metabolic-related fatty liver disease, which is a prevalent liver disease affecting one-third of adults worldwide, and is strongly associated with obesity, hyperlipidemia, and type 2 diabetes. It encompasses a broad spectrum of conditions ranging from simple liver fat accumulation to advanced stages like chronic inflammation, tissue damage, fibrosis, cirrhosis, and even hepatocellular carcinoma. With limited approved drugs for MAFLD, identifying promising drug targets and developing effective treatment strategies is essential. The liver plays a critical role in regulating human immunity, and enriching innate and adaptive immune cells in the liver can significantly improve the pathological state of MAFLD. In the modern era of drug discovery, there is increasing evidence that traditional Chinese medicine prescriptions, natural products and herb components can effectively treat MAFLD. Our study aims to review the current evidence supporting the potential benefits of such treatments, specifically targeting immune cells that are responsible for the pathogenesis of MAFLD. By providing new insights into the development of traditional drugs for the treatment of MAFLD, our findings may pave the way for more effective and targeted therapeutic approaches.
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Luan G, Li L, Yue H, Li Y, Lü H, Wang Y. Phenols from Potentilla anserina L. Improve Insulin Sensitivity and Inhibit Differentiation in 3T3-L1 Adipocytes in Vitro. Chem Biodivers 2023; 20:e202200784. [PMID: 36717756 DOI: 10.1002/cbdv.202200784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 01/25/2023] [Accepted: 01/30/2023] [Indexed: 02/01/2023]
Abstract
Potentilla anserina L., a well-known perennial herb, is widely used in traditional Tibetan medicine and used as a delicious food in humans. The present investigation reports on the activity of P. anserina phenols (PAP) in regulating glycolipid metabolism in 3T3-L1 adipocytes. Insulin sensitivity tests showed that PAP improved insulin-stimulated glucose uptake by promoting the phosphorylation of serine/threonine kinase Akt. Moreover, an assay involving the differentiation of 3T3-L1 preadipocytes demonstrated that PAP also decreased the accumulation of lipid droplets by suppressing the expression of adipokines during the differentiation process. In addition, the underlying mechanism from the aspects of energy metabolism and oxidative stress is also discussed. The improvement in energy metabolism was supported by an increase in mitochondrial membrane potential (MMP) and intracellular ATP. Amelioration of oxidative stress was supported by decreased levels of intracellular reactive oxygen species (ROS). In summary, our findings suggest that PAP can ameliorate the disorder of glycolipid metabolism in insulin resistant 3T3-L1 adipocytes by improving energy metabolism and oxidative stress and might be an attractive candidate for the treatment of diabetes.
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Affiliation(s)
- Guangxiang Luan
- Department of Pharmacy, Medical Institute of Qinghai University, Xining, 810016, Qinghai, China
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, 810016, Qinghai, China
| | - Linlin Li
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, 810016, Qinghai, China
| | - Hongxia Yue
- Department of Pharmacy, Medical Institute of Qinghai University, Xining, 810016, Qinghai, China
| | - Yongfang Li
- Department of Pharmacy, Medical Institute of Qinghai University, Xining, 810016, Qinghai, China
| | - Huiling Lü
- Department of Pharmacy, Medical Institute of Qinghai University, Xining, 810016, Qinghai, China
| | - Yuwei Wang
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, 810016, Qinghai, China
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Hidalgo NJ, Pando E, Alberti P, Mata R, Fernandes N, Adell M, Villasante S, Blanco L, Balsells J, Charco R. The role of high serum triglyceride levels on pancreatic necrosis development and related complications. BMC Gastroenterol 2023; 23:51. [PMID: 36829113 PMCID: PMC9955530 DOI: 10.1186/s12876-023-02684-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/17/2023] [Indexed: 02/26/2023] Open
Abstract
BACKGROUND The relevance of elevated serum triglyceride (TG) levels in the early stages of acute pancreatitis (AP) not induced by hypertriglyceridemia (HTG) remains unclear. Our study aims to determine the role of elevated serum TG levels at admission in developing pancreatic necrosis. METHODS We analyzed the clinical data collected prospectively from patients with AP. According to TG levels measured in the first 24 h after admission, we stratified patients into four groups: Normal TG (< 150 mg/dL), Borderline-high TG (150-199 mg/dL), High TG (200-499 mg/dL) and Very high TG (≥ 500 mg/dL). We analyzed the association of TG levels and other risk factors with the development of pancreatic necrosis. RESULTS A total of 211 patients were included. In the Normal TG group: 122, in Borderline-high TG group: 38, in High TG group: 44, and in Very high TG group: 7. Pancreatic necrosis developed in 29.5% of the patients in the Normal TG group, 26.3% in the Borderline-high TG group, 52.3% in the High TG group, and 85.7% in the Very high TG group. The trend analysis observed a significant association between higher TG levels and pancreatic necrosis (p = 0.001). A multivariable analysis using logistic regression showed that elevated TG levels ≥ 200 mg/dL (High TG and Very high TG groups) were independently associated with pancreatic necrosis (OR: 3.27, 95% CI - 6.27, p < 0.001). CONCLUSIONS An elevated TG level at admission ≥ 200 mg/dl is independently associated with the development of pancreatic necrosis. The incidence of pancreatic necrosis increases proportionally with the severity of HTG.
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Affiliation(s)
- Nils Jimmy Hidalgo
- grid.7080.f0000 0001 2296 0625Universitat Autonoma de Barcelona, Bellaterra, Spain ,grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Elizabeth Pando
- Universitat Autonoma de Barcelona, Bellaterra, Spain. .,Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d'Hebron, 119 Passeig de la Vall d'Hebron, 08035, Barcelona, Spain.
| | - Piero Alberti
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Rodrigo Mata
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Nair Fernandes
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Montse Adell
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Sara Villasante
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Laia Blanco
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Joaquim Balsells
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
| | - Ramon Charco
- grid.411083.f0000 0001 0675 8654Department of Hepato-Pancreato-Biliary and Transplant Surgery, Hospital Universitari Vall d’Hebron, 119 Passeig de la Vall d’Hebron, 08035 Barcelona, Spain
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Fehlberg LK, Guadagnin AR, Thomas BL, Ballou M, Loor JJ, Sugimoto Y, Shinzato I, Cardoso FC. Feeding rumen-protected lysine altered immune and metabolic biomarkers in dairy cows during the transition period. J Dairy Sci 2023; 106:2989-3007. [PMID: 36797190 DOI: 10.3168/jds.2022-22349] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 09/13/2022] [Indexed: 02/16/2023]
Abstract
This experiment was conducted to determine the effects of feeding rumen-protected lysine (RPL; AjiPro-L Generation 3, Ajinomoto Health and Nutrition North America Inc.) from -26 ± 4.6 d prepartum (0.54% RPL of dietary dry matter intake) to 28 d postpartum (0.39% RPL of dietary dry matter intake) on immunometabolic status and liver composition in dairy cows. Seventy-five multiparous Holstein cows, blocked by parity, previous 305-d mature-equivalent milk production, expected calving date, and body condition score during the far-off dry period were assigned to 1 of 4 dietary treatments in a randomized, complete block design with a 2 × 2 factorial arrangement of treatments. Treatments prepartum consisted of total mixed ration top dressed with RPL (PRE-L) or without RPL (PRE-C), and postpartum treatments consisted of total mixed ration top dressed PRE-L prepartum and postpartum, PRE-L prepartum and PRE-C postpartum, PRE-C prepartum and PRE-L postpartum, and PRE-C prepartum and postpartum in 300 g of molasses. Blood samples were taken on -7 ± 0.5, 0 ± 0.5, 7 ± 0.9, 14 ± 0.9, and 28 ± 0.5 d relative to calving. Whole blood samples were taken on -14 ± 0.5, -7 ± 0.5, 7 ± 0.9, and 14 ± 0.9 d relative to calving for oxidative burst and phagocytic capacity of monocytes and neutrophils. Liver samples were collected via a biopsy on -12 ± 4.95 and 13 ± 2.62 d relative to calving and analyzed for liver composition (triacylglyceride and carnitine concentrations), mRNA expression of hepatic genes, and protein abundance. Protein abundance was calculated by normalizing intensity bands for a specific protein with glyceraldehyde-3-phosphate dehydrogenase. Concentrations of haptoglobin and glutathione peroxidase activity in plasma were lower at d 0 for cows in PRE-L (102 µg/mL and 339 nmol/min per mL, respectively) compared with cows in PRE-C (165 µg/mL and 405 nmol/min per mL, respectively). Oxidative burst capacity in monocytes tended to be greater on d 7 postpartum for cows in PRE-L (65.6%) than cows in PRE-C (57.5%). Additionally, feeding RPL altered the mRNA expression in liver tissue prepartum [decreased INSR (insulin receptor), CPT1A (carnitine palmitoyltransferase 1A), and IL1B (interleukin 1 β)] and postpartum [increased IL8 (interleukin 8), EHMT2 (euchromatic histone lysine methyltransferase 2), TSPO (translocator protein), and SLC3A2 (solute carrier family 3 member 2); and decreased SLC7A1 (solute carrier family 7 member 1), SOD1 (superoxide dismutase 1), and SAA3 (serum amyloid A 3)] compared with cows not consuming RPL]. Additionally, cows in the PRE-C prepartum and PRE-L postpartum treatment tended to have greater protein abundance of mTOR postpartum compared with the PRE-C prepartum and postpartum treatment. Protein abundance of SLC7A7 (solute carrier family 7 member 7) pre- and postpartum tended to be greater and BBOX1 (gamma-butyrobetaine dioxygenase 1) tended to be less when RPL was consumed prepartum. In conclusion, cows that consumed RPL during the transition period had molecular changes related to liver composition, enhanced liver function indicated by greater total protein and albumin concentrations in plasma, and improved immune status indicated by decreased haptoglobin, glutathione peroxidase activity, and immune related mRNA expression.
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Affiliation(s)
- L K Fehlberg
- Department of Animal Sciences, University of Illinois, Urbana 61801
| | - A R Guadagnin
- Department of Animal Sciences, University of Illinois, Urbana 61801
| | - B L Thomas
- Department of Animal Sciences, University of Illinois, Urbana 61801
| | - M Ballou
- Department of Animal Science and Food Science, Texas Tech University, Lubbock 79409
| | - J J Loor
- Department of Animal Sciences, University of Illinois, Urbana 61801
| | - Y Sugimoto
- Ajinomoto Co. Inc., Tokyo 104-8315, Japan
| | - I Shinzato
- Ajinomoto Co. Inc., Tokyo 104-8315, Japan
| | - F C Cardoso
- Department of Animal Sciences, University of Illinois, Urbana 61801.
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Zapata-Restrepio LM, Hauton C, Hudson MD, Williams ID, Hauton D. Toxicity of tributyltin to the European flat oyster Ostrea edulis: Metabolomic responses indicate impacts to energy metabolism, biochemical composition and reproductive maturation. PLoS One 2023; 18:e0280777. [PMID: 36745593 PMCID: PMC9901812 DOI: 10.1371/journal.pone.0280777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 01/10/2023] [Indexed: 02/07/2023] Open
Abstract
Tri-Butyl Tin (TBT) remains as a legacy pollutant in the benthic environments. Although the toxic impacts and endocrine disruption caused by TBT to gastropod molluscs have been established, the changes in energy reserves allocated to maintenance, growth, reproduction and survival of European oysters Ostrea edulis, a target species of concerted benthic habitat restoration projects, have not been explored. This study was designed to evaluate the effect of TBT chloride (TBTCl) on potential ions and relevant metabolomic pathways and its association with changes in physiological, biochemical and reproductive parameters in O. edulis exposed to environmental relevant concentrations of TBTCl. Oysters were exposed to TBTCl 20 ng/L (n = 30), 200 ng/L (n = 30) and 2000 ng/L (n = 30) for nine weeks. At the end of the exposure, gametogenic stage, sex, energy reserve content and metabolomic profiling analysis were conducted to elucidate the metabolic alterations that occur in individuals exposed to those compounds. Metabolite analysis showed significant changes in the digestive gland biochemistry in oysters exposed to TBTCl, decreasing tissue ATP concentrations through a combination of the disruption of the TCA cycle and other important molecular pathways involved in homeostasis, mitochondrial metabolism and antioxidant response. TBTCl exposure increased mortality and caused changes in the gametogenesis with cycle arrest in stages G0 and G1. Sex determination was affected by TBTCl exposure, increasing the proportion of oysters identified as males in O. edulis treated at 20ng/l TBTCl, and with an increased proportion of inactive stages in oysters treated with 2000 ng/l TBTCl. The presence and persistence of environmental pollutants, such as TBT, could represent an additional threat to the declining O. edulis populations and related taxa around the world, by increasing mortality, changing reproductive maturation, and disrupting metabolism. Our findings identify the need to consider additional factors (e.g. legacy pollution) when identifying coastal locations for shellfish restoration.
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Affiliation(s)
- Lina M. Zapata-Restrepio
- School of Geography and Environmental Sciences, University of Southampton, Highfield Campus, Southampton, United Kingdom
- * E-mail:
| | - Chris Hauton
- Ocean and Earth Sciences, National Oceanography Centre, University of Southampton, Southampton, Hampshire, United Kingdom
| | - Malcolm D. Hudson
- School of Geography and Environmental Sciences, University of Southampton, Highfield Campus, Southampton, United Kingdom
| | - Ian D. Williams
- Faculty of Engineering and Physical Sciences, University of Southampton, Highfield Campus, Southampton, United Kingdom
| | - David Hauton
- Metabolomics Research Group, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom
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Huang W, Cao G, Deng C, Chen Y, Wang T, Chen D, Cai Z. Adverse effects of triclosan on kidney in mice: Implication of lipid metabolism disorders. J Environ Sci (China) 2023; 124:481-490. [PMID: 36182156 DOI: 10.1016/j.jes.2021.11.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/23/2021] [Accepted: 11/26/2021] [Indexed: 06/16/2023]
Abstract
Triclosan (TCS) is a ubiquitous antimicrobial used in daily consumer products. Previous reports have shown that TCS could induce hepatotoxicity, endocrine disruption, disturbance on immune function and impaired thyroid function. Kidney is critical in the elimination of toxins, while the effects of TCS on kidney have not yet been well-characterized. The aim of the present study was to investigate the effects of TCS exposure on kidney function and the possible underlying mechanisms in mice. Male C57BL/6 mice were orally exposed to TCS with the doses of 10 and 100 mg/(kg•day) for 13 weeks. TCS was dissolved in dimethyl sulfoxide (DMSO) and diluted by corn oil for exposure. Corn oil containing DMSO was used as vehicle control. Serum and kidney tissues were collected for study. Biomarkers associated with kidney function, oxidative stress, inflammation and fibrosis were assessed. Our results showed that TCS could cause renal injury as was revealed by increased levels of renal function markers including serum creatinine, urea nitrogen and uric acid, as well as increased oxidative stress, pro-inflammatory cytokines and fibrotic markers in a dose dependent manner, which were more significantly in 100 mg/(kg•day) group. Mass spectrometry-based analysis of metabolites related with lipid metabolism demonstrated the occurrence of lipid accumulation and defective fatty acid oxidation in 100 mg/(kg•day) TCS-exposed mouse kidney. These processes might lead to lipotoxicity and energy depletion, thus resulting in kidney fibrosis and functional decline. Taken together, the present study demonstrated that TCS could induce lipid accumulation and fatty acid metabolism disturbance in mouse kidney, which might contribute to renal function impairment. The present study further widens our insights into the adverse effects of TCS.
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Affiliation(s)
- Wei Huang
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong 999077, China; School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Guodong Cao
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong 999077, China
| | - Chengliang Deng
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Yanyan Chen
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong 999077, China
| | - Tao Wang
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong 999077, China; Analysis Center, School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Da Chen
- School of Environment, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong 999077, China.
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Rose TD, Köhler N, Falk L, Klischat L, Lazareva OE, Pauling JK. Lipid network and moiety analysis for revealing enzymatic dysregulation and mechanistic alterations from lipidomics data. Brief Bioinform 2023; 24:bbac572. [PMID: 36592059 PMCID: PMC9851308 DOI: 10.1093/bib/bbac572] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/10/2022] [Accepted: 11/24/2022] [Indexed: 01/03/2023] Open
Abstract
Lipidomics is of growing importance for clinical and biomedical research due to many associations between lipid metabolism and diseases. The discovery of these associations is facilitated by improved lipid identification and quantification. Sophisticated computational methods are advantageous for interpreting such large-scale data for understanding metabolic processes and their underlying (patho)mechanisms. To generate hypothesis about these mechanisms, the combination of metabolic networks and graph algorithms is a powerful option to pinpoint molecular disease drivers and their interactions. Here we present lipid network explorer (LINEX$^2$), a lipid network analysis framework that fuels biological interpretation of alterations in lipid compositions. By integrating lipid-metabolic reactions from public databases, we generate dataset-specific lipid interaction networks. To aid interpretation of these networks, we present an enrichment graph algorithm that infers changes in enzymatic activity in the context of their multispecificity from lipidomics data. Our inference method successfully recovered the MBOAT7 enzyme from knock-out data. Furthermore, we mechanistically interpret lipidomic alterations of adipocytes in obesity by leveraging network enrichment and lipid moieties. We address the general lack of lipidomics data mining options to elucidate potential disease mechanisms and make lipidomics more clinically relevant.
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Affiliation(s)
- Tim D Rose
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Nikolai Köhler
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Lisa Falk
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Lucie Klischat
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Olga E Lazareva
- Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
- Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Junior Clinical Cooperation Unit Multiparametric methods for early detection of prostate cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany
| | - Josch K Pauling
- LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
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Ma K, Sheng W, Gao R, Feng J, Huang W, Cui L, Liu J, Li Y. Ethanolic extract of root from Arctium lappa L ameliorates obesity and hepatic steatosis in rats by regulating the AMPK/ACC/CPT-1 pathway. J Food Biochem 2022; 46:e14455. [PMID: 36183168 DOI: 10.1111/jfbc.14455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/13/2022] [Accepted: 09/16/2022] [Indexed: 01/14/2023]
Abstract
Burdock (Arctium lappa L) root is eaten as a vegetable in many countries and used as an ethnomedicine because of its various pharmacological effects. The objective of this study was to investigate the underlying mechanisms of ethanolic extract of root from Arctium lappa L root (ALE) to lose weight and regulate lipid metabolism. The results showed that ALE can regulate lipid metabolism level and inhibit the weight gain of rats induced by the high-sugar and high-fat diet. The contents of triglyceride and cholesterol in the liver of obese rats significantly reduced, and hepatic steatosis was ameliorated. In addition, this study identified that ALE enhanced hepatic fatty acid β-oxidation and ameliorated hepatic steatosis by activating AMPK/ACC/CPT-1 pathway. These results indicated that ALE has a potential preventive and therapeutic effect on metabolic-associated fatty liver disease and obesity. PRACTICAL APPLICATIONS: Obesity is already a global health problem. Obesity causes accumulation of triglycerides, which leads to hepatic steatosis. Long-term steatosis causes liver damage and metabolic fatty liver disease. Plant-derived functional foods or herbal medicines have better effects on weight loss and liver protection, which are more conducive to long-term use with less toxic side effects. As a medicinal and edible plant material, Arctium lappa L root has the effect in losing weight. Our study showed that ethanolic extract of Arctium lappa L root effectively regulates lipid metabolism and inhibits hepatic steatosis. Arctium lappa L root may be used as a therapeutic drug and functional food raw material for obesity and fatty liver disease.
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Affiliation(s)
- Kaiyang Ma
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Weixi Sheng
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Rong Gao
- School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jin Feng
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Wuyang Huang
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Li Cui
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Jun Liu
- College of Food Science and Engineering, Yangzhou University, Yangzhou, People's Republic of China
| | - Ying Li
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing, China
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50
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Kim JT, Lim MA, Lee SE, Kim HJ, Koh HY, Lee JH, Jun SM, Kim JM, Kim KH, Shin HS, Cho SW, Kim KS, Shong M, Koo BS, Kang YE. Adrenomedullin2 stimulates progression of thyroid cancer in mice and humans under nutrient excess conditions. J Pathol 2022; 258:264-277. [PMID: 36098211 PMCID: PMC9826144 DOI: 10.1002/path.5997] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 07/28/2022] [Accepted: 08/02/2022] [Indexed: 01/11/2023]
Abstract
Thyroid cancer is associated with genetic alterations, e.g. BRAFV600E , which may cause carcinomatous changes in hormone-secreting epithelial cells. Epidemiological studies have shown that overnutrition is related to the development and progression of cancer. In this study, we attempted to identify the cell nonautonomous factor responsible for the progression of BRAFV600E thyroid cancer under overnutrition conditions. We developed a mouse model for inducible thyrocyte-specific activation of BRAFV600E , which showed features similar to those of human papillary thyroid cancer. LSL-BrafV600E ;TgCreERT2 showed thyroid tumour development in the entire thyroid, and the tumour showed more abnormal cellular features with mitochondrial abnormalities in mice fed a high-fat diet (HFD). Transcriptomics revealed that adrenomedullin2 (Adm2) was increased in LSL-BrafV600E ;TgCreERT2 mice fed HFD. ADM2 was upregulated on the addition of a mitochondrial complex I inhibitor or palmitic acid with integrated stress response (ISR) in cancer cells. ADM2 stimulated protein kinase A and extracellular signal-regulated kinase in vitro. The knockdown of ADM2 suppressed the proliferation and migration of thyroid cancer cells. We searched The Cancer Genome Atlas and Genotype-Tissue Expression databases and found that increased ADM2 expression was associated with ISR and poor overall survival. Consistently, upregulated ADM2 expression in tumour cells and circulating ADM2 molecules were associated with aggressive clinicopathological parameters, including body mass index, in thyroid cancer patients. Collectively, we identified that ADM2 is released from cancer cells under mitochondrial stress resulting from overnutrition and acts as a secretory factor determining the progressive properties of thyroid cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jung Tae Kim
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonRepublic of Korea,Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Mi Ae Lim
- Department of Otolaryngology‐Head and Neck SurgeryChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Seong Eun Lee
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Hyun Jung Kim
- Graduate School of Medical Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Hyun Yong Koh
- Graduate School of Medical Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Jeong Ho Lee
- Graduate School of Medical Science and EngineeringKorea Advanced Institute of Science and Technology (KAIST)DaejeonRepublic of Korea
| | - Sang Mi Jun
- Center for Research EquipmentKorea Basic Science InstituteCheongjuRepublic of Korea,Convergent Research Center for Emerging Virus InfectionKorea Research Institute of Chemical TechnologyDaejeonRepublic of Korea
| | - Jin Man Kim
- Department of PathologyChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Kun Ho Kim
- Department of Nuclear MedicineChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Hyo Shik Shin
- Department of Internal MedicineSeoul National University College of MedicineSeoulRepublic of Korea
| | - Sun Wook Cho
- Department of Internal MedicineSeoul National University College of MedicineSeoulRepublic of Korea,Department of Internal MedicineSeoul National University HospitalSeoulRepublic of Korea,Cellus Inc.SeoulRepublic of Korea
| | - Koon Soon Kim
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonRepublic of Korea,Division of Endocrinology and Metabolism, Department of Internal MedicineChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Minho Shong
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonRepublic of Korea,Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea,Division of Endocrinology and Metabolism, Department of Internal MedicineChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Bon Seok Koo
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea,Department of Otolaryngology‐Head and Neck SurgeryChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Yea Eun Kang
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonRepublic of Korea,Division of Endocrinology and Metabolism, Department of Internal MedicineChungnam National University School of MedicineDaejeonRepublic of Korea
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