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Yang J, Hou S, Zhao Y, Sun Z, Zhang L, Deng Y, Shang X, Yu H, Li Z, Li H. Buckwheat protein-derived peptide ameliorates insulin resistance by directing O-linked N-acetylglucosamine transferase to regulate the SIRT1/PGC1α pathway. Int J Biol Macromol 2025; 304:140925. [PMID: 39947565 DOI: 10.1016/j.ijbiomac.2025.140925] [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: 09/04/2024] [Revised: 01/31/2025] [Accepted: 02/09/2025] [Indexed: 02/17/2025]
Abstract
The antidiabetic activity of the novel Buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) and its associated protein glycosylation have been verified. Our preliminary study demonstrates the potential of AFYRW as a therapeutic agent for diabetes, but the mechanism needs further investigation. Given the vital role of O-linked N-acetylglucosamine transferase (OGT) in diabetes mellitus and insulin resistance (IR), we focused on the underlying molecular mechanisms of them in ameliorating IR. We found AFYRW protects against hyperglycemia in diabetic mice and improves glucose metabolism in an IR cell model. Mechanistically, we demonstrated that AFYRW decreases glutamine-fructose-6-phosphate amidotransferase (GFAT) expression via X-box binding protein 1 (XBP1) in the hexosamine biosynthesis pathway (HBP), consequently decreasing OGT and stimulating the SIRT1/PGC1α pathway. Of note, the overlapping roles of increased SIRT1 and decreased OGT caused by AFYRW ameliorated IR. The data presented here show that AFYRW contributes to metabolism by directly controlling glucose homeostasis. Taken together, our study unveils that AFYRW protects against both insulin resistance and diabetes mellitus-induced hyperglycemia through OGT to regulate the SIRT1/PGC1α pathway, which provides a mechanistic basis for novel AFYRW to be a potential therapeutic agent.
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Affiliation(s)
- Jiajun Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China; Key Laboratory of Endemic and Ethenic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou, China
| | - Siyu Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China
| | - Yuhui Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China
| | - Zhaoyang Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China
| | - Lilin Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China
| | - Yan Deng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China
| | - Xiaoli Shang
- School of Biology and Engineering (School of Modern Industry of Health Medicine), Guizhou Medical University, Guizhou, Guiyang 561113, China
| | - Hanjie Yu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, China
| | - Zheng Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an 710069, China.
| | - Hongmei Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang 561113, China; Key Laboratory of Endemic and Ethenic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550004, Guizhou, China.
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2
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Wong MT, Lin PH, Lin WC, Peng CJ, Wright JD, Lee HJ, Chu HM, Lim C, Chang TW. 2FA-Platform Generates Dual Fatty Acid-Conjugated GLP-1 Receptor Agonist TE-8105 with Enhanced Diabetes, Obesity, and NASH Efficacy Compared to Semaglutide. J Med Chem 2025; 68:6178-6192. [PMID: 40044142 PMCID: PMC11956005 DOI: 10.1021/acs.jmedchem.4c02153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 02/13/2025] [Accepted: 02/18/2025] [Indexed: 03/28/2025]
Abstract
Conjugating two fatty acids (2FAs) to peptide drugs can improve pharmacokinetics and therapeutic effects. However, optimizing FA spacing, chain combination, and attachment site to simultaneously enhance albumin binding and drug efficacy remains challenging. We introduce a multiarm linker technology enabling precise control of 2FA spacing, composition, and attachment. By applying this technology to a modified glucagon-like peptide-1 (GLP-1) and screening various 2FA-GLP-1 conjugates differing in linkage, linker, and FA properties for improved albumin affinity, pharmacokinetics, and pharmacodynamics, TE-8105 emerged as a promising candidate. TE-8105 outperformed semaglutide, showing improved long-term glycemic control, weight loss, and liver health in diabetic mice, and dose-dependent weight loss and favorable body composition changes in obese mice. A distinct advantage of TE-8105 over semaglutide is its low-dose reduction of liver steatosis and improvement of liver health in nonalcoholic steatohepatitis mice. The multiarm linker technology provides a versatile platform for developing improved 2FA-peptide therapeutics.
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Affiliation(s)
- Mun-Teng Wong
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Pei-Hsuan Lin
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Wei-Chen Lin
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Chi-Jiun Peng
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Jon D. Wright
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Hui-Ju Lee
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Hsing-Mao Chu
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Carmay Lim
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
| | - Tse Wen Chang
- Immunwork,
Inc., C520, No. 99, Lane
130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
- T-E
Meds, Inc., C423, No.
99, Lane 130, Academia Road, Section 1, Nangang, Taipei 115021, Taiwan
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3
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Mukherjee R, Pancholi P, Sharma M, Solomon H, Timaul MN, Thant C, McGriskin R, Hayatt O, Markov V, D'Allara J, Bekker S, Candelier J, Carrasco SE, de Stanchina E, Vanaja K, Rosen N. Diet induced insulin resistance is due to induction of PTEN expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.25.645201. [PMID: 40196497 PMCID: PMC11974787 DOI: 10.1101/2025.03.25.645201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Insulin resistance is a condition associated with obesity, type 2 diabetes(T2D), hyperinsulinemia, hyperglycemia and defined by reduced sensitivity to insulin signaling. Molecular causes and early signaling events underlying insulin resistance are not well understood. Here we show that insulin activation of PI3K/AKT/mTOR signaling in insulin target tissues, causes mTORC1 induction of PTEN translation, a negative regulator of PI3K signaling. We hypothesized that insulin resistance is due to insulin dependent induction of PTEN that prevents further increases in PI3K signaling. In a diet induced animal model of obesity and insulin resistance, we show that PTEN levels are increased in fat, muscle, and liver. Hyperinsulinemia and PTEN induction are followed by hyperglycemia, severe glucose intolerance, and hepatic steatosis. In response to chronic hyperinsulinemia, PTEN remains increased, while AKT activity is induced transiently before settling down to a PTEN-high and AKT-low state in the tissues, predicted by computational modeling of the PTEN-AKT feedback loop. Treatment with PTEN and mTORC1 inhibitors prevent and reverse the effect of PTEN induction, rescue insulin resistance and increase PI3K/AKT signaling. Thus, we show that PTEN induction by increased insulin levels elevates feedback inhibition of the pathway causing insulin resistance, its associated phenotypes, and is a potential therapeutic target.
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4
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Wang Q, Yang X, Chen C, Xing Y, Chitakwa N, Jiang J, Wei H, Ding X, Wu D. Sex-specific effects of aged polystyrene microplastics on hepatic AMPK pathway activation and lipid droplet accumulation in MAFLD mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 292:117963. [PMID: 40058092 DOI: 10.1016/j.ecoenv.2025.117963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 03/17/2025]
Abstract
Microplastics (MPs) are environmental pollutants attracting widespread attention due to their environmental omnipresence and potential health effects. MPs undergo ageing in the environment and our previous research found that aged Polystyrene microplastics (PS-MPs) affected lipid metabolism in healthy female mice, but not males. In this study, we examined the effects of aged PS-MP exposure on lipid metabolism in mice with Metabolic Associated Fatty Liver Disease (MAFLD). 14 female and 14 male mice were furnished with a high-fat diet (HFD) for eight weeks to create MAFLD model mice. They were then orally administered aged PS-MPs for four weeks, and changes in the AMP-activated protein kinase signalling pathway were examined in order to determine PS-MP's effect on hepatic metabolism. The outcomes showed that though serum estradiol, inflammatory gene expression and ROS levels increased significantly in both male and female HFD-aged PS-MP groups, hepatic steatosis was attenuated only in the female group. Furthermore, serum ERα, ERβ, AMPKα, acetyl-CoA carboxylase, sterol regulatory element binding protein-1c, and Fas expressions were significantly increased in the MAFLD mice groups compared to the control group. Combining serum E2 levels, AMPK pathway changes, oxidative stress markers, and inflammatory gene levels, aged PS-MPs may stimulate E2 production and mobilize the liver AMPK signalling pathway of both male and female MAFLD mice. However, lipid metabolism is only affected in female MAFLD mice, suggesting other possible mechanisms besides the AMPK pathway may be at play. These results provide a new perspective on the potential health effects of MP exposure in individuals with metabolic disorders such as MAFLD.
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Affiliation(s)
- Qing Wang
- Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Xiaona Yang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Disease Prevention and Control Center of Linping District, Hangzhou 311100, China
| | - Chuan Chen
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Ying Xing
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Natasha Chitakwa
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jing Jiang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Hongcheng Wei
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Xinliang Ding
- The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China.
| | - Di Wu
- Wuxi Medical Center, Nanjing Medical University, Wuxi 214023, China; State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
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Feješ A, Šebeková K, Borbélyová V. Pathophysiological Role of Neutrophil Extracellular Traps in Diet-Induced Obesity and Metabolic Syndrome in Animal Models. Nutrients 2025; 17:241. [PMID: 39861371 PMCID: PMC11768048 DOI: 10.3390/nu17020241] [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: 12/01/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
The global pandemic of obesity poses a serious health, social, and economic burden. Patients living with obesity are at an increased risk of developing noncommunicable diseases or to die prematurely. Obesity is a state of chronic low-grade inflammation. Neutrophils are first to be recruited to sites of inflammation, where they contribute to host defense via phagocytosis, degranulation, and extrusion of neutrophil extracellular traps (NETs). NETs are web-like DNA structures of nuclear or mitochondrial DNA associated with cytosolic antimicrobial proteins. The primary function of NETosis is preventing the dissemination of pathogens. However, neutrophils may occasionally misidentify host molecules as danger-associated molecular patterns, triggering NET formation. This can lead to further recruitment of neutrophils, resulting in propagation and a vicious cycle of persistent systemic inflammation. This scenario may occur when neutrophils infiltrate expanded obese adipose tissue. Thus, NETosis is implicated in the pathophysiology of autoimmune and metabolic disorders, including obesity. This review explores the role of NETosis in obesity and two obesity-associated conditions-hypertension and liver steatosis. With the rising prevalence of obesity driving research into its pathophysiology, particularly through diet-induced obesity models in rodents, we discuss insights gained from both human and animal studies. Additionally, we highlight the potential offered by rodent models and the opportunities presented by genetically modified mouse strains for advancing our understanding of obesity-related inflammation.
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Affiliation(s)
| | - Katarína Šebeková
- Institute of Molecular Biomedicine, Medical Faculty, Comenius University, 83303 Bratislava, Slovakia; (A.F.); (V.B.)
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6
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Sun J, Jin X, Li Y. OTUD7B inhibited hepatic injury from NAFLD by inhibiting K48-linked ubiquitination and degradation of β-catenin. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167555. [PMID: 39520879 DOI: 10.1016/j.bbadis.2024.167555] [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: 06/07/2024] [Revised: 09/27/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the prevalent liver disease. Ovarian tumor domain-containing 7B (OTUD7B) is a deubiquitinating enzyme and its role in NAFLD remains unclear. In high-fat diet (HFD)-induced NAFLD mouse model and palmitic acid (PA)-treated HepG2 cells, OTUD7B expression was decreased. Adenoviral overexpression of OTUD7B in mice resulted in reduced body weight and liver injury, with decreased serum aminotransferase (ALT) and aspartate aminotransferase (AST) levels. OTUD7B overexpression attenuated hepatic lipid deposition (serum TG, TC, LDL-C, HDLC, and FFA levels), which might be through the suppression of lipogenesis and β-oxidation-related genes. The contents of hepatic inflammatory factors (TNF-α, IL-6, and IL-1β) were decreased following OTUD7B overexpression in NAFLD mice. A mechanism study indicated that the protective effect of OTUD7B overexpression might be associated with β-catenin signal activation. OTUD7B overexpression promoted PA-induced β-catenin activity in TopFlash assay, and increased total β-catenin and c-myc levels in cells. The increase in β-catenin levels was contributed to the stabilization via inhibiting K48-linked ubiquitination and proteasomal degradation by OTUD7B. NR4A2 role in NASH has been proved. NR4A2 ChIP-seq and RNA-seq data excluded transcriptional regulation of NR4A2 to OTUD7B, and it was experimentally evidenced that NR4A2 bound to OTUD7B promoter region and positively transcriptionally regulate OTUD7B expression. In summary, OTUD7B overexpression ameliorated hepatic inflammation and steatosis in NAFLD. The possible mechanism of OTUD7B might be through the inhibition of β-catenin degradation by removing K48-linked ubiquitination, which might be regulated by NR4A2.
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Affiliation(s)
- Jing Sun
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiuli Jin
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yiling Li
- Department of Gastroenterology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
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7
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Jimenez V, Sacristan V, Jambrina C, Jaen ML, Casana E, Muñoz S, Marcó S, Molas M, Garcia M, Grass I, León X, Elias I, Ribera A, Elias G, Sanchez V, Vilà L, Casellas A, Ferre T, Rodó J, Carretero A, Pumarola M, Navarro M, Andaluz A, Moll X, Añor S, Franckhauser S, Vergara M, Caixàs A, Bosch F. Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy. Mol Ther 2024; 32:4285-4302. [PMID: 39489916 PMCID: PMC11638876 DOI: 10.1016/j.ymthe.2024.10.023] [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: 07/01/2024] [Revised: 09/25/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.
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Affiliation(s)
- Veronica Jimenez
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Victor Sacristan
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Claudia Jambrina
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Maria Luisa Jaen
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Estefania Casana
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Sergio Muñoz
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Sara Marcó
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Maria Molas
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Miquel Garcia
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Ignasi Grass
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Xavier León
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Ivet Elias
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Albert Ribera
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Gemma Elias
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Victor Sanchez
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Laia Vilà
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Alba Casellas
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Tura Ferre
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Jordi Rodó
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Ana Carretero
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Marti Pumarola
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Marc Navarro
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Anna Andaluz
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Xavier Moll
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Sonia Añor
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Universitat Autònoma Barcelona, 08193 Bellaterra, Spain
| | - Sylvie Franckhauser
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Mercedes Vergara
- Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), 08202 Sabadell, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Teaching Unit Parc Taulí, 08202 Sabadell, Spain; Department of Hepatology, Digestive Service, Hospital Universitari Parc Taulí, 08202 Sabadell, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Assumpta Caixàs
- Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), 08202 Sabadell, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Teaching Unit Parc Taulí, 08202 Sabadell, Spain; Department of Endocrinology and Nutrition, Hospital Universitari Parc Taulí, 08202 Sabadell, Spain
| | - Fatima Bosch
- Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
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8
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Rho H, Kim S, Kim SU, Kim JW, Lee SH, Park SH, Escorcia FE, Chung JY, Song J. CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion. Nat Commun 2024; 15:8519. [PMID: 39353976 PMCID: PMC11445385 DOI: 10.1038/s41467-024-53002-0] [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: 09/10/2023] [Accepted: 09/26/2024] [Indexed: 10/03/2024] Open
Abstract
The fusion of autophagosomes and lysosomes is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). Here, we generate a hepatocyte-specific CHIP knockout (H-KO) mouse model that develops NAFLD more rapidly in response to a high-fat diet (HFD) or high-fat, high-fructose diet (HFHFD). The accumulation of P62 and LC3 in the livers of H-KO mice and CHIP-depleted cells indicates the inhibition of autophagosome-lysosome fusion. AAV8-mediated overexpression of CHIP in the murine liver slows the progression of NAFLD induced by HFD or HFHFD feeding. Mechanistically, CHIP induced K63- and K27-linked polyubiquitination at the lysine 198 residue of STX17, resulting in increased STX17-SNAP29-VAMP8 complex formation. The STX17 K198R mutant was not ubiquitinated by CHIP; it interfered with its interaction with VAMP8, rendering STX17 incapable of inhibiting steatosis development in mice. These results indicate that a signaling regulatory mechanism involving CHIP-mediated non-degradative ubiquitination of STX17 is necessary for autophagosome-lysosome fusion.
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Affiliation(s)
- Hyunjin Rho
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Seungyeon Kim
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Jeong Won Kim
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Lee
- Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
- GENINUS Inc, Seoul, Republic of Korea
| | - Sang Hoon Park
- Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Freddy E Escorcia
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National institutes of Health, Bethesda, MD, USA
| | - Joon-Yong Chung
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National institutes of Health, Bethesda, MD, USA
| | - Jaewhan Song
- Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea.
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9
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Domingues I, Yagoubi H, Zhang W, Marotti V, Kambale EK, Vints K, Sliwinska MA, Leclercq IA, Beloqui A. Effects of semaglutide-loaded lipid nanocapsules on metabolic dysfunction-associated steatotic liver disease. Drug Deliv Transl Res 2024; 14:2917-2929. [PMID: 38615156 PMCID: PMC11385015 DOI: 10.1007/s13346-024-01576-z] [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] [Accepted: 03/11/2024] [Indexed: 04/15/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease that can progress to end-stage conditions with life-threatening complications, but no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNC) are very versatile platforms that are easy to produce and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being studied in clinical trials in the context of MASLD. Our nanosystem provides with increased levels of the native GLP-1 and increased plasmatic absorption of the encapsulated GLP-1 analog (semaglutide). Our goal was to use our strategy to demonstrate a better outcome and a greater impact on the metabolic syndrome associated with MASLD and on liver disease progression with our strategy compared with the oral marketed version of semaglutide, Rybelsus®. Therefore, we studied the effect of our nanocarriers on a dietary mouse model of MASLD, the Western diet model, during a daily chronic treatment of 4 weeks. Overall, the results showed a positive impact of semaglutide-loaded lipid nanocapsules towards the normalization of glucose homeostasis and insulin resistance. In the liver, there were no significant changes in lipid accumulation, but an improvement in markers related to inflammation was observed. Overall, our strategy had a positive trend on the metabolic syndrome and at reducing inflammation, mitigating the progression of the disease. Oral administration of the nanosystem was more efficient at preventing the progression of the disease to more severe states when compared to the administration of Rybelsus®, as a suspension.
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Affiliation(s)
- Inês Domingues
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200, Brussels, Belgium
| | - Hafsa Yagoubi
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200, Brussels, Belgium
| | - Wunan Zhang
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200, Brussels, Belgium
| | - Valentina Marotti
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200, Brussels, Belgium
| | - Espoir K Kambale
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200, Brussels, Belgium
| | - Katlijn Vints
- EM-platform, VIB Bio Imaging Core, KU Leuven, Campus Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium
| | | | - Isabelle A Leclercq
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research, Laboratory of Hepato-Gastroenterology, Avenue Emmanuel Mounier 53, 1200, Brussels, Belgium.
| | - Ana Beloqui
- UCLouvain, Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials Group, Avenue Emmanuel Mounier 73, 1200, Brussels, Belgium.
- WEL Research Institute, WELBIO Department, Avenue Pasteur, 6, 1300, Wavre, Belgium.
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10
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Tsai SF, Hsu PL, Yeh MC, Hung HC, Shih MMC, Chung BC, Wang CY, Chang CJ, Kuo YM. High-fat diet-induced increase in glucocorticoids contributes to adipogenesis in obese mice. Biomed J 2024:100772. [PMID: 39048079 DOI: 10.1016/j.bj.2024.100772] [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: 02/20/2024] [Revised: 07/02/2024] [Accepted: 07/21/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND This study was designed to examine how glucocorticoids (GCs) induced by a long-term ingestion of high-fat diet (HFD) mediate the HFD-induced adipose expansion and obesity. MATERIAL AND METHODS To address this goal, we used a unique L/L mouse model that fails to induce its corticosterone (CORT) level, a major type of GCs in rodents, after prolonged exposure to an HFD. RESULTS We found that, after receiving a 12-week HFD feeding, the L/L mice show less weight gain, milder adipose expansion, and higher plasma levels of triglycerides than the wild-type mice. These changes were reversed by replenishing CORT to L/L mice. When examining the expression levels of various molecules linked to lipid uptake and de novo lipogenesis in CORT-induced adipose expansion, we observed a reduction in the expression of adipose preadipocyte factor 1 (Pref-1), a key regulator in adipogenesis. In 3T3-L1 preadipocyte-like cells, dexamethasone, an agonist of the glucocorticoid receptor, also reduced expressions of Pref-1 and facilitated intracellular accumulation of lipids. CONCLUSIONS Our results suggest that fat ingestion-induced release of CORT contributes to adipose expansion and development of obesity and highlight the pathogenic role of CORT-mediated downregulation of adipose Pref-1 in diet-induced obesity.
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Affiliation(s)
- Sheng-Feng Tsai
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Pei-Ling Hsu
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807378, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Mei-Chen Yeh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, 710402, Taiwan
| | - Hao-Chang Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, 710402, Taiwan
| | - Monica Meng-Chun Shih
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, 115021, Taiwan
| | - Bon-Chu Chung
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei, 115021, Taiwan; Graduate Institute of Biomedical Sciences, Neuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan
| | - Chia-Yih Wang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan
| | - Chih-Jen Chang
- Department of Family Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600566, Taiwan.
| | - Yu-Min Kuo
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701401, Taiwan.
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11
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Rosen N, Mukherjee R, Pancholi P, Sharma M, Solomon H, Timaul M, Thant C, McGriskin R, Hayatt O, Markov V, D'Allara J, Bekker S, Candelier J, Carrasco S, de Stanchina E, Vanaja K. Diet induced insulin resistance is due to induction of PTEN expression. RESEARCH SQUARE 2024:rs.3.rs-4021885. [PMID: 38978604 PMCID: PMC11230483 DOI: 10.21203/rs.3.rs-4021885/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Type 2 Diabetes (T2D) is a condition that is often associated with obesity and defined by reduced sensitivity of PI3K signaling to insulin (insulin resistance), hyperinsulinemia and hyperglycemia. Molecular causes and early signaling events underlying insulin resistance are not well understood. Insulin activation of PI3K signaling causes mTOR dependent induction of PTEN translation, a negative regulator of PI3K signaling. We speculated that insulin resistance is due to insulin dependent induction of PTEN protein that prevent further increases in PI3K signaling. Here we show that in a diet induced model of obesity and insulin resistance, PTEN levels are increased in fat, muscle and liver tissues. Onset of hyperinsulinemia and PTEN induction in tissue is followed by hyperglycemia, hepatic steatosis and severe glucose intolerance. Treatment with a PTEN phosphatase inhibitor prevents and reverses these phenotypes, whereas an mTORC1 kinase inhibitor reverses all but the hepatic steatosis. These data suggest that induction of PTEN by increasing levels of insulin elevates feedback inhibition of the pathway to a point where downstream PI3K signaling is reduced and hyperglycemia ensues. PTEN induction is thus necessary for insulin resistance and the type 2 diabetes phenotype and a potential therapeutic target.
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12
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Sun S, Zhang R, Chen Y, Xu Y, Li X, Liu C, Chen G, Wei X. E4bp4-Cyp3a11 axis in high-fat diet-induced obese mice with weight fluctuation. Nutr Metab (Lond) 2024; 21:30. [PMID: 38802929 PMCID: PMC11131204 DOI: 10.1186/s12986-024-00803-1] [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: 01/01/2024] [Accepted: 05/01/2024] [Indexed: 05/29/2024] Open
Abstract
OBJECTIVE Weight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss. METHODS The male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot. RESULTS After 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups. CONCLUSION Obese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.
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Affiliation(s)
- Shuoshuo Sun
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China
| | - Ruixiang Zhang
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China
| | - Yu Chen
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China
| | - Yijiao Xu
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China
| | - Xingjia Li
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China
| | - Chao Liu
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China
| | - Guofang Chen
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China.
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China.
| | - Xiao Wei
- Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China.
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13
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Hayashi H, Sawada K, Tanaka H, Muro K, Hasebe T, Nakajima S, Okumura T, Fujiya M. The effect of heat-killed Lactobacillus brevis SBL88 on improving selective hepatic insulin resistance in non-alcoholic fatty liver disease mice without altering the gut microbiota. J Gastroenterol Hepatol 2023; 38:1847-1854. [PMID: 37646384 DOI: 10.1111/jgh.16337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND AND AIM There have been several reports that some probiotics improve non-alcoholic fatty liver disease (NAFLD); however, many studies have involved cocktail therapies. We evaluated whether heat-killed Lactobacillus brevis SBL88 (L. brevis SBL88) monotherapy improves the clinical features of NAFLD. METHODS The NAFLD model was induced in mice fed a high-fat diet (HFD) (HFD mice) or HFD + 1% heat-killed L. brevis SBL88 (SBL mice) for 16 weeks. Histopathological liver findings were analyzed. To evaluate the gut microbiota, a modified terminal restriction fragment length polymorphism analysis of the feces was performed. RNA sequencing in the liver was performed with Ion Proton™. To investigate the direct effects of heat-killed L. brevis SBL88, an in vitro study was performed. RESULTS Histopathological findings revealed that fat droplets in the liver were significantly reduced in SBL mice; however, terminal restriction fragment length polymorphism did not show alterations in the gut microbiota between HFD mice and SBL mice. RNA sequencing and pathway analysis revealed that the regulation of lipid and insulin metabolism was affected. The mRNA expression of insulin receptor substrate 2 (IRS-2) was significantly higher in SBL mice, whereas the expression of IRS-1 was not significantly different. Phospho-IRS-2 expression was also significantly increased in SBL mice. In addition, an in vitro study revealed significant alterations in IRS-2 and forkhead box protein O1 expression levels. CONCLUSION SBL mice exhibited partially improved selective hepatic insulin resistance. Our data suggest that heat-killed L. brevis SBL88 could attenuate the clinical features of NAFLD that are not mediated by alterations in the gut microbiota.
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Affiliation(s)
- Hidemi Hayashi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Koji Sawada
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hiroki Tanaka
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Kazuki Muro
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Takumu Hasebe
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Shunsuke Nakajima
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Mikihiro Fujiya
- Gastroenterology and Endoscopy, Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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14
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Wu M, Lo TH, Li L, Sun J, Deng C, Chan KY, Li X, Yeh STY, Lee JTH, Lui PPY, Xu A, Wong CM. Amelioration of non-alcoholic fatty liver disease by targeting adhesion G protein-coupled receptor F1 ( Adgrf1). eLife 2023; 12:e85131. [PMID: 37580962 PMCID: PMC10427146 DOI: 10.7554/elife.85131] [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: 11/23/2022] [Accepted: 07/28/2023] [Indexed: 08/16/2023] Open
Abstract
Background Recent research has shown that the adhesion G protein-coupled receptor F1 (Adgrf1; also known as GPR110; PGR19; KPG_012; hGPCR36) is an oncogene. The evidence is mainly based on high expression of Adgrf1 in numerous cancer types, and knockdown Adgrf1 can reduce the cell migration, invasion, and proliferation. Adgrf1 is, however, mostly expressed in the liver of healthy individuals. The function of Adgrf1 in liver has not been revealed. Interestingly, expression level of hepatic Adgrf1 is dramatically decreased in obese subjects. Here, the research examined whether Adgrf1 has a role in liver metabolism. Methods We used recombinant adeno-associated virus-mediated gene delivery system, and antisense oligonucleotide was used to manipulate the hepatic Adgrf1 expression level in diet-induced obese mice to investigate the role of Adgrf1 in hepatic steatosis. The clinical relevance was examined using transcriptome profiling and archived biopsy specimens of liver tissues from non-alcoholic fatty liver disease (NAFLD) patients with different degree of fatty liver. Results The expression of Adgrf1 in the liver was directly correlated to fat content in the livers of both obese mice and NAFLD patients. Stearoyl-coA desaturase 1 (Scd1), a crucial enzyme in hepatic de novo lipogenesis, was identified as a downstream target of Adgrf1 by RNA-sequencing analysis. Treatment with the liver-specific Scd1 inhibitor MK8245 and specific shRNAs against Scd1 in primary hepatocytes improved the hepatic steatosis of Adgrf1-overexpressing mice and lipid profile of hepatocytes, respectively. Conclusions These results indicate Adgrf1 regulates hepatic lipid metabolism through controlling the expression of Scd1. Downregulation of Adgrf1 expression can potentially serve as a protective mechanism to stop the overaccumulation of fat in the liver in obese subjects. Overall, the above findings not only reveal a new mechanism regulating the progression of NAFLD, but also proposed a novel therapeutic approach to combat NAFLD by targeting Adgrf1. Funding This work was supported by the National Natural Science Foundation of China (81870586), Area of Excellence (AoE/M-707/18), and General Research Fund (15101520) to CMW, and the National Natural Science Foundation of China (82270941, 81974117) to SJ.
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Affiliation(s)
- Mengyao Wu
- Department of Chemistry and Chemical Engineering, Guangzhou UniversityGuangzhouChina
| | - Tak-Ho Lo
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | - Liping Li
- Zhujiang Hospital, Southern Medical UniversityChinaChina
| | - Jia Sun
- Zhujiang Hospital, Southern Medical UniversityChinaChina
| | - Chujun Deng
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | - Ka-Ying Chan
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | - Xiang Li
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
| | | | - Jimmy Tsz Hang Lee
- Department of Medicine, University of Hong KongHong KongHong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong KongHong KongChina
| | - Pauline Po Yee Lui
- Department of Orthopaedics and Traumatology, Chinese University of Hong KongHong KongHong Kong
| | - Aimin Xu
- Department of Medicine, University of Hong KongHong KongHong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong KongHong KongChina
| | - Chi-Ming Wong
- Department of Health Technology and Informatics, Hong Kong Polytechnic UniversityHong KongHong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong KongHong KongChina
- Hong Kong Polytechnic University, Shenzhen Research InstituteHong KongChina
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15
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Yang J, Zuo J, Deng Y, Zhang L, Yu H, Zhang C, Li Z, Li H. Antidiabetic activity of Tartary buckwheat protein-derived peptide AFYRW and its effects on protein glycosylation of pancreas in mice. Amino Acids 2023; 55:1063-1071. [PMID: 37341830 DOI: 10.1007/s00726-023-03294-1] [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: 03/13/2023] [Accepted: 06/11/2023] [Indexed: 06/22/2023]
Abstract
Diabetes Mellitus (DM) is one of the most important public health problems, and new antidiabetic drugs with fewer side effects are urgently needed. Here, we measured the antidiabetic effects of an antioxidant peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) from Tartary Buckwheat Albumin (TBA) in a high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mouse model. The data showed that AFYRW suppressed hepatocyte steatosis and triglycerides while ameliorating insulin resistance in mice. Successively, the influence of AFYRW on aberrant protein glycosylation in diabetic mice was further investigated by lectin microarrays. The results suggested AFYRW could restore the expression of GalNAc, GalNAcα1-3Gal and GalNAcα1-3Galβ1-3/4Glc recognized by PTL-I, Siaα2-3Galβ1-4Glc(NAc)/Glc, Siaα2-3Gal, Siaα2-3 and Siaα2-3GalNAc recognized by MAL-II, terminating in GalNAcα/β1-3/6Gal recognized by WFA and αGalNAc, αGal, anti-A and B recognized by GSI-I to normal levels in the pancreas of HFD-STZ-induced diabetic mice. This work may provide new targets for the future discovery of potential biomarkers to evaluate the efficacy of food-derived antidiabetic drugs based on precise alterations of glycopatterns in DM.
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Affiliation(s)
- Jiajun Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, People's Republic of China
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China
| | - Jie Zuo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, People's Republic of China
| | - Yan Deng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, People's Republic of China
| | - Lilin Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, People's Republic of China
| | - Hanjie Yu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, People's Republic of China
| | - Chen Zhang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, People's Republic of China
| | - Zheng Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, People's Republic of China.
| | - Hongmei Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, People's Republic of China.
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China.
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16
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Ding Y, Dai X, Bao M, Xing Y, Liu J, Zhao S, Liu E, Yuan Z, Bai L. Hepatic transcriptome signatures in mice and humans with nonalcoholic fatty liver disease. Animal Model Exp Med 2023; 6:317-328. [PMID: 37565549 PMCID: PMC10486336 DOI: 10.1002/ame2.12338] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/12/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is the main reason for cirrhosis and hepatocellular carcinoma. As a starting point for NAFLD, the treatment of nonalcoholic fatty liver (NAFL) is receiving increasing attention. Mice fed a high-fat diet (HFD) and hereditary leptin deficiency (ob/ob) mice are important NAFL animal models. However, the comparison of these mouse models with human NAFL is still unclear. METHODS In this study, HFD-fed mice and ob/ob mice were used as NAFL animal models. Liver histopathological characteristics were compared, and liver transcriptome from both mouse models was performed using RNA sequencing (RNA-seq). RNA-seq data obtained from the livers of NAFL patients was downloaded from the GEO database. Global gene expression profiles in the livers were further analyzed using functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. RESULTS Our results showed that the biochemical parameters of both mouse models and human NAFL were similar. Compared with HFD-fed mice, ob/ob mice were more similar in histologic appearance to NAFL patients. The liver transcriptome characteristics partly overlapped in mice and humans. Furthermore, in the NAFL pathway, most genes showed similar trends in mice and humans, thus demonstrating that both types of mice can be used as models for basic research on NAFL, considering the differences. CONCLUSION Our findings show that HFD-fed mice and ob/ob mice can mimic human NAFL partly in pathophysiological process. The comparative analysis of liver transcriptome profile in mouse models and human NAFL presented here provides insights into the molecular characteristics across these NAFL models.
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Affiliation(s)
- Yiming Ding
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Department of CardiologyFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Xulei Dai
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Miaoye Bao
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Yuanming Xing
- Department of CardiologyFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Junhui Liu
- Department of Clinical LaboratoryFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Sihai Zhao
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Enqi Liu
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
| | - Zuyi Yuan
- Department of CardiologyFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Liang Bai
- Department of Laboratory Animal Science, School of Basic Medical SciencesXi'an Jiaotong University Health Science CenterXi'anChina
- Institute of Cardiovascular Science, Translational Medicine InstituteXi'an Jiaotong University Health Science CenterXi'anChina
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17
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Nehme J, Altulea A, Gheorghe T, Demaria M. The effects of macronutrients metabolism on cellular and organismal aging. Biomed J 2023; 46:100585. [PMID: 36801257 PMCID: PMC10209809 DOI: 10.1016/j.bj.2023.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/08/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
Evidence supports the notion that metabolic pathways are major regulators of organismal aging, and that metabolic perturbations can extend health- and lifespan. For this reason, dietary interventions and compounds perturbing metabolism are currently explored as anti-aging strategies. A common target for metabolic interventions delaying aging is cellular senescence, a state of stable growth arrest that is accompanied by various structural and functional changes including the activation of a pro-inflammatory secretome. Here, we summarize the current knowledge on the molecular and cellular events associated with carbohydrate, lipid and protein metabolism, and define how macronutrients can regulate induction or prevention of cellular senescence. We discuss how various dietary interventions can achieve prevention of disease and extension of healthy longevity by partially modulating senescence-associated phenotypes. We also emphasize the importance of developing personalized nutritional interventions that take into account the current health and age status of the individual.
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Affiliation(s)
- Jamil Nehme
- University of Groningen, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), Groningen, Netherlands
| | - Abdullah Altulea
- University of Groningen, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), Groningen, Netherlands
| | - Teodora Gheorghe
- University of Groningen, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), Groningen, Netherlands
| | - Marco Demaria
- University of Groningen, European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), Groningen, Netherlands.
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18
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Dauwe Y, Mary L, Oliviero F, Grimaldi M, Balaguer P, Gayrard V, Mselli-Lakhal L. Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides. Cells 2023; 12:cells12081201. [PMID: 37190111 DOI: 10.3390/cells12081201] [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: 02/17/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation results in metabolic disorders, including non-alcoholic fatty liver disease, by activating lipogenesis in the liver. Our objective was to determine whether synergistic activations of the CAR/RXR heterodimer could occur in vivo as described in vitro by other authors, and to assess the metabolic consequences. For this purpose, six pesticides, ligands of CAR, were selected, and Tri-butyl-tin (TBT) was used as an RXR agonist. In mice, CAR's synergic activation was induced by dieldrin associated with TBT, and combined effects were induced by propiconazole, bifenox, boscalid, and bupirimate. Moreover, a steatosis, characterized by increased triglycerides, was observed when TBT was combined with dieldrin, propiconazole, bifenox, boscalid, and bupirimate. Metabolic disruption appeared in the form of increased cholesterol and lowered free fatty acid plasma levels. An in-depth analysis revealed increased expression of genes involved in lipid synthesis and lipid import. These results contribute to the growing understanding of how environmental contaminants can influence nuclear receptor activity and associated health risks.
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Affiliation(s)
- Yannick Dauwe
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Lucile Mary
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Fabiana Oliviero
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Marina Grimaldi
- Institut de Recherche en Cancérologie de Montpellier, Inserm U1194-Université Montpellier-Institut régional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France
| | - Patrick Balaguer
- Institut de Recherche en Cancérologie de Montpellier, Inserm U1194-Université Montpellier-Institut régional du Cancer Montpellier, CEDEX 5, F-34298 Montpellier, France
| | - Véronique Gayrard
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
| | - Laïla Mselli-Lakhal
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France
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19
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Karimkhanloo H, Keenan SN, Bayliss J, De Nardo W, Miotto PM, Devereux CJ, Nie S, Williamson NA, Ryan A, Watt MJ, Montgomery MK. Mouse strain-dependent variation in metabolic associated fatty liver disease (MAFLD): a comprehensive resource tool for pre-clinical studies. Sci Rep 2023; 13:4711. [PMID: 36949095 PMCID: PMC10033881 DOI: 10.1038/s41598-023-32037-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 03/21/2023] [Indexed: 03/24/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH), characterized as the joint presence of steatosis, hepatocellular ballooning and lobular inflammation, and liver fibrosis are strong contributors to liver-related and overall mortality. Despite the high global prevalence of NASH and the substantial healthcare burden, there are currently no FDA-approved therapies for preventing or reversing NASH and/or liver fibrosis. Importantly, despite nearly 200 pharmacotherapies in different phases of pre-clinical and clinical assessment, most therapeutic approaches that succeed from pre-clinical rodent models to the clinical stage fail in subsequent Phase I-III trials. In this respect, one major weakness is the lack of adequate mouse models of NASH that also show metabolic comorbidities commonly observed in NASH patients, including obesity, type 2 diabetes and dyslipidaemia. This study provides an in-depth comparison of NASH pathology and deep metabolic profiling in eight common inbred mouse strains (A/J, BALB/c, C3H/HeJ, C57BL/6J, CBA/CaH, DBA/2J, FVB/N and NOD/ShiLtJ) fed a western-style diet enriched in fat, sucrose, fructose and cholesterol for eight months. Combined analysis of histopathology and hepatic lipid metabolism, as well as measures of obesity, glycaemic control and insulin sensitivity, dyslipidaemia, adipose tissue lipolysis, systemic inflammation and whole-body energy metabolism points to the FVB/N mouse strain as the most adequate diet-induced mouse model for the recapitulation of metabolic (dysfunction) associated fatty liver disease (MAFLD) and NASH. With efforts in the pharmaceutical industry now focussed on developing multi-faceted therapies; that is, therapies that improve NASH and/or liver fibrosis, and concomitantly treat other metabolic comorbidities, this mouse model is ideally suited for such pre-clinical use.
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Affiliation(s)
- Hamzeh Karimkhanloo
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia
- Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, and Department of Physiology, Monash University, Clayton, VIC, Australia
| | - Stacey N Keenan
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Jacqueline Bayliss
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - William De Nardo
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Paula M Miotto
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Camille J Devereux
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Shuai Nie
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia
| | - Nicholas A Williamson
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, Australia
| | - Andrew Ryan
- TissuPath, Mount Waverley, VIC, 3149, Australia
| | - Matthew J Watt
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
| | - Magdalene K Montgomery
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, 3010, Australia.
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20
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Polysaccharides from Ostrea rivularis rebuild the balance of gut microbiota to ameliorate non-alcoholic fatty liver disease in ApoE -/- mice. Int J Biol Macromol 2023; 235:123853. [PMID: 36863676 DOI: 10.1016/j.ijbiomac.2023.123853] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 02/10/2023] [Accepted: 02/23/2023] [Indexed: 03/02/2023]
Abstract
The purpose of this study was to investigate the preventive effects of polysaccharide from Ostrea rivularis (ORP) on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in mice and the underlying mechanism. The results showed that NAFLD model group mice had significant fatty liver lesions. ORP could significantly reduce TC, TG and LDL level, and increase HDL level in serum of HFD mice. Besides, it could also reduce the contents of serum AST and ALT and alleviate pathological changes of fatty liver disease. ORP could also enhance the intestinal barrier function. 16sRNA analysis showed that ORP could reduce the abundance of Firmicutes and Proteobacteria and the ratio of Firmicutes/ Bacteroidetes at the phylum level. These results suggested that ORP could regulate the composition of gut microbiota in NAFLD mice, enhance intestinal barrier function, reduce intestinal permeability, and finally delay the progress and reduce the occurrence of NAFLD. In brief, ORP is an ideal polysaccharide for prevention and treatment of NAFLD, which can be developed as functional food or candidate drugs.
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21
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Reolizo L, Matsuda M, Seki E. Experimental Workflow for Preclinical Studies of Human Antifibrotic Therapies. Methods Mol Biol 2023; 2669:285-306. [PMID: 37247068 DOI: 10.1007/978-1-0716-3207-9_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Chronic liver diseases accompanied by liver fibrosis have caused significant morbidity and mortality in the world with increasing prevalence. Nonetheless, there are no approved antifibrotic therapies. Although numerous preclinical studies showed satisfactory results in targeting fibrotic pathways, these animal studies have not led to success in humans. In this chapter, we summarize the experimental approaches currently available, including in vitro cell culture models, in vivo animal models, and new experimental tools relevant to humans, and discuss how we translate laboratory results to clinical trials. We will also address the obstacles in transitioning promising therapies from preclinical studies to human antifibrotic treatments.
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Affiliation(s)
- Lien Reolizo
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michitaka Matsuda
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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22
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Salvia plebeia R. Br. Water Extract Ameliorates Hepatic Steatosis in a Non-Alcoholic Fatty Liver Disease Model by Regulating the AMPK Pathway. Nutrients 2022; 14:nu14245379. [PMID: 36558538 PMCID: PMC9780835 DOI: 10.3390/nu14245379] [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: 11/09/2022] [Revised: 12/07/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Salvia plebeia R. Br. (SP), grown from autumn to spring, is used as a medicinal herb from roots to leaves. This herb exhibits antioxidant activities and various physiological effect, including anti-asthma, immune-promoting, anti-obesity, and anti-cholesterol effects. However, the effectiveness of SP against non-alcoholic fatty liver disease (NAFLD) and the associated mechanism have not been elucidated. In this study, alleviation of NAFLD by SP was confirmed in a mouse model of hepatic steatosis induced by a high-fat diet and in HepG2 cells administered free fatty acids (FFA). In the experimental model, intrahepatic lipid accumulation was investigated using the AdipoRedTM assay, Oil Red O staining, biomarker analysis, and hematoxylin and eosin staining. Furthermore, glucose tolerance was examined based on the fasting glucose levels and oral glucose tolerance. The molecular mechanisms related to hepatic steatosis were determined based on marker mRNA levels. Blood FFAs were found to flow into the liver via the action of fatty acid translocase, cluster of differentiation 36, and fatty acid transporter proteins 2 and 5. Salvia plebeia R. Br. water extract (SPW) suppressed the FFAs inflow by regulating the expression of the above-mentioned proteins. Notably, modulating the expression of AMP-activated protein kinase (AMPK) and liver X receptor, which are involved in the regulation of lipid metabolism, stimulated peroxisome proliferator activated receptor α in the nucleus to induce the expression genes involved in β-oxidation and increase β-oxidation in the mitochondria. AMPK modulation also increased the expression of sterol regulatory element binding protein-1c, which activated lipid synthesis enzymes. As a consequence of these events, triglyceride synthesis was reduced and lipid accumulation in hepatocytes was alleviated. Overall, our findings suggested that SPW could ameliorate NAFLD by inhibiting hepatic steatosis through AMPK modulation.
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23
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Onyango AN. Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae. Heliyon 2022; 8:e12294. [PMID: 36582692 PMCID: PMC9792795 DOI: 10.1016/j.heliyon.2022.e12294] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/18/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Background Hepatic insulin signaling suppresses gluconeogenesis but promotes de novo lipid synthesis. Paradoxically, hepatic insulin resistance (HIR) enhances both gluconeogenesis and de novo lipid synthesis. Elucidation of the etiology of this paradox, which participates in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, the metabolic syndrome and hepatocellular carcinoma, has not been fully achieved. Scope of review This article briefly outlines the previously proposed hypotheses on the etiology of the HIR paradox. It then discusses literature consistent with an alternative hypothesis that excessive gluconeogenesis, the direct effect of HIR, is responsible for the aberrant lipogenesis. The mechanisms involved therein are explained, involving de novo synthesis of fructose and uric acid, promotion of glutamine anaplerosis, and induction of glucagon resistance. Thus, gluconeogenesis via lipogenesis promotes hepatic steatosis, a component of NAFLD, and dyslipidemia. Gluconeogenesis-centred mechanisms for the progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis are suggested. That NAFLD often precedes and predicts type 2 diabetes is explained by the ability of lipogenesis to cushion against blood glucose dysregulation in the earlier stages of NAFLD. Major conclusions HIR-induced excessive gluconeogenesis is a major cause of the HIR paradox and its sequelae. Such involvement of gluconeogenesis in lipid synthesis rationalizes the fact that several types of antidiabetic drugs ameliorate NAFLD. Thus, dietary, lifestyle and pharmacological targeting of HIR and hepatic gluconeogenesis may be a most viable approach for the prevention and management of the HIR-associated network of diseases.
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24
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Tukhovskaya EA, Shaykhutdinova ER, Pakhomova IA, Slashcheva GA, Goryacheva NA, Sadovnikova ES, Rasskazova EA, Kazakov VA, Dyachenko IA, Frolova AA, Brovkin AN, Kaluzhsky VE, Beburov MY, Murashev AN. AICAR Improves Outcomes of Metabolic Syndrome and Type 2 Diabetes Induced by High-Fat Diet in C57Bl/6 Male Mice. Int J Mol Sci 2022; 23:ijms232415719. [PMID: 36555360 PMCID: PMC9778872 DOI: 10.3390/ijms232415719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/16/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
The aim of the study was to investigate the effect of AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on the consequences of metabolic syndrome and type 2 diabetes induced by the consumption of a high-fat diet (HFD) in male C57Bl/6 mice. Additionally, the animals from group 6 were administered Methotrexate (MTX) at a dose of 1 mg/kg in parallel with AICAR, which slows down the metabolism of AICAR. The animals were recorded with signs of metabolic syndrome and type 2 diabetes mellitus by recording their body weights, glucose and insulin levels, and the calculating HOMA-IRs. At the end of the study, at the end of the 13th week, during necropsy, the internal organs were assessed, the masses of the organs were recorded, and special attention was paid to visceral fat, assessing its amount and the mass of the fat surrounding epididymis. The biochemical parameters and histology of the internal organs and tissues were assessed. The animals showed signs of metabolic syndrome and type 2 diabetes, namely, weight gain, hyperglycemia, hyperinsulinemia, an increase in the amount and mass of abdominal fat, and metabolic disorders, all expressed in a pathological change in biochemical parameters and pathological changes in internal organs. The AICAR treatment led to a decrease in body weight, a decrease in the amount and mass of abdominal fat, and an improvement in the pathomorphological picture of internal organs. However, some hepatotoxic effects were observed when the animals, on a received standard diet (STD), were treated with AICAR starting from the first day of the study. The additional administration of MTX, an AICAR metabolic inhibitor, did not improve its efficacy. Thus, AICAR has therapeutic potential for the treatment of metabolic syndrome and type 2 diabetes.
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Affiliation(s)
- Elena A. Tukhovskaya
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
- Correspondence:
| | - Elvira R. Shaykhutdinova
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Irina A. Pakhomova
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Gulsara A. Slashcheva
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Natalya A. Goryacheva
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Elena S. Sadovnikova
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Ekaterina A. Rasskazova
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Vitaly A. Kazakov
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Igor A. Dyachenko
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
| | - Alina A. Frolova
- LLC “OKA-BIOTECH”, Novatorov St., d. 34, bldg. 7, apt. 42, 119421 Moscow, Russia
| | - Alexey N. Brovkin
- LLC “OKA-BIOTECH”, Novatorov St., d. 34, bldg. 7, apt. 42, 119421 Moscow, Russia
| | - Vasiliy E. Kaluzhsky
- LLC “OKA-BIOTECH”, Novatorov St., d. 34, bldg. 7, apt. 42, 119421 Moscow, Russia
| | - Mikhail Yu. Beburov
- LLC “OKA-BIOTECH”, Novatorov St., d. 34, bldg. 7, apt. 42, 119421 Moscow, Russia
| | - Arkady N. Murashev
- Biological Testing Laboratory, Branch of Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, 142290 Moscow, Russia
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25
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Ruan L, Wang G, Qing Lv Z, Li S, Liu Q, Ren Y, Zhang Q, Lv X, Wu R, Ji Z. The effect of varied exercise intensity on antioxidant function, aortic endothelial function, and serum lipids in rats with non-alcoholic fatty liver disease. INVESTIGACIÓN CLÍNICA 2022. [DOI: 10.54817/ic.v63n4a01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
This study aimed to compare the effects of diet and exercise of different intensities on antioxidant function, aortic endothelial cell function and serum lipids in NAFLD (nonalcoholic fatty liver disease) rats. Fifty Sprague-Dawley (SD) rats (180-220g) were randomly divided into two experimental groups and fed either a standard rodent chow diet (CON; n=10) or a high-fat diet (HFD; n=40). After 16 weeks, the animals that received the HFD were randomly separated into a high-fat control group (HFC; n=10) or three ex-ercise training groups: HFD and low-intensity exercise (LE; n=10), HFD and moderate-intensity exercise (ME; n=10), and HFD and incremental intensity exercise (IE; n=10). These experimental rats keep sedentary or trained for the next six weeks. A detection kit was used to detect nitric oxide synthase (NOs), nitric oxide (NO), malondialdehyde (MDA) and other markers of aor-tic oxidative stress. The expression levels of endothelial nitric oxide synthase (e-NOS) and endothelin-1 (ET-1) were detected by immunohistochemistry. TC, TG, and other lipid metabolism parameters were detected by an auto-matic analyzer. Exercise with different intensities could improve lipid me-tabolism, enhance antioxidant function, reduce MDA (P<0.01), increase NO (P<0.01), and improve the expression of e-NOS and ET-1 (P<0.01) protein levels in NAFLD rats. Decreased blood lipids were exhibited in all exercise groups. Notably, the moderate-intensity exercise demonstrated more effecton increasing glutathione (GSH) contents (P<0.01) and decreased the ex-pression of ET-1protein levels (P<0.01). The results showed that exercise at different intensities improved lipid metabolism and enhanced anti-oxidation function. Moderate exercise could improve the function of aortic endothelial cells.
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Affiliation(s)
- Ling Ruan
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Guanghua Wang
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Zhen Qing Lv
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Shoubang Li
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Qin Liu
- College of Physical Education, Ankang University, Ankang, Shaanxi, China
| | - Yiling Ren
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Quancheng Zhang
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Xianli Lv
- College of Physical Education, Ankang University, Ankang, Shaanxi, China
| | - Rongping Wu
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
| | - Zhan Ji
- Department of Physical Education, Xi’an Shiyou University, Xi’an, Shaanxi, China
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Kim MY, Lee SJ, Randolph G, Han YH. Lubiprostone significantly represses fatty liver diseases via induction of mucin and HDL release in mice. Life Sci 2022; 311:121176. [PMID: 36372211 DOI: 10.1016/j.lfs.2022.121176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/31/2022] [Accepted: 11/07/2022] [Indexed: 11/11/2022]
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Trifylli EM, Kriebardis AG, Koustas E, Papadopoulos N, Deutsch M, Aloizos G, Fortis SP, Papageorgiou EG, Tsagarakis A, Manolakopoulos S. The Emerging Role of Extracellular Vesicles and Autophagy Machinery in NASH-Future Horizons in NASH Management. Int J Mol Sci 2022; 23:12185. [PMID: 36293042 PMCID: PMC9603426 DOI: 10.3390/ijms232012185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 09/30/2022] [Accepted: 10/06/2022] [Indexed: 11/17/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the most frequent chronic hepatic disease in the general population, while it is the first cause of liver transplantation in the US. NAFLD patients will subsequently develop non-alcoholic steatohepatitis (NASH), which is characterized by aberrant hepatocellular inflammation with or without the presence of fibrosis. The lack of specific biomarkers and therapeutic strategies makes non-alcoholic steatohepatitis (NASH) management a difficult task for clinicians. Extracellular vesicles (EVs) constitute a heterogenic population of vesicles produced by inward or outward plasma-membrane budding. There is an emerging connection between autophagy EVs production, via an unconventional non-degradative procedure. Alterations in the amount of the secreted EVs and the cargo they carry are also involved in the disease progression and development of NASH. Autophagy constitutes a multistep lysosomal degradative pathway that reassures cell homeostasis and survival under stressful conditions, such as oxygen and energy deprivation. It prevents cellular damage by eliminating defected proteins or nοn-functional intracellular organelles. At the same time, it reassures the optimal conditions for the cells via a different mechanism that includes the removal of cargo via the secretion of EVs. Similarly, autophagy machinery is also associated with the pathogenetic mechanism of NAFLD, while it has a significant implication for the progression of the disease and the development of NASH. In this review, we will shed light on the interplay between autophagy and EVs in NASH, the emerging connection of EVs production with the autophagy pathway, and their possible manipulation for developing future therapeutic strategies for NASH.
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Affiliation(s)
- Eleni-Myrto Trifylli
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Anastasios G. Kriebardis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece
| | - Evangelos Koustas
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Nikolaos Papadopoulos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Melanie Deutsch
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, Leof. Vasilissis Sofias Avenue Str., 11527 Athens, Greece
| | - Georgios Aloizos
- First Department of Internal Medicine, 417 Army Share Fund Hospital, 11521 Athens, Greece
| | - Sotirios P. Fortis
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece
| | - Effie G. Papageorgiou
- Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str., 12243 Egaleo, Greece
| | - Ariadne Tsagarakis
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, Leof. Vasilissis Sofias Avenue Str., 11527 Athens, Greece
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Yang MH, Li WY, Wu CF, Lee YC, Chen AYN, Tyan YC, Chen YMA. Reversal of High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Metformin Combined with PGG, an Inducer of Glycine N-Methyltransferase. Int J Mol Sci 2022; 23:ijms231710072. [PMID: 36077467 PMCID: PMC9456083 DOI: 10.3390/ijms231710072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidities and mortality, and no effective drug treatment currently exists. We aimed to develop a novel treatment strategy to induce the expression of glycine N-methyltransferase (GNMT), which is an important enzyme regulating S-adenosylmethionine metabolism whose expression is downregulated in patients with NAFLD. Because 1,2,3,4,6-pentagalloyl glucose (PGG) is a GNMT inducer, and metformin was shown to upregulate liver mitochondrial GNMT protein expression, the effect of PGG and metformin was evaluated. Biochemical analysis, histopathological examination, immunohistochemical staining, reverse transcription-quantitative PCR (RT-qPCR), Western blotting (WB), proteomic analysis and Seahorse XF Cell Mito Stress Test were performed. The high-fat diet (HFD)-induced NAFLD mice were treated with PGG and metformin. Combination of PGG and metformin nearly completely reversed weight gain, elevation of serum aminotransferases, and hepatic steatosis and steatohepatitis. In addition, the downregulated GNMT expression in liver tissues of HFD-induced NAFLD mice was restored. The GNMT expression was further confirmed by RT-qPCR and WB analysis using both in vitro and in vivo systems. In addition, PGG treatment was shown to increase oxygen consumption rate (OCR) maximum capacity in a dose-dependent manner, and was capable of rescuing the suppression of mitochondrial OCR induced by metformin. Proteomic analysis identified increased expression of glutathione S-transferase mu 4 (GSTM4), heat shock protein 72 (HSP72), pyruvate carboxylase (PYC) and 40S ribosomal protein S28 (RS28) in the metformin plus PGG treatment group. Our findings show that GNMT expression plays an important role in the pathogenesis of NAFLD, and combination of an inducer of GNMT and metformin can be of therapeutic potential for patients with NAFLD.
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Affiliation(s)
- Ming-Hui Yang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
- Center of General Education, Shu-Zen Junior College of Medicine and Management, Kaohsiung 821, Taiwan
| | - Wei-You Li
- Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Ching-Fen Wu
- Department of Veterinary Medicine, National Chiayi University, Chiayi City 600, Taiwan
| | - Yi-Ching Lee
- Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Allan Yi-Nan Chen
- School of Medicine, University of California, Davis, Sacramento, CA 95817, USA
| | - Yu-Chang Tyan
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 804, Taiwan
- Correspondence: (Y.-C.T.); (Y.-M.A.C.)
| | - Yi-Ming Arthur Chen
- Laboratory of Important Infectious Diseases and Cancer, Graduate Institute of Biomedical and Pharmacological Science, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 350, Taiwan
- Correspondence: (Y.-C.T.); (Y.-M.A.C.)
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Akbari G, Mard SA, Savari F, Barati B, Sameri MJ. Characterization of diet based nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in rodent models: Histological and biochemical outcomes. Histol Histopathol 2022; 37:813-824. [PMID: 35475465 DOI: 10.14670/hh-18-462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), as the most common chronic liver disease, is rapidly increasing worldwide. This complex disorder can include simple liver steatosis to more serious stages of nonalcoholic fibrosis and steatohepatitis (NASH). One of the critical concerns in NASH research is selecting and confiding in relying on preclinical animal models and experimental methods that can accurately reflect the situation in human NASH. Recently, creating nutritional models of NASH with a closer dietary pattern in human has been providing reliable, simple, and reproducible tools that hope to create a better landscape for showing the recapitulation of disease pathophysiology. This review focuses on recent research on rodent models (mice, rats, and hamsters) in the induction of the dietary model of NAFLD /NASH. This research tries to compile the different dietary compositions of NASH, time frames required for disease development, and their impact on liver histological features as well as metabolic parameters.
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Affiliation(s)
- Ghaidafeh Akbari
- Medical Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Seyyed Ali Mard
- Clinical Sciences Research Institute, Alimentary Tract Research Center, Department of Physiology, The school of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Feryal Savari
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran.
| | - Barat Barati
- Department of Radiologic Technology, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran
| | - Maryam J Sameri
- Department of Physiology, The School of Medicine, Ahvaz Jundishpur University of Medical Sciences, Ahvaz, Iran
- Department of Physiology, The School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
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Tan LJ, Shin S. Effects of oily fish and its fatty acid intake on non-alcoholic fatty liver disease development among South Korean adults. Front Nutr 2022; 9:876909. [PMID: 35938102 PMCID: PMC9353947 DOI: 10.3389/fnut.2022.876909] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/28/2022] [Indexed: 12/02/2022] Open
Abstract
Background The benefits of fish fatty acid intake for non-alcoholic fatty liver disease (NAFLD) are rarely reported, although a previous study assessed the relationship between oily fish consumption and the prevalence of NAFLD. Aims We investigated whether oily fish and fish-based monounsaturated fatty acids, polyunsaturated fatty acids, and omega-3 fatty acids affect the development of NAFLD in South Korean adults. Methods In this large-scale cohort study, 44,139 participants of the Health Examinees study were selected for analysis after 5 years of follow-up. NAFLD is diagnosed with a non-invasive index, the fatty liver index. Using multivariable Cox proportional hazards models, adjusted for age, body mass index, total energy intake, education, physical activity, smoking status, and drinking (alcohol) status, we calculated the hazard ratios and 95% confidence intervals. Results For men, NAFLD had no statistically significant associations with quartiles of total oily fish or its fatty acid intake. However, among women, an inverse association was observed (all p for trend <0.05). Regarding the standard deviation (SD) increment of total oily fish or its fatty acid intake by one, all fatty acids from oily fish showed inverse associations for NAFLD in both men and women. After stratified analyses, we found that drinking status and menopause status were independent risk factors for NAFLD. Oily fish or its fatty acid intake has the same benefit pattern on metabolic dysfunction-associated fatty liver disease as NAFLD. Conclusion Oily fish and its fatty acid intake showed a preventative benefit for NAFLD and metabolic dysfunction-associated fatty liver disease, especially in South Korean women.
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31
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Tiedemann K, Muthu ML, Reinhardt DP, Komarova SV. Male Marfan mice are predisposed to high fat diet induced obesity, diabetes, and fatty liver. Am J Physiol Cell Physiol 2022; 323:C354-C366. [PMID: 35759435 DOI: 10.1152/ajpcell.00062.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Gene mutations in the extracellular matrix protein fibrillin-1 cause connective tissue disorders including Marfan syndrome (MFS) with clinical symptoms in the cardiovascular, skeletal, and ocular systems. MFS patients also exhibit alterations in adipose tissues, which in some individuals leads to lipodystrophy, whereas in others to obesity. We have recently demonstrated that fibrillin-1 regulates adipose tissue homeostasis. Here, we examined how fibrillin-1 abnormality affects metabolic adaptation to different diets. We used two MFS mouse models: Hypomorph Fbn1mgR/mgR mice and Fbn1C1041G/+ mice with a fibrillin-1 missense mutation. When Fbn1mgR/mgR mice were fed with high fat diet (HFD) for 12 weeks, male mice were heavier than littermate controls (LC), whereas female mice gained less weight compared to LC. Female Fbn1C1041G/+ mice on a HFD for 24 weeks were similarly protected from weight gain. Male Fbn1C1041G/+ mice on HFD demonstrated higher insulin levels, insulin intolerance, circulating levels of cholesterol and high-density lipoproteins. Moreover, male HFD-fed Fbn1C1041G/+ mice showed a higher liver weight and a fatty liver phenotype, which was reduced to LC levels after orchiectomy. Phosphorylation of protein kinase-like endoplasmic reticulum kinase (PERK) as well as the expression of sterol regulatory element-binding protein 1 (Srebp1) in livers of HFD-fed male Fbn1C1041G/+ mice were elevated. In conclusion, the data demonstrate that male mice of both MFS models are susceptible to HFD-induced obesity and diabetes. Moreover, male Fbn1C1041G/+ mice develop a fatty liver phenotype, likely mediated by a baseline increased endoplasmic reticulum stress. In contrast, female MFS mice were protected from the consequence of HFD.
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Affiliation(s)
- Kerstin Tiedemann
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, Canada.,Shriners Hospital for Children - Canada, Montréal, Canada
| | - Muthu L Muthu
- Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, McGill University, Montréal, Canada
| | - Dieter P Reinhardt
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, Canada.,Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, McGill University, Montréal, Canada
| | - Svetlana V Komarova
- Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montréal, Canada.,Shriners Hospital for Children - Canada, Montréal, Canada
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Narciso L, Martinelli A, Torriani F, Frassanito P, Bernardini R, Chiarotti F, Marianelli C. Natural Mineral Waters and Metabolic Syndrome: Insights From Obese Male and Female C57BL/6 Mice on Caloric Restriction. Front Nutr 2022; 9:886078. [PMID: 35685873 PMCID: PMC9172593 DOI: 10.3389/fnut.2022.886078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/04/2022] [Indexed: 01/01/2023] Open
Abstract
Metabolic syndrome (MetS) represents one of the greatest challenges to public health given its serious consequences on cardiovascular diseases and type 2 diabetes. A carbohydrate-restricted, low-fat diet is the current therapy for MetS. Natural mineral waters (NMWs) are known to exert beneficial effects on human health. Our primary objective was to shed light on the potential therapeutic properties of NMWs in MetS. A total of 125 C57BL/6 male and female mice were included in the study. Of these, 10 were left untreated. They were fed a standard diet with tap water throughout the study period, and stayed healthy. The remaining 115 mice were initially fed a high-calorie diet (HCD) consisting of a high-fat feed (60% of energy from fat) with 10% fructose in tap water, served ad libitum over a period of 4 months to induce MetS (the MetS induction phase). Mice were then randomly divided into six treatment groups and a control group, all of which received a low-calorie diet (LCD), but with a different kind of drinking water, for 2 months (the treatment phase). Five groups were each treated with a different kind of NMW, one group by alternating the five NMWs, and one group – the control group – was given tap water. Body weight and blood biochemistry were monitored over the 6-month trial. After 4 months, male and female mice on HCD developed obesity, hypercholesterolaemia and hyperglycaemia, although gains in body weight, total cholesterol, and blood glucose in males were greater than those observed in females (P < 0.0001). When combined with an LCD, the NMWs rich in sulphate, magnesium and bicarbonate, and the minimally mineralised one were the most effective in reducing the blood levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and glucose. Sex differences emerged during both the MetS induction phase and the treatment phase. These results suggest that NMWs rich in specific macronutrients, such as bicarbonate, sulphate and magnesium, and minimally mineralised water, in combination with an LCD, may contribute to controlling blood lipid and glucose levels in subjects with MetS. Further studies are needed to confirm these results and to extend them to humans.
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Affiliation(s)
- Laura Narciso
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy
| | - Andrea Martinelli
- Centre for Animal Experimentation and Well-Being, Istituto Superiore di Sanità, Rome, Italy
| | - Flavio Torriani
- Centre for Animal Experimentation and Well-Being, Istituto Superiore di Sanità, Rome, Italy
| | - Paolo Frassanito
- Centre for Animal Experimentation and Well-Being, Istituto Superiore di Sanità, Rome, Italy
| | - Roberta Bernardini
- Interdepartmental Center for Comparative Medicine, Alternative Techniques and Aquaculture, University of Rome “Tor Vergata,”Rome, Italy
| | - Flavia Chiarotti
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy
| | - Cinzia Marianelli
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Rome, Italy
- *Correspondence: Cinzia Marianelli,
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Mohammed HM. Zingerone ameliorates non-alcoholic fatty liver disease in rats by activating AMPK. J Food Biochem 2022; 46:e14149. [PMID: 35338494 DOI: 10.1111/jfbc.14149] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 02/19/2022] [Accepted: 02/23/2022] [Indexed: 11/29/2022]
Abstract
This study was conducted to test the protective potential of Zingerone against a high-fat diet (HFD)-mediated non-alcoholic fatty liver disease (NAFLD) development in rats and examined in this protection is mediated modulating AMP-activated protein kinase (AMPK). Animals were segregated based on their diet and treatment into four groups (n = 6 each): (a) fed standard diet (STD), (b) treated with Zingerone (100 mg/kg), (c) fed HFD, (d) HFD + Zingerone (100 mg/kg), and (e) HFD + Zingerone (100 mg/kg) + compound c (CC) (an AMPK inhibitor) (0.2 mg/kg). The treatment with Zingerone attenuated the gain in final body weights, preserved liver structure, and downregulated the transcription of Bax and cleaved caspase-3. In the HFD and STD-fed rats, Zingerone reduced levels of fasting glucose and insulin and circulatory levels of cholesterol (CHOL) and triglycerides (TGs). Concomitantly, Zingerone enhanced glutathione (GSH) and superoxide dismutase (SOD) levels, depleted levels of malondialdehyde (MDA), and enhanced the nuclear levels of the nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, it lowered the levels of inflammatory cytokines and the nuclear levels of the nuclear factor kappa beta p65 (NF-κB p65). All these biochemical changes were associated with an increment in the phosphorylation of AMPK (p-AMPK) (activation) and reduced mRNA levels of SREBP1 and SREBP2. All observed effects afforded by Zingerone were abolished by CC. In conclusion, Zingerone prevents hepatic oxidative stress, inflammation, and apoptosis by activating AMPK. PRACTICAL APPLICATIONS: The findings of this study identified Zingerone, isolated from ginger, as a very effective drug that not only can attenuate fasting hyperglycemia and hyperlipidemia, but also prevent hepatic deposition, steatosis, and oxidative damage induced by high-fat-fed rats by activating the AMPK/Nrf2 antioxidant axis and concomitant suppression of SREBP1, SREBp2, and NF-κB p65. These data list Zingerone as a potent stimulator of AMPK which suggests an effective strategy to treat and alleviate NAFLD and encourages further translational and clinical trials.
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Affiliation(s)
- Heitham M Mohammed
- Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia
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Zhang LY, Shi HH, Wang CC, Wang YM, Wei ZH, Xue CH, Mao XZ, Zhang TT. Targeted Lipidomics Reveal the Effects of Different Phospholipids on the Phospholipid Profiles of Hepatic Mitochondria and Endoplasmic Reticulum in High-Fat/High-Fructose-Diet-Induced Nonalcoholic Fatty Liver Disease Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:3529-3540. [PMID: 35212227 DOI: 10.1021/acs.jafc.1c07538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The lipid alternation in mitochondria and endoplasmic reticulum (ER) might be indicative of their abnormal morphology and function, which contribute to development of nonalcoholic fatty liver disease (NAFLD). However, the influence of dietary phospholipids (PLs) on the PL composition of the organellar membrane is largely unknown. High-fat/high-fructose (HFHF)-diet-induced NAFLD mice were administrated with different PLs (2%, w/w) with specific fatty acids and headgroups, including eicosapentaenoic acid (EPA)-phosphatidylcholine (PC)/phosphatidylethanolamine (PE)/phosphatidylserine (PS), docosahexaenoic acid (DHA)-PC/PE/PS, egg-PC/PE/PS, and soy-PC/PE/PS. After 8 weeks of feeding, PLs dramatically decreased hepatic lipid accumulation, in which EPA/DHA-PS had the best efficiency. Furthermore, lipidomic analysis revealed that the HFHF diet narrowed the difference in PL composition between mitochondria and ER, significantly reduced the PC/PE ratio, and changed the unsaturation of cardiolipin in mitochondria. Dietary PLs reversed these alterations. Heatmap analysis indicated that dietary PL groups containing the same fatty acids clustered together. Moreover, dietary PLs significantly increased the ratio of PC/PE in both hepatic mitochondria and ER, especially EPA-PE. This study showed that fatty acid composition of PLs might represent greater impact on the PL composition of the organellar membrane than headgroups.
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Affiliation(s)
- Ling-Yu Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
- College of Food and Biological Engineering, Jimei University, Xiamen, Fujian 361021, People's Republic of China
| | - Hao-Hao Shi
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
| | - Cheng-Cheng Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
| | - Yu-Ming Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong 266237, People's Republic of China
| | - Zi-Hao Wei
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
| | - Chang-Hu Xue
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong 266237, People's Republic of China
| | - Xiang-Zhao Mao
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
- Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, Shandong 266237, People's Republic of China
| | - Tian-Tian Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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Luo W, Ye L, Hu XT, Wang MH, Wang MX, Jin LM, Xiao ZX, Qian JC, Wang Y, Zuo W, Huang LJ, Liang G. MD2 deficiency prevents high-fat diet-induced AMPK suppression and lipid accumulation through regulating TBK1 in non-alcoholic fatty liver disease. Clin Transl Med 2022; 12:e777. [PMID: 35343085 PMCID: PMC8958353 DOI: 10.1002/ctm2.777] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. METHODS Wild-type, Md2-/- and bone marrow reconstitution mice fed with high-fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA-seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. RESULTS Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD-mediated suppression of AMP-activated protein kinase (AMPK). This preservation of AMPK in Md2-deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2-increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. CONCLUSION Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1-AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non-inflammatory function of MD2 and evidence for the important role of MD2 in NALFD.
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Affiliation(s)
- Wu Luo
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- Medical Research Center, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Lin Ye
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xue-Ting Hu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Mei-Hong Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Min-Xiu Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lei-Ming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhong-Xiang Xiao
- Affiliated Yueqing Hospital, Wenzhou Medical University, Yueqing, China
| | - Jian-Chang Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wei Zuo
- Affiliated Yueqing Hospital, Wenzhou Medical University, Yueqing, China
| | - Li-Jiang Huang
- Affiliated Xiangshan Hospital, Wenzhou Medial University (Xiangshan First People's Hospital Medical and Health Group), Xiangshan, China
| | - Guang Liang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
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Jarukamjorn K, Sukkasem N, Chatuphonprasert W. Alteration of murine cytochrome P450 profiles in fatty liver disease by hesperidin and myricetin. Pharmacogn Mag 2022. [DOI: 10.4103/pm.pm_321_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Tsai SF, Hung HC, Shih MMC, Chang FC, Chung BC, Wang CY, Lin YL, Kuo YM. High-fat diet-induced increases in glucocorticoids contribute to the development of non-alcoholic fatty liver disease in mice. FASEB J 2021; 36:e22130. [PMID: 34959259 DOI: 10.1096/fj.202101570r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/08/2021] [Accepted: 12/16/2021] [Indexed: 12/19/2022]
Abstract
This study aimed to investigate the causal relationship between chronic ingestion of a high-fat diet (HFD)-induced secretion of glucocorticoids (GCs) and the development of non-alcoholic fatty liver disease (NAFLD). We have produced a strain of transgenic mice (termed L/L mice) that have normal levels of circulating corticosterone (CORT), the major type of GCs in rodents, but unlike wild-type (WT) mice, their circulating CORT was not affected by HFD. Compared to WT mice, 12-week HFD-induced fatty liver was less pronounced with higher plasma levels of triglycerides in L/L mice. These changes were reversed by CORT supplement to L/L mice. By analyzing a sort of lipid metabolism-related proteins, we found that expressions of the hepatic cluster of differentiation 36 (CD36) were upregulated by HFD-induced CORT and involved in CORT-mediated fatty liver. Dexamethasone, an agonist of the glucocorticoid receptor (GR), upregulated expressions of CD36 in HepG2 hepatocytes and facilitated lipid accumulation in the cells. In conclusion, the fat ingestion-induced release of CORT contributes to NAFLD. This study highlights the pathogenic role of CORT-mediated upregulation of hepatic CD 36 in diet-induced NAFLD.
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Affiliation(s)
- Sheng-Feng Tsai
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hao-Chang Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | | | - Fu-Chuan Chang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bon-Chu Chung
- Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
| | - Chia-Yih Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Ling Lin
- Division of Gastroenterology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Yu-Min Kuo
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Sanjay K, Vishwakarma S, Zope BR, Mane VS, Mohire S, Dhakshinamoorthy S. ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2021; 2:100051. [PMID: 34909677 PMCID: PMC8663992 DOI: 10.1016/j.crphar.2021.100051] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/20/2021] [Accepted: 08/31/2021] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 mg kg−1, po, qd, and 30 mg kg−1, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as Mcp-1/Ccl2, Timp-1 & Col1α1. Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.
Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis in a long term HFD induced NASH animal model. Mechanism of action includes modulation of lipid profile, inflammatory & fibrotic genes and inhibition of body weight gain. Overall improvement in NAS score was observed with Bempedoic acid treatment. Our study shows a promising role for Bempedoic acid in amelioration of metabolic disorders and NASH.
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Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis. Int J Mol Sci 2021; 22:ijms222212545. [PMID: 34830427 PMCID: PMC8624051 DOI: 10.3390/ijms222212545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
Understanding the pathomechanism of steatohepatitis (SH) is hampered by the difficulty of distinguishing between causes and consequences, by the broad spectrum of aetiologies that can produce the phenotype, and by the long time-span during which SH develops, often without clinical symptoms. We propose that SH develops in four phases with transitions: (i) priming lowers stress defence; (ii) triggering leads to acute damage; (iii) adaptation, possibly associated with cellular senescence, mitigates tissue damage, leads to the phenotype, and preserves liver function at a lower level; (iv) finally, senescence prevents neoplastic transformation but favours fibrosis (cirrhosis) and inflammation and further reduction in liver function. Escape from senescence eventually leads to hepatocellular carcinoma. This hypothesis for a pathomechanism of SH is supported by clinical and experimental observations. It allows organizing the various findings to uncover remaining gaps in our knowledge and, finally, to provide possible diagnostic and intervention strategies for each stage of SH development.
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Tetrahydropalmatine Alleviates Hyperlipidemia by Regulating Lipid Peroxidation, Endoplasmic Reticulum Stress, and Inflammasome Activation by Inhibiting the TLR4-NF- κB Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6614985. [PMID: 34760017 PMCID: PMC8575622 DOI: 10.1155/2021/6614985] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 08/04/2021] [Indexed: 01/11/2023]
Abstract
Hyperlipidemia (HLP) is a lipid metabolism disorder that can induce a series of cardiovascular and cerebrovascular diseases, such as atherosclerosis, myocardial infarction, coronary heart disease, and stroke, which seriously threaten human health. Tetrahydropalmatine (THP) is a component of the plant Rhizoma corydalis and has been shown to exert hepatoprotective and anti-inflammatory effects in HLP. However, whether THP regulates lipid peroxidation in hyperlipidemia, endoplasmic reticulum (ER) stress and inflammasome activation and even the underlying protective mechanism against HLP remain unclear. An animal model of HLP was established by feeding a high-fat diet to golden hamsters. Our results showed that THP reduced the body weight and adipose index; decreased the serum content of ALT, AST, TC, TG, and LDL-C; decreased the free fatty acid hepatic lipid content (liver index, TC, TG, and free fatty acid); inhibited oxidative stress and lipid peroxidation; extenuated hepatic steatosis; and inhibited ER stress and inflammasome activation in high-fat diet-fed golden hamsters. In addition, for the first time, the potential mechanism by which THP protects against HLP through the TLR4-NF-κB signaling pathway was demonstrated. In conclusion, these data indicate that THP attenuates HLP through a variety of effects, including antioxidative stress, anti-ER stress, and anti-inflammatory effects. In addition, THP also inhibited the TLR4-NF-κB signaling pathway in golden hamsters.
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Ferreira RGDS, Guilhon-Simplicio F, Acho LDR, Batista NY, Guedes-Junior FDC, Ferreira MSL, Barcellos JFM, Veiga-Junior VF, Lima ES. Anti-hyperglycemic, lipid-lowering, and anti-obesity effects of the triterpenes α and β-amyrenones in vivo. AVICENNA JOURNAL OF PHYTOMEDICINE 2021; 11:451-463. [PMID: 34745917 PMCID: PMC8554285 DOI: 10.22038/ajp.2021.18076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 12/04/2020] [Accepted: 12/12/2020] [Indexed: 01/10/2023]
Abstract
Objective: Diabetes, obesity, and their associated metabolic disorders are public health problems that require prevention and new efficient drugs for treatment. We evaluated the anti-hyperglycemic, lipid-lowering, and anti-obesity effects of semisynthetic α, β-amyrenones (ABA). Materials and Methods: BALB/c mice were used for performing an acute model of oral carbohydrate and triglyceride tolerance, and in a streptozotocin-induced diabetes model, where glycemia and body weight changes were measured during ten days. C57BL/6 strain mice were used in the diet-induced obesity model, where lipidemia and body weight were measured during four weeks, and biochemical and histological parameters were analyzed after euthanasia. The doses considered in this study were 25, 50, and 100 mg/kg of ABA, used following some criteria for each experiment. Results: ABA 25 mg/kg reduced the postprandial glycemia peak higher than acarbose 50 mg/kg (p<0.05). ABA 50 mg/kg significantly reduced glycemia in diabetic mice compared to acarbose 50 mg/kg (p<0.05). There was a reduction in the weight of the obese animals treated with ABA 25 and 50 mg/kg (p<0.05). ABA 50 mg/kg also significantly reduced lipidemia in these animals compared to orlistat 50 mg/kg. Conclusion: This study presents evidence of ABA's action in reducing postprandial glycemia and obesity in mice.
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Affiliation(s)
| | - Fernanda Guilhon-Simplicio
- Faculty of Pharmaceutical Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
| | - Leonard Domingo Rosales Acho
- Faculty of Pharmaceutical Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
| | - Nayana Yared Batista
- Institute of Biological Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
| | - Frank do Carmo Guedes-Junior
- Faculty of Pharmaceutical Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
| | - Mayla Silva Leão Ferreira
- Institute of Biological Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
| | - José Fernando Marques Barcellos
- Institute of Biological Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
| | - Valdir Florêncio Veiga-Junior
- Department of Chemistry, Military Institute of Engineering, Praça General Tibúrcio 80, Urca, 22290-270, Rio de Janeiro, RJ, Brazil
| | - Emerson Silva Lima
- Faculty of Pharmaceutical Sciences, Federal University of Amazonas, General Rodrigo Otávio 6200, Coroado 1, 69080-900, Manaus, AM, Brazil
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Gómez-Zorita S, Milton-Laskibar I, Macarulla MT, Biasutto L, Fernández-Quintela A, Miranda J, Lasa A, Segues N, Bujanda L, Portillo MP. Pterostilbene modifies triglyceride metabolism in hepatic steatosis induced by high-fat high-fructose feeding: a comparison with its analog resveratrol. Food Funct 2021; 12:3266-3279. [PMID: 33877249 DOI: 10.1039/d0fo03320k] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The use of phenolic compounds as a new therapeutic approach against NAFLD has emerged recently. In the present study, we aim to study the effect of pterostilbene in the prevention of liver steatosis developed as a consequence of high-fat (saturated) high-fructose feeding, by analysing the changes induced in metabolic pathways involved in triglyceride accumulation. Interestingly, a comparison with the anti-steatotic effect of its parent compound resveratrol will be made for the first time. Rats were distributed into 5 experimental groups and fed either a standard laboratory diet or a high-fat high-fructose diet supplemented with or without pterostilbene (15 or 30 mg per kg per d) or resveratrol (30 mg per kg per d) for 8 weeks. Serum triglyceride, cholesterol, NEFA and transaminase levels were quantified. Liver histological analysis was carried out by haematoxylin-eosin staining. Different pathways involved in liver triglyceride metabolism, including fatty acid synthesis, uptake and oxidation, triglyceride assembly and triglyceride release, were studied. Pterostilbene was shown to partially prevent high-fat high-fructose feeding induced liver steatosis in rats, demonstrating a dose-response pattern. In this dietary model, it acts mainly by reducing de novo lipogenesis and increasing triglyceride assembly and release. Improvement in mitochondrial functionality was also appreciated. At the same dose, the magnitude of pterostilbene and resveratrol induced effects, as well as the involved mechanisms of action, were similar.
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Affiliation(s)
- S Gómez-Zorita
- Nutrition and Obesity group, Department of Nutrition and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Lucio Lascaray Research Center, 01006 Vitoria-Gasteiz, Spain.
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Preguiça I, Alves A, Nunes S, Fernandes R, Gomes P, Viana SD, Reis F. Diet-induced rodent models of obesity-related metabolic disorders-A guide to a translational perspective. Obes Rev 2020; 21:e13081. [PMID: 32691524 DOI: 10.1111/obr.13081] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/12/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022]
Abstract
Diet is a critical element determining human health and diseases, and unbalanced food habits are major risk factors for the development of obesity and related metabolic disorders. Despite technological and pharmacological advances, as well as intensification of awareness campaigns, the prevalence of metabolic disorders worldwide is still increasing. Thus, novel therapeutic approaches with increased efficacy are urgently required, which often depends on cellular and molecular investigations using robust animal models. In the absence of perfect rodent models, those induced by excessive consumption of fat and sugars better replicate the key aspects that are the root causes of human metabolic diseases. However, the results obtained using these models cannot be directly compared, particularly because of the use of different dietary protocols, and animal species and strains, among other confounding factors. This review article revisits diet-induced models of obesity and related metabolic disorders, namely, metabolic syndrome, prediabetes, diabetes and nonalcoholic fatty liver disease. A critical analysis focused on the main pathophysiological features of rodent models, as opposed to the criteria defined for humans, is provided as a practical guide with a translational perspective for the establishment of animal models of obesity-related metabolic diseases.
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Affiliation(s)
- Inês Preguiça
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - André Alves
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - Sara Nunes
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - Rosa Fernandes
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
| | - Pedro Gomes
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal.,Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,Center for Health Technology and Services Research (CINTESIS), University of Porto, Porto, Portugal
| | - Sofia D Viana
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal.,ESTESC-Coimbra Health School, Pharmacy, Polytechnic Institute of Coimbra, Coimbra, Portugal
| | - Flávio Reis
- Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), University of Coimbra, Coimbra, Portugal
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Bashyam A, Frangieh CJ, Raigani S, Sogo J, Bronson RT, Uygun K, Yeh H, Ausiello DA, Cima MJ. A portable single-sided magnetic-resonance sensor for the grading of liver steatosis and fibrosis. Nat Biomed Eng 2020; 5:240-251. [PMID: 33257853 DOI: 10.1038/s41551-020-00638-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 09/28/2020] [Indexed: 12/19/2022]
Abstract
Low-cost non-invasive diagnostic tools for staging the progression of non-alcoholic chronic liver failure from fatty liver disease to steatohepatitis are unavailable. Here, we describe the development and performance of a portable single-sided magnetic-resonance sensor for grading liver steatosis and fibrosis using diffusion-weighted multicomponent T2 relaxometry. In a diet-induced mouse model of non-alcoholic fatty liver disease, the sensor achieved overall accuracies of 92% (Cohen's kappa, κ = 0.89) and 86% (κ = 0.78) in the ex vivo grading of steatosis and fibrosis, respectively. Localization of the measurements in living mice through frequency-dependent spatial encoding led to an overall accuracy of 87% (κ = 0.81) for the grading of steatosis. In human liver samples, the sensor graded steatosis with an overall accuracy of 93% (κ = 0.88). The use of T2 relaxometry as a sensitive measure in fully automated low-cost magnetic-resonance devices at the point of care would alleviate the accessibility and cost limits of magnetic-resonance imaging for diagnosing liver disease and assessing liver health before liver transplantation.
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Affiliation(s)
- Ashvin Bashyam
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Electrical Engineering & Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Chris J Frangieh
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Electrical Engineering & Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Siavash Raigani
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Jeremy Sogo
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Electrical Engineering & Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Roderick T Bronson
- Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, MA, USA
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Heidi Yeh
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Dennis A Ausiello
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.,Center for Assessment Technology and Continuous Health, Massachusetts General Hospital, Boston, MA, USA
| | - Michael J Cima
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. .,Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
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Kwon EY, Choi MS. Eriocitrin Improves Adiposity and Related Metabolic Disorders in High-Fat Diet-Induced Obese Mice. J Med Food 2020; 23:233-241. [PMID: 32191577 DOI: 10.1089/jmf.2019.4638] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Eriocitrin (EC) is an abundant flavonoid in lemons, which is known as a strong antioxidant agent. This study investigated the biological and molecular mechanisms underlying the anti-obesity effect of EC in high-fat diet (HFD)-fed obese mice. C57BL/6N mice were fed an HFD (40 kcal% fat) with or without 0.005% (w/w) EC for 16 weeks. Dietary EC improved adiposity by increasing adipocyte fatty acid (FA) oxidation, energy expenditure, and mRNA expression of thermogenesis-related genes in brown adipose tissue (BAT) and skeletal muscle, whereas it also decreased lipogenesis-related gene expression in white adipose tissue. In addition to adiposity, EC prevented hepatic steatosis by diminishing lipogenesis while enhancing FA oxidation in the liver and fecal lipid excretion, which was linked to attenuation of hyperlipidemia. Moreover, EC improved insulin sensitivity by decreasing hepatic gluconeogenesis and proinflammatory responses. These findings indicate that EC may protect against diet-induced adiposity and related metabolic disorders by controlling thermogenesis of BAT and skeletal muscle, FA oxidation, lipogenesis, fecal lipid excretion, glucose utilization, and gluconeogenesis.
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Affiliation(s)
- Eun-Young Kwon
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, Korea.,Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, Korea
| | - Myung-Sook Choi
- Department of Food Science and Nutrition, Kyungpook National University, Daegu, Korea.,Center for Food and Nutritional Genomics Research, Kyungpook National University, Daegu, Korea
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High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms. Chem Biol Interact 2020; 330:109199. [DOI: 10.1016/j.cbi.2020.109199] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
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Zheng X, Ren B, Li X, Yan H, Xie Q, Liu H, Zhou J, Tian J, Huang K. Selenoprotein F knockout leads to glucose and lipid metabolism disorders in mice. J Biol Inorg Chem 2020; 25:1009-1022. [DOI: 10.1007/s00775-020-01821-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 08/30/2020] [Indexed: 02/07/2023]
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Bimro ET, Hovav R, Nyska A, Glazer TA, Madar Z. High oleic peanuts improve parameters leading to fatty liver development and change the microbiota in mice intestine. Food Nutr Res 2020; 64:4278. [PMID: 33033472 PMCID: PMC7520627 DOI: 10.29219/fnr.v64.4278] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 04/20/2020] [Accepted: 05/18/2020] [Indexed: 12/11/2022] Open
Abstract
Background Oleic-acid consumption can possibly prevent or delay metabolic diseases. In Israel, a Virginia-type peanut cultivar with a high content of oleic acid has been developed. Objective This study examined the effect of consuming high oleic peanuts (D7) on the development of fatty liver compared to the standard HN strain. Design The two peanut cultivars were added to normal diet (ND) and high-fat (HF) mouse diet. Male C57BL/6 mice were fed for 8 and 10 weeks on a 4% D7, 4% HN, or control diet. At the end of the experiments, blood and tissues were collected. Triglyceride, lipid levels, histology, and protein expression were examined. The diets’ effects on intestinal microbiota were also evaluated. Results Both D7 and HFD7 led to a reduction in plasma triglycerides. Lipids, triglycerides, and free fatty acids in the liver were low in diets containing D7. Additionally, CD36 expression decreased in the D7 group. Consumption of D7 led to higher Prevotella levels, and consumption of ND that contained HN or D7 led to a lower Firmicutes/Bacteroidetes ratio. Conclusion These findings suggest that consumption of peanuts high in oleic acid (D7) may have the potential to delay primary fatty liver symptoms.
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Affiliation(s)
- Elise Taieb Bimro
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Ran Hovav
- Department of Field Crops and Vegetables Research, Plant Sciences Institute, Agricultural Research Organization, Bet-Dagan, Israel
| | - Abraham Nyska
- Toxicologic Pathology, Timrat and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tal Assa Glazer
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Zecharia Madar
- Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
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Tahara A, Takasu T. SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model. Physiol Rep 2020; 7:e14286. [PMID: 31782258 PMCID: PMC6883099 DOI: 10.14814/phy2.14286] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) has become the most common cause of chronic liver disease worldwide in recent years. The pathogenesis of NASH is closely linked to metabolic diseases such as insulin resistance, obesity, dyslipidemia, and type 2 diabetes. However, there is currently no pharmacological agent for preventing the progression of NASH. Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion by inhibiting renal glucose reabsorption, and improve various pathological conditions of type 2 diabetes, including insulin resistance. In the present study, we examined the effects of ipragliflozin, a SGLT2-selective inhibitor, alone and in combination with pioglitazone on NASH in high-fat diet-fed KK/Ay type 2 diabetic mice. Type 2 diabetic mice with NASH exhibited steatosis, inflammation, and fibrosis in the liver as well as hyperglycemia, insulin resistance, and obesity, features that are observed in human NASH. Four-week repeated administration of ipragliflozin (0.1-3 mg/kg) led to significant improvements in hyperglycemia, insulin resistance, and obesity in addition to hyperlipidemia and liver injury including hepatic steatosis and fibrosis. Moreover, ipragliflozin reduced inflammation and oxidative stress in the liver. Repeated administration of pioglitazone (3-30 mg/kg) also significantly improved various parameters of diabetes and NASH, excluding obesity. Furthermore, combined treatment comprising ipragliflozin (1 mg/kg) and pioglitazone (10 mg/kg) additively improved these parameters. These findings indicate that the SGLT2-selective inhibitor ipragliflozin improves hyperglycemia as well as NASH in type 2 diabetic mice. Therefore, treatment with ipragliflozin monotherapy or coadministered with pioglitazone is expected to be a potential therapeutic option for the treatment of type 2 diabetes with NASH.
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Affiliation(s)
- Atsuo Tahara
- Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan
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