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Xie F, Yan Y, Gao X, She H, Wang J, Li J, Zhang Y, Zhang J, Zhang Z, Ai L. The impact of supplementation with highland barley in different nutrients on weight loss: The nutrients and function relationship. Food Chem X 2025; 27:102417. [PMID: 40241698 PMCID: PMC12002971 DOI: 10.1016/j.fochx.2025.102417] [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: 01/07/2025] [Revised: 03/20/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
The dietary fiber in highland barley (HB) may be a key nutrient in exerting its physiological functions. How about the effects of other nutrients? In this study, a high-fat diet (HFD)-induced obese mice was constructed to investigate the effects of HB in different nutrients on weight loss. The results showed that peeling treatment had varying effects on HB nutrients. Consumption of HB significantly mitigated weight gain, postprandial blood glucose levels, organ weight, adipose tissue weight, and fat accumulation in obese mice. Consumption of HB also ameliorated hepatic steatosis, hyperlipemia, abnormal liver function, and dysregulation of inflammatory factor expression in mice. Unpeeled and once peeled HB presented the best effect. Furthermore, HB consumption improved the imbalance of gut microbiota in HFD-induced mice, with protein and dietary fiber being the key factors in exerting the improvement effect. This study highlights the potential of protein and dietary fiber in HB for treating obesity.
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Affiliation(s)
- Fan Xie
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yuting Yan
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Xin Gao
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Haocheng She
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Jingyi Wang
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Jie Li
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Yi Zhang
- Crop Breeding & Cultivation Research Institute, Shanghai Academy of Agricultural Sciences, Shanghai 201403, China
| | - Jun Zhang
- Shidong Hospital, Yangpu Destrict, Shanghai 200438, China
| | - Zhou Zhang
- Shidong Hospital, Yangpu Destrict, Shanghai 200438, China
| | - Lianzhong Ai
- Shanghai Engineering Research Center of Food Microbiology, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
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Li M, Chen P, Xue M, Wang J, Wang H, Liang X. AKT-FoxO1-PCK/ChREBP signaling pathway regulates metabolic liver disease induced by high glucose in largemouth bass. Int J Biol Macromol 2025; 295:139703. [PMID: 39793804 DOI: 10.1016/j.ijbiomac.2025.139703] [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: 05/23/2024] [Revised: 12/18/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025]
Abstract
Starch is widely used in aquaculture because of its low price and the advantages for processing expanded feed. Largemouth bass are naturally type 2 diabetic and intolerant to dietary carbohydrates. In this study, we found that the phosphorylation of AKT and FoxO1 were down-regulated in the fish suffering from metabolic liver disease (MLD). High glucose (25 mM) stimulation in hepatocytes significantly reduced AKT and FoxO1 phosphorylation level, while enhancing glycolysis and gluconeogenesis enzyme activities, leading to acute glucose metabolism disorder. However, after treatment of insulin or FoxO1 inhibitor, the related parameters returned to control level. The mRNA levels of ChREBP and lipid synthesis genes were increased after high glucose stimulation, and then decreased after adding FoxO1 inhibitor, accompanied by a reduction of TG content. Furtherly, plasmid transfection, dual-luciferase reporter assay experiments and EMSA proved that AKT positively regulated the phosphorylation of FoxO1 and FoxO1 positively regulated the promoter activities of PCK and ChREBP, and the transcription factor binding sites were found. In summary, these results support a critical role of AKT-FoxO1-PCK/ChREBP signaling pathway in regulating the occurrence of MLD in largemouth bass. Moreover, we identified a novel FoxO1-mediated gene regulation mechanism, revealing a previously unrecognized cross-talk between FoxO1 and ChREBP.
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Affiliation(s)
- Min Li
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Pei Chen
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China; Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei 443100, China
| | - Min Xue
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Jie Wang
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Hao Wang
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Xiaofang Liang
- National Aquafeed Safety Assessment Center, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
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Lu C, Han M, Ma Q, Ying L, Zhang Y. Identification of biomarkers associated with coronary artery disease and non-alcoholic fatty liver disease by bioinformatics analysis and machine learning. Sci Rep 2025; 15:3557. [PMID: 39875572 PMCID: PMC11775188 DOI: 10.1038/s41598-025-87923-7] [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: 04/08/2024] [Accepted: 01/22/2025] [Indexed: 01/30/2025] Open
Abstract
The constantly emerging evidence indicates a close association between coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). However, the exact mechanisms underlying their mutual relationship remain undefined. This study aims to explore the common signature genes, potential mechanisms, diagnostic markers, and therapeutic targets for CAD and NAFLD. We downloaded CAD and NAFLD datasets from the Gene Expression Omnibus (GEO) database and analyzed the differentially expressed genes (DEGs) by limma. Protein-protein interaction (PPI) network was constructed with common DEGs (co-DEGs), and hub genes were screened by Maximal Clique Centrality (MCC) algorithm. Candidate biomarkers were selected from intersection of three machine learning algorithms. Expression levels, nomogram, the areas under the receiver operating characteristic curve (AUC) of candidate biomarkers were performed. CIBERSORT algorithm was used to assess the immune cell infiltration, and Spearman's correlations tests were used for calculating the correlation of biomarker genes. A total of 554 overlapping DEGs associated with CAD and NAFLD were obtained by analysis of GSE113079 and GSE89632 datasets. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that the co-DEGs were significantly enriched in immune effector process, inflammation response and lipid metabolism. The PPI network generated a 1245-edge network, and top 50 genes were selected using the MCC algorithm. The candidate biomarkers were screened from intersection of machine learning in GSE89632, including CEBPA, CXCL2, JUN and FOXO1. The ROC results showed that these four biomarker genes have good diagnostic value for patients with both CAD and NAFLD. Then we explored the immune landscape, immune infiltration and the correlation between biomarker gene expression in CAD and NAFLD samples. In this study, we predict that CEBPA, CXCL2, JUN and FOXO1 can be used to diagnose CAD and NAFLD. Our study provided new insights for potential biomarkers, molecular mechanism and therapeutic targets for both diseases.
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Affiliation(s)
- Chuan Lu
- Department of Cardiology, the Second Hospital of Dalian Medical University, Dalian, 116021, China
| | - Mei Han
- Department of Gastroenterology, the Second Hospital of Dalian Medical University, Dalian, 116021, China
| | - Qiqi Ma
- Department of Gastroenterology, the Second Hospital of Dalian Medical University, Dalian, 116021, China
| | - Li Ying
- Department of Gastroenterology, the Second Hospital of Dalian Medical University, Dalian, 116021, China.
| | - Yue Zhang
- Department of Gastroenterology, the Second Hospital of Dalian Medical University, Dalian, 116021, China.
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Kaur P, Khan H, Grewal AK, Dua K, Singh SK, Gupta G, Singh TG. Exploring Therapeutic Strategies: The Relationship between Metabolic Disorders and FOXO Signalling in Alzheimer's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2025; 24:196-207. [PMID: 39473249 DOI: 10.2174/0118715273321002240919102841] [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: 04/03/2024] [Revised: 07/28/2024] [Accepted: 08/08/2024] [Indexed: 02/25/2025]
Abstract
Alzheimer's disease is an ailment that is linked with the degeneration of the brain cells, and this illness is the main cause of dementia. Metabolic stress affects the activity of the brain in AD via FOXO signaling. The occurrence of AD will significantly surge as the world's population ages, along with lifestyle changes perceived in current decades, indicating a main contributor to such augmented prevalence. Similarly, metabolic disorders of current adulthood, such as obesity, stroke, and diabetes mellitus, have been observed as the risk-causing factors of AD. Environmental influences induce genetic mutations that result in the development of several diseases. Metabolic disorders develop when individuals are exposed to an environment where food is easily accessible and requires minimal energy expenditure. Obesity and diabetes are among the most significant worldwide health concerns. Obesity arises because of an imbalance between the amount of energy consumed and the amount of energy expended, which is caused by both behavioral and physiological factors. Obesity, insulin resistance syndrome, hypertension, and inflammation are factors that contribute to the worldwide risk of developing diabetes mellitus and neurodegenerative diseases. FOXO transcription factors are preserved molecules that play an important part in assorted biological progressions, precisely in aging as well as metabolism. Apoptosis, cell division and differentiation, oxidative stress, metabolism, and lifespan are among the physiological processes that the FOXO proteins are adept at controlling. In this review, we explored the correlation between signaling pathways and the cellular functions of FOXO proteins. We have also summarized the intricate role of FOXO in AD, with a focus on metabolic stress, and discussed the prospect of FOXO as a molecular link between AD and metabolic disorders.
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Affiliation(s)
- Parneet Kaur
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
| | - Heena Khan
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
| | - Amarjot Kaur Grewal
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Sachin Kumar Singh
- Department of Pharmacology, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Mahal Road, Jaipur, India
- Centre for Transdisciplinary Research, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
- Department of Pharmacology, School of Pharmacy, Graphic Era Hill University, Dehradun, 248007, India
| | - Thakur Gurjeet Singh
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
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Sabatini S, Sen P, Carli F, Pezzica S, Rosso C, Lembo E, Verrastro O, Daly A, Govaere O, Cockell S, Hyötyläinen T, Mingrone G, Bugianesi E, Anstee QM, Orešič M, Gastaldelli A. Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis. Cell Rep Med 2024; 5:101820. [PMID: 39566466 PMCID: PMC11604487 DOI: 10.1016/j.xcrm.2024.101820] [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: 08/25/2023] [Revised: 07/25/2024] [Accepted: 10/16/2024] [Indexed: 11/22/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.
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Affiliation(s)
- Silvia Sabatini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Partho Sen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Samantha Pezzica
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Chiara Rosso
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, 10124 Turin, Italy
| | - Erminia Lembo
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ornella Verrastro
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ann Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Olivier Govaere
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Simon Cockell
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Tuulia Hyötyläinen
- School of Science and Technology, Örebro University, 70281 Örebro, Sweden
| | - Geltrude Mingrone
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College Hospital, London, UK
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, 10124 Turin, Italy
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE7 7DN, UK
| | - Matej Orešič
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; School of Medical Sciences, Örebro University, 70281 Örebro, Sweden.
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy; Diabetes Division, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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Xu D, Qu X, Yang T, Sheng M, Bian X, Zhan Y, Tian Y, Lin Y, Jin Y, Wang X, Ke M, Jiang L, Li C, Xia Q, Farmer DG, Ke B. The Foxo1-YAP-Notch1 axis reprograms STING-mediated innate immunity in NASH progression. Exp Mol Med 2024; 56:1843-1855. [PMID: 39122845 PMCID: PMC11372114 DOI: 10.1038/s12276-024-01280-5] [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: 09/29/2023] [Revised: 03/10/2024] [Accepted: 04/21/2024] [Indexed: 08/12/2024] Open
Abstract
Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-β1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1-YAP-Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH.
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Affiliation(s)
- Dongwei Xu
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Xiaoye Qu
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Tao Yang
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Mingwei Sheng
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Xiyun Bian
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yongqiang Zhan
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yizhu Tian
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yuanbang Lin
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Yuting Jin
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiao Wang
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Michael Ke
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Longfeng Jiang
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Changyong Li
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Douglas G Farmer
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Bibo Ke
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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Yang J, Félix-Soriano E, Martínez-Gayo A, Ibañez-Santos J, Sáinz N, Martínez JA, Moreno-Aliaga MJ. SIRT1 and FOXO1 role on MASLD risk: effects of DHA-rich n-3 PUFA supplementation and exercise in aged obese female mice and in post-menopausal overweight/obese women. J Physiol Biochem 2024; 80:697-712. [PMID: 39264516 PMCID: PMC11502560 DOI: 10.1007/s13105-024-01044-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 08/07/2024] [Indexed: 09/13/2024]
Abstract
Sirtuins 1 (SIRT1) and Forkhead box protein O1 (FOXO1) expression have been associated with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Exercise and/or docosahexaenoic acid (DHA) supplementation have shown beneficial effects on MASLD. The current study aims to assess the relationships between Sirt1, Foxo1 mRNA levels and several MASLD biomarkers, as well as the effects of DHA-rich n-3 PUFA supplementation and/or exercise in the steatotic liver of aged obese female mice, and in peripheral blood mononuclear cells (PBMCs) of postmenopausal women with overweight/obesity. In the liver of 18-month-old mice, Sirt1 levels positively correlated with the expression of genes related to fatty acid oxidation, and negatively correlated with lipogenic and proinflammatory genes. Exercise (long-term treadmill training), especially when combined with DHA, upregulated hepatic Sirt1 mRNA levels. Liver Foxo1 mRNA levels positively associated with hepatic triglycerides (TG) content and the expression of lipogenic and pro-inflammatory genes, while negatively correlated with the lipolytic gene Hsl. In PBMCs of postmenopausal women with overweight/obesity, FOXO1 mRNA expression negatively correlated with the hepatic steatosis index (HSI) and the Zhejiang University index (ZJU). After 16-weeks of DHA-rich PUFA supplementation and/or progressive resistance training (RT), most groups exhibited reduced MASLD biomarkers and risk indexes accompanying with body fat mass reduction, but no significant changes were found between the intervention groups. However, in PBMCs n-3 supplementation upregulated FOXO1 expression, and the RT groups exhibited higher SIRT1 expression. In summary, SIRT1 and FOXO1 could be involved in the beneficial mechanisms of exercise and n-3 PUFA supplementation related to MASLD manifestation.
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Affiliation(s)
- Jinchunzi Yang
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Current Address: Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, 518000, China
| | - Elisa Félix-Soriano
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Alejandro Martínez-Gayo
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Javier Ibañez-Santos
- Studies, Research and Sports Medicine Centre (CEIMD), Government of Navarre, 31005, Pamplona, Spain
| | - Neira Sáinz
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - J Alfredo Martínez
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - María J Moreno-Aliaga
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
- IdISNA, Navarra Institute for Health Research, 31008, Pamplona, Spain.
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8
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Sha X, Zou X, Liu S, Guan C, Shi W, Gao J, Zhong X, Jiang X. Forkhead box O1 in metabolic dysfunction-associated fatty liver disease: molecular mechanisms and drug research. Front Nutr 2024; 11:1426780. [PMID: 39021599 PMCID: PMC11253077 DOI: 10.3389/fnut.2024.1426780] [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: 05/02/2024] [Accepted: 06/21/2024] [Indexed: 07/20/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.
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Affiliation(s)
| | | | | | | | | | | | - Xiangyu Zhong
- General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xingming Jiang
- General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
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9
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Abdelrahman Z, Maxwell AP, McKnight AJ. Genetic and Epigenetic Associations with Post-Transplant Diabetes Mellitus. Genes (Basel) 2024; 15:503. [PMID: 38674437 PMCID: PMC11050138 DOI: 10.3390/genes15040503] [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: 03/12/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation. PTDM prevalence varies due to different diabetes definitions. Consensus guidelines for the diagnosis of PTDM have been published based on random blood glucose levels, glycated hemoglobin (HbA1c), and oral glucose tolerance test (OGTT). The task of diagnosing PTDM continues to pose challenges, given the potential for diabetes to manifest at different time points after transplantation, thus demanding constant clinical vigilance and repeated testing. Interpreting HbA1c levels can be challenging after renal transplantation. Pre-transplant risk factors for PTDM include obesity, sedentary lifestyle, family history of diabetes, ethnicity (e.g., African-Caribbean or South Asian ancestry), and genetic risk factors. Risk factors for PTDM include immunosuppressive drugs, weight gain, hepatitis C, and cytomegalovirus infection. There is also emerging evidence that genetic and epigenetic variation in the organ transplant recipient may influence the risk of developing PTDM. This review outlines many known risk factors for PTDM and details some of the pathways, genetic variants, and epigenetic features associated with PTDM. Improved understanding of established and emerging risk factors may help identify people at risk of developing PTDM and may reduce the risk of developing PTDM or improve the management of this complication of organ transplantation.
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Affiliation(s)
- Zeinab Abdelrahman
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
| | - Alexander Peter Maxwell
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, UK
| | - Amy Jayne McKnight
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
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10
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Samy AM, Kandeil MA, Sabry D, Abdel-Ghany AA, Mahmoud MO. Exosomal miR-122, miR-128, miR-200, miR-298, and miR-342 as novel diagnostic biomarkers in NAFL/NASH: Impact of LPS/TLR-4/FoxO3 pathway. Arch Pharm (Weinheim) 2024; 357:e2300631. [PMID: 38574101 DOI: 10.1002/ardp.202300631] [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: 10/30/2023] [Accepted: 12/19/2023] [Indexed: 04/06/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder affecting a quarter of the global residents. Progression of NAFL into nonalcoholic steatohepatitis (NASH) may cause cirrhosis, liver cancer, and failure. Gut microbiota imbalance causes microbial components translocation into the circulation, triggering liver inflammation and NASH-related fibrosis. MicroRNAs (miRNAs) regulate gene expression via repressing target genes. Exosomal miRNAs are diagnostic and prognostic biomarkers for NAFL and NASH liver damage. Our work investigated the role of the gut microbiota in NAFLD pathogenesis via the lipopolysaccharide/toll-like receptor 4/Forkhead box protein O3 (LPS/TLR-4/FoxO3) pathway and certain miRNAs as noninvasive biomarkers for NAFL or its development to NASH. miRNA expression levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 50 NAFL patients, 50 NASH patients, and 50 normal controls. Plasma LPS, TLR-4, adiponectin, peroxisome proliferator-activated receptor γ (PPAR-γ), and FoxO3 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). In NAFL and NASH patients, miR-122, miR-128, FoxO3, TLR-4, LPS, and PPAR-γ were upregulated while miR-200, miR-298, miR-342, and adiponectin were downregulated compared with the normal control. The examined miRNAs might distinguish NAFL and NASH patients from the normal control using receiver operating characteristic analysis. Our study is the first to examine these miRNAs in NAFLD. Our findings imply that these are potentially promising biomarkers for noninvasive early NAFL diagnosis and NASH progression. Understanding the LPS/TLR-4/FoxO3 pathway involvement in NAFL/NASH pathogenesis may aid disease management.
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Affiliation(s)
- Ahmed M Samy
- Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Mohamed A Kandeil
- Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University in Cairo, Cairo, Egypt
| | - A A Abdel-Ghany
- Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assuit branch, Egypt
| | - Mohamed O Mahmoud
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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11
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Engin A. Protein Kinases in Obesity, and the Kinase-Targeted Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:199-229. [PMID: 39287853 DOI: 10.1007/978-3-031-63657-8_7] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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12
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Tsuji-Tamura K, Ogawa M. FOXO1 promotes endothelial cell elongation and angiogenesis by up-regulating the phosphorylation of myosin light chain 2. Angiogenesis 2023; 26:523-545. [PMID: 37488325 DOI: 10.1007/s10456-023-09884-7] [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: 01/06/2023] [Accepted: 07/11/2023] [Indexed: 07/26/2023]
Abstract
The forkhead box O1 (FOXO1) is an important transcription factor related to proliferation, metabolism, and homeostasis, while the major phenotype of FOXO1-null mice is abnormal vascular morphology, such as vessel enlargement and dilation. In in vitro mouse embryonic stem cell (ESC)-differentiation system, Foxo1-/- vascular endothelial cells (ECs) fail to elongate, and mimic the abnormalities of FOXO1-deficiency in vivo. Here, we identified the PPP1R14C gene as the FOXO1 target genes responsible for elongating using transcriptome analyses in ESC-derived ECs (ESC-ECs), and found that the FOXO1-PPP1R14C-myosin light chain 2 (MLC2) axis is required for EC elongation during angiogenesis. MLC2 is phosphorylated by MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP). PPP1R14C is an inhibitor of PP1, the catalytic subunit of MLCP. The abnormal morphology of Foxo1-/- ESC-ECs was associated with low level of PPP1R14C and loss of MLC2 phosphorylation, which were reversed by PPP1R14C-introduction. Knockdown of either FOXO1 or PPP1R14C suppressed vascular cord formation and reduced MLC2 phosphorylation in human ECs (HUVECs). The mouse and human PPP1R14C locus possesses an enhancer element containing conserved FOXO1-binding motifs. In vivo chemical inhibition of MLC2 phosphorylation caused dilated vascular structures in mouse embryos. Furthermore, foxo1 or ppp1r14c-knockdown zebrafish exhibited vascular malformations, which were also restored by PPP1R14C-introduction. Mechanistically, FOXO1 suppressed MLCP activity by up-regulating PPP1R14C expression, thereby promoting MLC2 phosphorylation and EC elongation, which are necessary for vascular development. Given the importance of MLC2 phosphorylation in cell morphogenesis, this study may provide novel insights into the role of FOXO1 in control of angiogenesis.
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Affiliation(s)
- Kiyomi Tsuji-Tamura
- Oral Biochemistry and Molecular Biology, Department of Oral Health Science, Faculty of Dental Medicine and Graduate School of Dental Medicine, Hokkaido University, Kita 13, Nishi 7, Kita-Ku, Sapporo, 060-8586, Japan.
| | - Minetaro Ogawa
- Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-Ku, Kumamoto, 860-0811, Japan
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13
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Pan Q, Gao M, Kim D, Ai W, Yang W, Jiang W, Brashear W, Dai Y, Li S, Sun Y, Qi Y, Guo S. Hepatocyte FoxO1 Deficiency Protects From Liver Fibrosis via Reducing Inflammation and TGF-β1-mediated HSC Activation. Cell Mol Gastroenterol Hepatol 2023; 17:41-58. [PMID: 37678798 PMCID: PMC10665954 DOI: 10.1016/j.jcmgh.2023.08.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND & AIMS The O-class of the forkhead transcription factor FoxO1 is a crucial factor mediating insulin→PI3K→Akt signaling and governs diverse cellular processes. However, the role of hepatocyte FoxO1 in liver fibrosis has not been well-established. In his study, we investigated the role of hepatocyte FoxO1 in liver fibrosis and uncovered the underlying mechanisms. METHODS Liver fibrosis was established by carbon tetrachloride (CCL4) administration and compared between liver-specific deletion of FoxO1 deletion (F1KO) and control (CNTR) mice. Using genetic and bioinformatic strategies in vitro and in vivo, the role of hepatic FoxO1 in liver fibrosis and associated mechanisms was established. RESULTS Increased FoxO1 expression and FoxO1 signaling activation were observed in CCL4-induced fibrosis. Hepatic FoxO1 deletion largely attenuated CCL4-induced liver injury and fibrosis compared with CNTR mice. F1KO mice showed ameliorated CCL4-induced hepatic inflammation and decreased TGF-β1 mRNA and protein levels compared with those of CNTR mice. In primary hepatocytes, FoxO1 deficiency reduced TGF-β1 expression and secretion. Conditioned medium (CM) collected from wild-type hepatocytes treated with CCL4 activated human HSC cell line (LX-2); such effect was attenuated by FoxO1 deletion in primary hepatocytes or neutralization of TGF-β1 in the CM using TGF-β1 antibody. Hepatic FoxO1 overexpression in CNTR mice promoted CCL4-induced HSC activation; such effect was blocked in L-TGF-β1KO mice. CONCLUSIONS Hepatic FoxO1 mediates CCL4-inducled liver fibrosis via upregulating hepatocyte TGF-β1 expression, stimulating hepatic inflammation and TGF-β1-mediated HSC activation. Hepatic FoxO1 may be a therapeutic target for prevention and treatment of liver fibrosis.
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Affiliation(s)
- Quan Pan
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas
| | - Mingming Gao
- Department of Pharmacology, School of Basic Medical Science, North China University of Science and Technology. Tangshan, China
| | - DaMi Kim
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas
| | - Weiqi Ai
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas
| | - Wanbao Yang
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas
| | - Wen Jiang
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas
| | - Wesley Brashear
- High Performance Research Computing, Texas A&M University, College Station, Texas
| | - Yujiao Dai
- Department of Pharmacology, School of Basic Medical Science, North China University of Science and Technology. Tangshan, China
| | - Sha Li
- Department of Pharmacology, School of Basic Medical Science, North China University of Science and Technology. Tangshan, China
| | - Yuxiang Sun
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas
| | - Yajuan Qi
- Department of Pharmacology, School of Basic Medical Science, North China University of Science and Technology. Tangshan, China.
| | - Shaodong Guo
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas.
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14
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Infante-Menéndez J, López-Pastor AR, González-Illanes T, González-López P, Huertas-Lárez R, Rey E, González-Rodríguez Á, García-Monzón C, Patil NP, de Céniga MV, Baker AB, Gómez-Hernández A, Escribano O. Increased let-7d-5p in non-alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis. Liver Int 2023; 43:1714-1728. [PMID: 37057737 PMCID: PMC10523911 DOI: 10.1111/liv.15581] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/15/2023] [Accepted: 03/26/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND AND AIMS The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d-5p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker. METHODS We evaluated let-7d-5p levels and its targets in liver biopsies from a cross-sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d-5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d-5p in vitro to corroborate the results observed in vivo. Circulating let-7d-5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR. RESULTS Our results demonstrate that hepatic let-7d-5p was significantly up-regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin-like growth factor 1 (IGF1), IGF-I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let-7d-5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let-7d-5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let-7d-5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker. CONCLUSIONS Our results highlight the emerging role of let-7d-5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non-invasive biomarker for NAFLD diagnosis.
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Affiliation(s)
- Jorge Infante-Menéndez
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Andrea R. López-Pastor
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Tamara González-Illanes
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Paula González-López
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Raquel Huertas-Lárez
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Esther Rey
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa. Madrid, Spain
| | - Águeda González-Rodríguez
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa. Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
| | - Carmelo García-Monzón
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa. Madrid, Spain
- CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Nikita P. Patil
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Melina Vega de Céniga
- Department of Angiology and Vascular Surgery, Hospital de Galdakao-Usansolo, Galdakao, Bizkaia, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Aaron B. Baker
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Almudena Gómez-Hernández
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Oscar Escribano
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
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15
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Zafirovska M, Zafirovski A, Rotovnik Kozjek N. Current Insights Regarding Intestinal Failure-Associated Liver Disease (IFALD): A Narrative Review. Nutrients 2023; 15:3169. [PMID: 37513587 PMCID: PMC10385050 DOI: 10.3390/nu15143169] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Intestinal failure-associated liver disease (IFALD) is a spectrum of liver disease including cholestasis, biliary cirrhosis, steatohepatitis, and gallbladder disease in patients with intestinal failure (IF). The prevalence of IFALD varies considerably, with ranges of 40-60% in the pediatric population, up to 85% in neonates, and between 15-40% in the adult population. IFALD has a complex and multifactorial etiology; the risk factors can be parenteral nutrition-related or patient-related. Because of this, the approach to managing IFALD is multidisciplinary and tailored to each patient based on the etiology. This review summarizes the current knowledge on the etiology and pathophysiology of IFALD and examines the latest evidence regarding preventative measures, diagnostic approaches, and treatment strategies for IFALD and its associated complications.
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Affiliation(s)
- Marija Zafirovska
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Association of General Practice/Family Medicine of South-East Europe (AGP/FM SEE), St. Vladimir Komarov No. 40/6, 1000 Skopje, North Macedonia
| | - Aleksandar Zafirovski
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- General Hospital Jesenice, Cesta Maršala Tita 112, 4270 Jesenice, Slovenia
- Clinical Institute of Radiology, University Medical Centre Ljubljana, Zaloška Cesta 7, 1000 Ljubljana, Slovenia
| | - Nada Rotovnik Kozjek
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Department for Clinical Nutrition, Institute of Oncology Ljubljana, Zaloška Cesta 2, 1000 Ljubljana, Slovenia
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16
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Kundu D, Kennedy L, Zhou T, Ekser B, Meadows V, Sybenga A, Kyritsi K, Chen L, Ceci L, Wu N, Wu C, Glaser S, Carpino G, Onori P, Gaudio E, Alpini G, Francis H. p16 INK4A drives nonalcoholic fatty liver disease phenotypes in high fat diet fed mice through biliary E2F1/FOXO1/IGF-1 signaling. Hepatology 2023; 78:243-257. [PMID: 36799449 PMCID: PMC10410572 DOI: 10.1097/hep.0000000000000307] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 01/03/2023] [Indexed: 02/18/2023]
Abstract
BACKGROUND AND AIMS NAFLD is characterized by steatosis, hepatic inflammation, and fibrosis, which can develop into NASH. Patients with NAFLD/NASH have increased ductular reaction (DR) and biliary senescence. High fat/high cholesterol diet feeding increases biliary senescence, DR, and biliary insulin-like growth factor-1 (IGF-1) expression in mice. p16/IGF-1 converges with fork-head box transcription factor O1 (FOXO1) through E2F1. We evaluated p16 inhibition on NAFLD phenotypes and biliary E2F1/FOXO1/IGF-1 signaling. APPROACH AND RESULTS 4-week wild-type (C57BL/6J) male mice were fed a control diet (CD) or high fat/high cholesterol diet and received either p16 or control Vivo Morpholino (VM) by tail vein injection 2× during the 16th week of feeding. We confirmed p16 knockdown and examined: (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling. Human normal, NAFLD, and NASH liver samples and isolated cholangiocytes treated with control or p16 VM were evaluated for p16/E2F1/FOXO1/IGF-1 signaling. p16 VM treatment reduced cholangiocyte and hepatocyte p16. In wild-type high fat/high cholesterol diet mice with control VM, there were increased (i) NAFLD phenotypes; (ii) DR and biliary senescence; (iii) serum metabolites; and (iv) biliary E2F1/FOXO1/IGF-1 signaling; however, p16 VM treatment reduced these parameters. Biliary E2F1/FOX-O1/IGF-1 signaling increased in human NAFLD/NASH but was blocked by p16 VM. In vitro , p16 VM reduced biliary E2f1 and Foxo1 transcription by inhibiting RNA pol II binding and E2F1 binding at the Foxo1 locus, respectively. Inhibition of E2F1 reduced biliary FOXO1 in vitro. CONCLUSION Attenuating hepatic p16 expression may be a therapeutic approach for improving NAFLD/NASH phenotypes.
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Affiliation(s)
- Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Lindsey Kennedy
- Department of Research, Richard L. Roudebush VA Medical Center
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Burcin Ekser
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | | | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Chaodong Wu
- Department of Nutrition, Texas A&M University, College Station, Texas
| | | | - Guido Carpino
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Gianfranco Alpini
- Department of Research, Richard L. Roudebush VA Medical Center
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
| | - Heather Francis
- Department of Research, Richard L. Roudebush VA Medical Center
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine Research
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17
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Krishnan U A, Viswanathan P, Venkataraman AC. AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice. Tissue Cell 2023; 82:102054. [PMID: 36913846 DOI: 10.1016/j.tice.2023.102054] [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: 09/07/2022] [Revised: 03/01/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023]
Abstract
Dysregulation of 5'-adenosine monophosphate-activated protein kinase (AMPK) occurs in metabolic disorders including non-alcoholic fatty liver disease (NAFLD) which makes it a molecular target for treatment. An AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) alleviates NAFLD in experimental rats, however the specific mechanism remains to be explored. We aimed to study the effect of AICAR on lipid levels, oxidant-antioxidant balance, AMPK and mTOR activation and FOXO3 gene expression in liver of mice model. Fatty liver was induced in two groups of C57BL/6 mice (groups 2 and 3) by providing a high fat high fructose diet (HFFD) for 10 weeks while groups 1 and 4 animals were fed normal pellet. For the last two weeks, groups 3 and 4 were administered AICAR (150 mg/kg bw/day, i.p.) while groups 1 and 2 were administered saline. AICAR decreased fatty liver, decreased glucose and insulin in circulation, prevented the accumulation of triglycerides and collagen and ameliorated oxidative stress in HFFD fed mice. At the molecular level, AICAR upregulated FOXO3 and p-AMPK expression and reduced p-mTOR expression. AMPK activation may involve FOXO3 in protection against NAFLD. The role of AMPK, mTOR and FOXO3 crosstalk in NAFLD needs to be characterised in future.
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Affiliation(s)
- Ajay Krishnan U
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India
| | - Periyasamy Viswanathan
- Department of Pathology, Karpaga Vinayaga Institute of Medical Sciences and Research Centre, Madhuranthagam, Tamil Nadu, India
| | - Anuradha Carani Venkataraman
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India.
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Zhang J, Yu H, Wang Q, Cai H, Shen F, Ruan S, Wu Y, Liu T, Feng F, Zhao M. Dietary additive octyl and decyl glycerate modulates metabolism and inflammation under different dietary patterns with the contribution of the gut microbiota. Food Funct 2023; 14:525-540. [PMID: 36520115 DOI: 10.1039/d2fo03059d] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Octyl and decyl glycerate (ODG), a medium-chain triglyceride (MCT), is widely used as a food additive. Medium-chain monoglycerides, such as glycerol monolaurate and glycerol monocaprylate, were found to change the composition of the gut microbiota and influence glucose and lipid metabolism and inflammation. However, whether ODG influences the gut microbiota and whether the alteration in the gut microbiota contributes to the metabolic phenotype remain unknown. Under a normal-chow diet, mice were treated with or without different dosages of ODG (150, 800, 1600 mg kg-1) for 22 weeks. All doses of ODG significantly decreased the ratio of HDL to LDL cholesterol, improved the inflammation and insulin resistance, and increased the α-diversity of the gut microbiota and the abundance of Bifidobacterium and Turicibacter. Under a high-fat diet, mice were treated with or without 1600 mg kg-1 ODG for 16 weeks. The results demonstrated that ODG significantly alleviated the increase in the ratio of HDL to LDL cholesterol, insulin resistance, and inflammation caused by HFD. The expression of related genes was consistent with the above observations. ODG also altered the composition of the gut microbiota and increased the Bifidobacterium abundance under HFD. Our findings indicated that ODG similarly improved glucose metabolism and inflammation but exhibited differential effects on lipid metabolism under different dietary patterns. Furthermore, changes in the gut microbiota caused by ODG supplementation might contribute to the alteration in glucose and lipid metabolism and inflammation, which might be influenced by dietary patterns.
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Affiliation(s)
- Junhui Zhang
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Huilin Yu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Qianqian Wang
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Haiying Cai
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,School of Biological & Chemical Engineering, Zhejiang University of Science &Technology, Hangzhou, 310023, China
| | - Fei Shen
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Shengyue Ruan
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Yue Wu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Tao Liu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Fengqin Feng
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
| | - Minjie Zhao
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, 310058, China. .,National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, Hangzhou, 310058, China
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Tranilast protects pancreatic β-cells from palmitic acid-induced lipotoxicity via FoxO-1 inhibition. Sci Rep 2023; 13:101. [PMID: 36596838 PMCID: PMC9810694 DOI: 10.1038/s41598-022-25428-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 11/29/2022] [Indexed: 01/05/2023] Open
Abstract
Tranilast, an anti-allergic drug used in the treatment of bronchial asthma, was identified as an inhibitor of the transcription factor Forkhead box O-1 (FoxO-1) by high throughput chemical library screening in the present study. Based on FoxO-1's role in apoptotic cell death and differentiation, we examined the effect of tranilast on palmitic acid (PA)-induced cell damage in INS-1 cells. Tranilast substantially inhibited lipoapoptosis and restored glucose-stimulated insulin secretion under high PA exposure. Moreover, PA-mediated downregulation of PDX-1, MafA, and insulin expression was attenuated by tranilast. PA-induced oxidative and ER stress were also reduced in the presence of tranilast. These protective effects were accompanied by increased phosphorylation and decreased nuclear translocation of FoxO-1. Conversely, the effects of tranilast were diminished when treated in transfected cells with FoxO-1 phosphorylation mutant (S256A), suggesting that the tranilast-mediated effects are associated with inactivation of FoxO-1. Examination of the in vivo effects of tranilast using wild type and diabetic db/db mice showed improved glucose tolerance along with FoxO-1 inactivation in the pancreas of the tranilast-treated groups. Thus, we report here that tranilast has protective effects against PA-induced lipotoxic stress in INS-1 cells, at least partly, via FoxO-1 inactivation, which results in improved glucose tolerance in vivo.
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20
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Nguyen TK, Phung HH, Choi WJ, Ahn HC. Network Pharmacology and Molecular Docking Study on the Multi-Target Mechanisms of Aloe vera for Non-Alcoholic Steatohepatitis Treatment. PLANTS (BASEL, SWITZERLAND) 2022; 11:3585. [PMID: 36559697 PMCID: PMC9783676 DOI: 10.3390/plants11243585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 06/17/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease with limited treatment options. The widely distributed plant Aloe vera has shown protective effects against NASH in animals, yet the precise mechanism remains unknown. In this study, we investigated the potential mechanisms underlying the anti-NASH effects of Aloe vera using a network pharmacology and molecular docking approach. By searching online databases and analyzing the Gene Expression Omnibus dataset, we obtained 260 Aloe vera-NASH common targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the common targets were strongly associated with the key pathological processes implicated in NASH, including lipid and glucose metabolism, inflammation, apoptosis, oxidative stress, and liver fibrosis. Four core proteins, AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor alpha (TNFα), transcription factor c-Jun, and tumor suppressor protein p53, were identified from compound-target-pathway and protein-protein interaction networks. Molecular docking analysis verified that the active ingredients of Aloe vera were able to interact with the core proteins, especially AKT1 and TNFα. The results demonstrate the multi-compound, multi-target, and multi-pathway mechanisms of Aloe vera against NASH. Our study has shown the scientific basis for further experiments in terms of the mechanism to develop Aloe vera-based natural products as complementary treatments for NASH. Furthermore, it identifies novel drug candidates based on the structures of Aloe vera's active compounds.
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21
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Zhou Y, Li Z, Xu M, Zhang D, Ling J, Yu P, Shen Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells 2022; 11:cells11223637. [PMID: 36429065 PMCID: PMC9688300 DOI: 10.3390/cells11223637] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.
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Affiliation(s)
- Yicheng Zhou
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, Nanchang 330031, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Jitao Ling
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
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22
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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23
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Sabir U, Irfan HM, Alamgeer, Umer I, Niazi ZR, Asjad HMM. Phytochemicals targeting NAFLD through modulating the dual function of forkhead box O1 (FOXO1) transcription factor signaling pathways. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:741-755. [PMID: 35357518 DOI: 10.1007/s00210-022-02234-2] [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: 12/22/2021] [Accepted: 03/18/2022] [Indexed: 02/06/2023]
Abstract
Literature evidence reveals that natural compounds are potential candidates for ameliorating obesity-associated non-alcoholic fatty liver disease (NAFLD) by targeting forkhead box O1 (FOXO1) transcription factor. FOXO1 has a dual and complex role in regulating both increase and decrease in lipid accumulation in hepatocytes and adipose tissues (AT) at different stages of NAFLD. In insulin resistance (IR), it is constitutively expressed, resulting in increased hepatic glucose output and lipid metabolism irregularity. The studies on different phytochemicals indicate that dysregulation of FOXO1 causes disturbance in cellular nutrients homeostasis, and the natural entities have an enduring impact on the mitigation of these abnormalities. The current review communicates and evaluates certain phytochemicals through different search engines, targeting FOXO1 and its downstream cellular pathways to find lead compounds as potential therapeutic agents for treating NAFLD and related metabolic disorders. The findings of this review confirm that polyphenols, flavonoids, alkaloids, terpenoids, and anthocyanins are capable of modulating FOXO1 and associated signaling pathways, and they are potential therapeutic agents for NAFLD and related complications. HIGHLIGHTS: • FOXO1 has the potential to be targeted by novel drugs from natural sources for the treatment of NAFLD and obesity. • FOXO1 regulates cellular autophagy, inflammation, oxidative stress, and lipogenesis through alternative mechanisms. • Phytochemicals treat NAFLD by acting on FOXO1 or SREBP1c and PPARγ transcription factor signaling pathways.
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Affiliation(s)
- Usman Sabir
- Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Pakistan
| | - Hafiz Muhammad Irfan
- Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Pakistan.
| | - Alamgeer
- Punjab University College of Pharmacy, University of the Punjab Lahore, Lahore, Pakistan
| | - Ihtisham Umer
- Pharmacy Department, Comsat International University Lahore Campus, Lahore, Pakistan
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24
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Lee S, Usman TO, Yamauchi J, Chhetri G, Wang X, Coudriet GM, Zhu C, Gao J, McConnell R, Krantz K, Rajasundaram D, Singh S, Piganelli J, Ostrowska A, Soto-Gutierrez A, Monga SP, Singhi AD, Muzumdar RH, Tsung A, Dong HH. Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis. J Clin Invest 2022; 132:154333. [PMID: 35700043 PMCID: PMC9282937 DOI: 10.1172/jci154333] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 05/27/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatic inflammation is culpable for the evolution of asymptomatic steatosis to nonalcoholic steatohepatitis (NASH). Hepatic inflammation results from abnormal macrophage activation. We found that FoxO1 links overnutrition to hepatic inflammation by regulating macrophage polarization and activation. FoxO1 was upregulated in hepatic macrophages, correlating with hepatic inflammation, steatosis and fibrosis in mice and patients with NASH. Myeloid cell-conditional FoxO1 knockout skewed macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, accompanied by the reduction of macrophage infiltration in liver. These effects mitigated overnutrition-induced hepatic inflammation and insulin resistance, contributing to improved hepatic metabolism and increased energy expenditure in myeloid cell FoxO1 knockout mice on HFD. When fed a NASH-inducing diet, myeloid cell FoxO1 knockout mice were protected from developing NASH, culminating in the reduction of hepatic inflammation, steatosis and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures to perpetuate hepatic inflammation in NASH. FoxO1 appears as a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.
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Affiliation(s)
- Sojin Lee
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Taofeek O Usman
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Jun Yamauchi
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Goma Chhetri
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Xingchun Wang
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Gina M Coudriet
- Department of Surgery, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Cuiling Zhu
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Jingyang Gao
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Riley McConnell
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Kyler Krantz
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Dhivyaa Rajasundaram
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Jon Piganelli
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Alina Ostrowska
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Radhika H Muzumdar
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
| | - Allan Tsung
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, United States of America
| | - H Henry Dong
- Department of Pediatrics, Children's Hospital, University of Pittsburgh School of Medicine, Pittsburgh, United States of America
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25
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Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice. Nat Commun 2022; 13:1025. [PMID: 35197460 PMCID: PMC8866405 DOI: 10.1038/s41467-022-28692-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 02/03/2022] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a large population with incompletely defined mechanism(s). Here we report that Kindlin-2 is dramatically up-regulated in livers in obese mice and patients with NAFLD. Kindlin-2 haploinsufficiency in hepatocytes ameliorates high-fat diet (HFD)-induced NAFLD and glucose intolerance without affecting energy metabolism in mice. In contrast, Kindlin-2 overexpression in liver exacerbates NAFLD and promotes lipid metabolism disorder and inflammation in hepatocytes. A C-terminal region (aa 570-680) of Kindlin-2 binds to and stabilizes Foxo1 by inhibiting its ubiquitination and degradation through the Skp2 E3 ligase. Kindlin-2 deficiency increases Foxo1 phosphorylation at Ser256, which favors its ubiquitination by Skp2. Thus, Kindllin-2 loss down-regulates Foxo1 protein in hepatocytes. Foxo1 overexpression in liver abrogates the ameliorating effect of Kindlin-2 haploinsufficiency on NAFLD in mice. Finally, AAV8-mediated shRNA knockdown of Kindlin-2 in liver alleviates NAFLD in obese mice. Collectively, we demonstrate that Kindlin-2 insufficiency protects against fatty liver by promoting Foxo1 degradation. Here, the authors show that expression of kindlin-2 is increased in patients with nonalcoholic fatty liver disease (NAFLD). In mouse models, specific deletion of kindlin-2 in liver ameliorates, while its overexpression exacerbates, NAFLD by modulating Foxo1 in hepatocytes.
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26
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Ibata T, Lyu J, Imachi H, Fukunaga K, Sato S, Kobayashi T, Saheki T, Yoshimura T, Murao K. Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells. Nutrients 2022; 14:nu14020288. [PMID: 35057469 PMCID: PMC8779252 DOI: 10.3390/nu14020288] [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: 12/02/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 02/04/2023] Open
Abstract
ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME2) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME2 on the hepatic lipid content and ABCA1 expression. We found that 2-ME2 dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME2 enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME2 on ABCA1 promoter activity. Further, 2-ME2 stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME2, which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME2 on ABCA1 expression. All of our results demonstrated that 2-ME2 might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.
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Affiliation(s)
- Tomohiro Ibata
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Jingya Lyu
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
- Department of Physiology, School of Medicine, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou 510632, China
| | - Hitomi Imachi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Kensaku Fukunaga
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Seisuke Sato
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Toshihiro Kobayashi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Takanobu Saheki
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Takafumi Yoshimura
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
| | - Koji Murao
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kagawa, Japan; (T.I.); (J.L.); (H.I.); (K.F.); (S.S.); (T.K.); (T.S.); (T.Y.)
- Correspondence:
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27
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TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver. Cell Metab 2022; 34:158-170.e5. [PMID: 34914893 PMCID: PMC8732315 DOI: 10.1016/j.cmet.2021.11.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/12/2021] [Accepted: 11/18/2021] [Indexed: 01/07/2023]
Abstract
Increased hepatic glucose production (HGP) contributes to hyperglycemia in type 2 diabetes. Hormonal regulation of this process is primarily, but not exclusively, mediated by the AKT-FoxO1 pathway. Here, we show that cAMP and dexamethasone regulate the high-mobility group superfamily member TOX4 to mediate HGP, independent of the insulin receptor/FoxO1 pathway. TOX4 inhibition decreases glucose production in primary hepatocytes and liver and increases glucose tolerance. Combined genetic ablation of TOX4 and FoxO1 in liver has additive effects on glucose tolerance and gluconeogenesis. Moreover, TOX4 ablation fails to reverse the metabolic derangement brought by insulin receptor knockout. TOX4 expression is increased in livers of patients with steatosis and diabetes and in diet-induced obese and db/db mice. In the latter two murine models, knockdown Tox4 decreases glycemia and improves glucose tolerance. We conclude that TOX4 is an insulin receptor-independent regulator of HGP and a candidate contributor to the pathophysiology of diabetes.
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Jiang Y, Zhu H, Chen Z, Yu YC, Guo XH, Chen Y, Yang MM, Chen BW, Sagnelli M, Xu D, Zhao BH, Luo Q. Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation. Front Endocrinol (Lausanne) 2022; 13:844707. [PMID: 35432202 PMCID: PMC9011096 DOI: 10.3389/fendo.2022.844707] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/24/2022] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE The offspring of women with gestational diabetes mellitus (GDM) have a high predisposition to developing type 2 diabetes during childhood and adulthood. The aim of the study was to evaluate how GDM exposure in the second half of pregnancy contributes to hepatic glucose intolerance through a mouse model. METHODS By creating a GDM mouse model, we tested glucose and insulin tolerance of offspring by intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). In addition, we checked the expression of genes IGF2/H19, FoxO1, and DNMTs in the mouse liver by RT-qPCR. Pyrosequencing was used to detect the methylation status on IGF2/H19 differentially methylated regions (DMRs). In vitro insulin stimulation experiments were performed to evaluate the effect of different insulin concentrations on HepG2 cells. Moreover, we detect the interaction between FoxO1 and DNMT3A by chromatin immunoprecipitation-quantitative PCR (Chip-qPCR) and knock-down experiments on HepG2 cells. RESULTS We found that the first generation of GDM offspring (GDM-F1) exhibited impaired glucose tolerance (IGT) and insulin resistance, with males being disproportionately affected. In addition, the expression of imprinted genes IGF2 and H19 was downregulated in the livers of male mice via hypermethylation of IGF2-DMR0 and IGF2-DMR1. Furthermore, increased expression of transcriptional factor FoxO1 was confirmed to regulate DNMT3A expression, which contributed to abnormal methylation of IGF2/H19 DMRs. Notably, different insulin treatments on HepG2 demonstrated those genetic alterations, suggesting that they might be induced by intrauterine hyperinsulinemia. CONCLUSION Our results demonstrated that the intrauterine hyperinsulinemia environment has increased hepatic FoxO1 levels and subsequently increased expression of DNMT3A and epigenetic alterations on IGF2/H19 DMRs. These findings provide potential molecular mechanisms responsible for glucose intolerance and insulin resistance in the first male generation of GDM mice.
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Affiliation(s)
- Ying Jiang
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Hong Zhu
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Zi Chen
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Yi-Chen Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Xiao-Han Guo
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Yuan Chen
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Meng-Meng Yang
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Bang-Wu Chen
- Department of Obstetrics, Ninghai Maternal and Child Health Hospital, Ningbo, China
| | - Matthew Sagnelli
- University of Connecticut School of Medicine, Farmington, CT, United States
| | - Dong Xu
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Bai-Hui Zhao
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Qiong Luo
- Department of Obstetrics, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, China
- *Correspondence: Qiong Luo,
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Luo D, Dong X, Huang J, Huang C, Fang G, Huang Y. Pueraria lobata root polysaccharide alleviates glucose and lipid metabolic dysfunction in diabetic db/db mice. PHARMACEUTICAL BIOLOGY 2021; 59:382-390. [PMID: 33794128 PMCID: PMC8018507 DOI: 10.1080/13880209.2021.1898648] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/04/2021] [Accepted: 02/28/2021] [Indexed: 05/25/2023]
Abstract
CONTEXT Pueraria lobata (Willd.) Ohwi (Fabaceae) root extract can lower blood glucose levels; however, whether Pueraria lobata root polysaccharide (PLP) possesses these effects is still unknown. OBJECTIVE This study evaluates the therapeutic effect of PLP on diabetic metabolic syndrome. MATERIALS AND METHODS The db/m mice were assigned to normal control group (NC), db/db mice were divided into four groups randomly (n = 8). The db/db mice received rosiglitazone (10 mg/kg BW) or PLP (100 or 200 mg/kg BW) via oral gavage for 6 weeks. Afterward, blood glucose, insulin, and glycogen content were assayed, and insulin tolerance test (ITT), oral glucose tolerance test (OGTT) were performed. Glucose and lipid metabolism-related parameters and gene expression levels were assayed by ELISA and RT-PCR, respectively. RESULTS After treatment with HPLP, the values of body weight, epididymal fat, subcutaneous fat, fasting blood glucose, insulin, and HOMA-IR decreased to 45.89 ± 1.66 g, 1.65 ± 0.14 g, 1.97 ± 0.16 g, 14.84 ± 1.52 mM, 9.35 ± 0.98 mU/L, and 5.56 ± 1.26, respectively; the levels of TG, TC, LDL-C, and FFA decreased to 1.67 ± 0.11 mmol/L, 6.23 ± 0.76 mmol/L, 1.29 ± 0.07 mmol/L, and 1.71 ± 0.16 mmol/L, respectively. HPLP down-regulated PEPCK, G6PC, FOXO1, SREBP-1, and ACC mRNA expression (p < 0.01), and up-regulated GS, Akt2, PI3K, GLUT2, PPARα, and LDLR mRNA expression in the liver (p < 0.01). DISCUSSION AND CONCLUSION PLP exerts antidiabetic effects via activating the PI3K/AKT signalling pathway, thus improving insulin resistance, glucose, and lipid metabolism in db/db mice. Thus, PLP may be considered as a potential antidiabetic agent in clinical therapy.
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Affiliation(s)
- Dan Luo
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China
| | - Xiaokang Dong
- Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China
| | - Jie Huang
- School of Health, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China
| | - Chengcheng Huang
- Clinical Education Management Division, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China
| | - Guowei Fang
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China
| | - Yanqin Huang
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, PR China
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Valenti L, Romeo S, Pajvani U. A genetic hypothesis for burnt-out steatohepatitis. Liver Int 2021; 41:2816-2818. [PMID: 34935283 DOI: 10.1111/liv.15103] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022]
Affiliation(s)
- Luca Valenti
- Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.,Precision Medicine Lab, Biological Resource Center, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.,Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.,Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy
| | - Utpal Pajvani
- Department of Medicine, Columbia University, New York, New York, USA
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Bhatt SP, Guleria R. Association of IRS1 (Gly972Arg) and IRS2 (Gly1057Asp) genes polymorphisms with OSA and NAFLD in Asian Indians. PLoS One 2021; 16:e0245408. [PMID: 34449768 PMCID: PMC8396739 DOI: 10.1371/journal.pone.0245408] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 07/31/2021] [Indexed: 12/12/2022] Open
Abstract
AIM AND OBJECTIVE The aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians. METHOD A total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing. RESULT Mean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45-60 years group as compared to 20-45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06-12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8-2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the 'Gly' allele were inclined to develop more severe OSA. CONCLUSION We concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.
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Affiliation(s)
- Surya Prakash Bhatt
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
- * E-mail:
| | - Randeep Guleria
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
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Garcinol promotes hepatic gluconeogenesis by inhibiting P300/CBP-associated factor in late-pregnant sows. Br J Nutr 2021; 126:1-8. [PMID: 32967737 DOI: 10.1017/s000711452000375x] [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] [Indexed: 11/06/2022]
Abstract
Disorder of hepatic glucose metabolism is the characteristic of late-pregnant sows. The purpose of our study was to look into the mechanism of garcinol on the improvement of hepatic gluconeogenic enzyme in late-pregnant sows. Thirty second- and third-parity sows (Duroc × Yorkshire × Landrace, n 10/diet) were fed a basal diet (control) or that diet supplemented with 100 mg/kg (Low Gar) or 500 mg/kg (High Gar) garcinol from day 90 of gestation to the end of farrowing. The livers were processed to measure enzymatic activity. Hepatocytes from pregnant sows were transfected with P300/CBP-associating factor (PCAF) small interfering RNA (siRNA) or treated with garcinol. Dietary garcinol had no effect on average daily feed intake, body weight (BW), backfat and BW gain of late-pregnant sows. Garcinol promoted plasma glucose levels in pregnant sows and newborn piglets. Garcinol up-regulated hepatic gluconeogenic enzyme expression and decreased PCAF activity. Garcinol had no effect on the expression of PPAR-γ co-activator 1α (PGC-1α) and Forkhead box O1 (FOXO1) but significantly increased their activity and decreased their acetylation in late-pregnant sows. Transfection of PCAF siRNA to hepatocytes of pregnant sows increased PGC-1α and FOXO1 activities. Furthermore, in hepatocytes of pregnant sows, garcinol treatment also up-regulated the activities of PGC-1α and FOXO1 and inhibited the acetylation of PGC-1α and FOXO1. Garcinol improves hepatic gluconeogenic enzyme expression in late-pregnant sows, and this may be due to the mechanism of down-regulating the acetylation of PGC-1α and FOXO1 induced by PCAF in isolated hepatocytes.
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Sun X, Cao Z, Ma Y, Shao Y, Zhang J, Yuan G, Guo X. Resveratrol attenuates dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and suppressing the FoxO1 pathway in type 2 diabetes. Food Funct 2021; 12:1207-1218. [PMID: 33432947 DOI: 10.1039/d0fo02387f] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Dapagliflozin alleviates hyperglycemia by increasing glycosuria, but it induces renal gluconeogenesis, thus neutralizing its efficacy. Resveratrol (Rsv), a natural polyphenolic chemical, improves insulin sensitivity in type 2 diabetes (T2D). Here, we investigated the regulatory effects and underlying mechanisms of Rsv on dapagliflozin-induced renal gluconeogenesis. Male ob/ob mice were given the vehicle (HF), dapagliflozin (1 mg kg-1), Rsv (10 mg kg-1), or dapagliflozin and Rsv combination for 10 weeks. Glucose metabolism was evaluated by glucose and pyruvate tolerance tests. HK-2 cells (human renal proximal tubule cells) were treated with dapagliflozin (1 μmol L-1) for 2 h and further incubated with Rsv (10 μmol L-1) for 12 h. The effects of Rsv on gluconeogenesis and insulin signaling were assessed. Dapagliflozin treatment increased glucose production in HK-2 cells and lowered blood glucose and induced gluconeogenesis in ob/ob mice. After Rsv treatment, the enhanced glucose production and gluconeogenesis were alleviated. The upregulated mRNA and protein expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and the activation of the forkhead transcription factor O1 (FoxO1) protein in the dapagliflozin group were attenuated by Rsv administration. Rsv also improved renal insulin signaling by increasing PI3K and Akt phosphorylation. The PI3K inhibitor LY294002 dramatically decreased the p-Akt expression and activated FoxO1 by dephosphorylation, thus diminishing the inhibitory effects of Rsv on dapagliflozin-induced PEPCK and G6Pase expression. The data showed the mechanisms of Rsv in attenuating dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and further suppressing FoxO1 activation, suggesting a potential intervention to achieve better glucose-lowering effects for SGLT2 inhibitors in T2D therapy.
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Affiliation(s)
- Xiaoya Sun
- Endocrinology, Peking University First Hospital, Beijing 100034, China.
| | - Ziqiang Cao
- Endocrinology, Peking University First Hospital, Beijing 100034, China.
| | - Yuanyuan Ma
- Animal Center, Peking University First Hospital, Beijing 100034, China
| | - Yimin Shao
- Endocrinology, Peking University First Hospital, Beijing 100034, China.
| | - Junqing Zhang
- Endocrinology, Peking University First Hospital, Beijing 100034, China.
| | - Geheng Yuan
- Endocrinology, Peking University First Hospital, Beijing 100034, China.
| | - Xiaohui Guo
- Endocrinology, Peking University First Hospital, Beijing 100034, China.
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Ge W, Zhao Y, Yang Y, Ding Z, Xu X, Weng D, Wang S, Cheng R, Zhang J. An insulin-independent mechanism for transcriptional regulation of Foxo1 in type 2 diabetic mice. J Biol Chem 2021; 297:100846. [PMID: 34058194 PMCID: PMC8233149 DOI: 10.1016/j.jbc.2021.100846] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/08/2021] [Accepted: 05/26/2021] [Indexed: 11/29/2022] Open
Abstract
Hepatic gluconeogenesis is the major contributor to the hyperglycemia observed in both patients and animals with type 2 diabetes. The transcription factor FOXO1 plays a dominant role in stimulating hepatic gluconeogenesis. FOXO1 is mainly regulated by insulin under physiological conditions, but liver-specific disruption of Foxo1 transcription restores normal gluconeogenesis in mice in which insulin signaling has been blocked, suggesting that additional regulatory mechanisms exist. Understanding the transcriptional regulation of Foxo1 may be conducive to the development of insulin-independent strategies for the control of hepatic gluconeogenesis. Here, we found that elevated plasma levels of adenine nucleotide in type 2 diabetes are the major regulators of Foxo1 transcription. We treated lean mice with 5'-AMP and examined their transcriptional profiles using RNA-seq. KEGG analysis revealed that the 5'-AMP treatment led to shifted profiles that were similar to db/db mice. Many of the upregulated genes were in pathways associated with the pathology of type 2 diabetes including Foxo1 signaling. As observed in diabetic db/db mice, lean mice treated with 5'-AMP displayed enhanced Foxo1 transcription, involving an increase in cellular adenosine levels and a decrease in the S-adenosylmethionine to S-adenosylhomocysteine ratio. This reduced methylation potential resulted in declining histone H3K9 methylation in the promoters of Foxo1, G6Pc, and Pepck. In mouse livers and cultured cells, 5'-AMP induced expression of more FOXO1 protein, which was found to be localized in the nucleus, where it could promote gluconeogenesis. Our results revealed that adenine nucleotide-driven Foxo1 transcription is crucial for excessive glucose production in type 2 diabetic mice.
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Affiliation(s)
- Wenhao Ge
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yang Zhao
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yunxia Yang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Zhao Ding
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Xi Xu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Dan Weng
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Shiming Wang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Rui Cheng
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.
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Kowalczuk A, Bourebaba N, Kornicka-Garbowska K, Turlej E, Marycz K, Bourebaba L. Hyoscyamus albus nortropane alkaloids reduce hyperglycemia and hyperinsulinemia induced in HepG2 cells through the regulation of SIRT1/NF-kB/JNK pathway. Cell Commun Signal 2021; 19:61. [PMID: 34034759 PMCID: PMC8152357 DOI: 10.1186/s12964-021-00735-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/24/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Chronic superphysiological glucose and insulin concentrations are known to trigger several tissue and organ failures, including insulin resistance, oxidative stress and chronic low-grade inflammation. Hence, the screening for molecules that may counteract such conditions is essential in current existing therapeutic strategies, thereby the use of medicinal plant derivatives represents a promising axis in this regard. METHODS In this study, the effect of a selected traditional medicinal plant, Hyoscyamus albus from which, calystegines have been isolated, was investigated in an experimental model of hyperinsulinemia and hyperglycemia induced on HepG2 cells. The mRNA and protein expression levels of different insulin signaling, gluconeogenic and inflammatory pathway- related molecules were examined. Additionally, cell viability and apoptosis, oxidative stress extent and mitochondrial dysfunctions were assayed using flow cytometric and qRT-PCR techniques. RESULTS Treatment of IR HepG2 cells with calystegines strongly protected the injured cells from apoptosis, oxidative stress and mitochondrial integrity loss. Interestingly, nortropane alkaloids efficiently regulated the impaired glucose metabolism in IR HepG2 cells, through the stimulation of glucose uptake and the modulation of SIRT1/Foxo1/G6PC/mTOR pathway, which is governing the hepatic gluconeogenesis. Furthermore, the alkaloidal extract restored the defective insulin signaling pathway, mainly by promoting the expression of Insr at the mRNA and protein levels. What is more, treated cells exhibited significant mitigated inflammatory response, as evidenced by the modulation and the regulation of the NF- κB/JNK/TLR4 axis and the downstream proinflammatory cytokines recruitment. CONCLUSION Overall, the present investigation demonstrates that calystegines from Hyoscyamus albus provide cytoprotection to the HepG2 cells against insulin/glucose induced insulin resistance and apoptosis due to the regulation of SIRT1/Foxo1/G6PC/mTOR and NF-κB/JNK/TLR4 signaling pathways. Video Abstract.
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Affiliation(s)
- Anna Kowalczuk
- grid.419694.70000 0004 0622 0266National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
| | - Nabila Bourebaba
- International Institute of Translational Medicine, Jesionowa 11, 55-114 Malin, Wisznia Mała, Poland ,grid.411200.60000 0001 0694 6014Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
| | | | - Eliza Turlej
- grid.411200.60000 0001 0694 6014Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
| | - Krzysztof Marycz
- International Institute of Translational Medicine, Jesionowa 11, 55-114 Malin, Wisznia Mała, Poland ,Collegium Medicum, Institute of Medical Science, Cardinal Stefan Wyszyński University (UKSW), Dewajtis 5, 01-815 Warsaw, Poland
| | - Lynda Bourebaba
- International Institute of Translational Medicine, Jesionowa 11, 55-114 Malin, Wisznia Mała, Poland ,grid.411200.60000 0001 0694 6014Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375 Wrocław, Poland
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Choi HE, Kim Y, Lee HJ, Cheon HG. Novel FoxO1 inhibitor, JY-2, ameliorates palmitic acid-induced lipotoxicity and gluconeogenesis in a murine model. Eur J Pharmacol 2021; 899:174011. [PMID: 33705803 DOI: 10.1016/j.ejphar.2021.174011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 02/26/2021] [Accepted: 02/28/2021] [Indexed: 11/25/2022]
Abstract
Forkhead transcription factor forkhead box O1 (FoxO1) plays an important role in glucose and lipid metabolism, contributing to the pathogenesis of metabolic disorders. This study aimed to discover a novel FoxO1 inhibitor as a potential new anti-diabetic drug candidate, and describes the biological effects of JY-2, 5-(2,4-dichlorophenyl)-3-(pyridin-2-yl)-1,2,4-oxadiazole in vitro and in vivo. JY-2 inhibited FoxO1 transcriptional activity in a concentration-dependent manner, with an IC50 value of 22 μM. The inhibitory effects of JY-2 on FoxO3a and FoxO4 appeared to be weaker than that on FoxO1. Consistent with its inhibitory effect on FoxO1, JY-2 reduced the palmitic acid (PA)-stimulated mRNA expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in gluconeogenesis in HepG2 cells. In association with the reduced expression of lipid metabolism genes, triglyceride accumulation was also reduced by JY-2, as determined by Oil Red O staining. In addition, JY-2 restored PA-impaired glucose-stimulated insulin secretion (GSIS), in conjunction with an increased mRNA expression of PDX1, MafA, and insulin in INS-1 cells. The in vivo efficacy of JY-2 was examined using C57BL/6J, db/db, and high fat-diet induced obese and diabetic (DIO) mice models, and showed that JY-2 improved glucose tolerance, in parallel with a reduced mRNA expression of gluconeogenic genes. Pharmacokinetic analysis revealed that JY-2 exhibited excellent oral bioavailability (98%), with little adverse effects. These results demonstrated that the novel FoxO1 inhibitor, JY-2, may exert beneficial anti-diabetic effects and that it warrants further investigation as a novel anti-diabetic drug candidate.
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Affiliation(s)
- Hye-Eun Choi
- Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21999, South Korea
| | - YuSik Kim
- Severance Institute for Vascular and Metabolic Research Yonsei University School of Medicine, Seoul, 06230, South Korea
| | - Han-Joo Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, South Korea
| | - Hyae Gyeong Cheon
- Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21999, South Korea; Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
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Sharma R, Tiwari S. Renal gluconeogenesis in insulin resistance: A culprit for hyperglycemia in diabetes. World J Diabetes 2021; 12:556-568. [PMID: 33995844 PMCID: PMC8107972 DOI: 10.4239/wjd.v12.i5.556] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/27/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Renal gluconeogenesis is one of the major pathways for endogenous glucose production. Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes. We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes. A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up. Insulin-resistant models exhibit reduced insulin receptor (IR) expression and/or post-receptor signaling in their kidney tissue. Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys, which may increase renal gluconeogenesis in the state of insulin resistance. It is now established that the kidney contributes up to 20% of all glucose production via gluconeogenesis in the post-absorptive phase. However, the rate of renal glucose release excessively increases in diabetes. The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels. Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis. Overall, the available literature suggests that impairment in renal gluconeogenesis in an insulin-resistant state may contribute to hyperglycemia in type 2 diabetes.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Zhang X, Jiang L, Liu H. Forkhead Box Protein O1: Functional Diversity and Post-Translational Modification, a New Therapeutic Target? DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1851-1860. [PMID: 33976536 PMCID: PMC8106445 DOI: 10.2147/dddt.s305016] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/19/2021] [Indexed: 11/23/2022]
Abstract
Forkhead box protein O1 (FoXO1) is a transcription factor involved in the regulation of a wide variety of physiological process including glucose metabolism, lipogenesis, bone mass, apoptosis, and autophagy. FoXO1 dysfunction is involved in the pathophysiology of various diseases including metabolic diseases, atherosclerosis, and tumors. FoXO1 activity is regulated in response to different physiological or pathogenic conditions by changes in protein expression and post-translational modifications. Various modifications cooperate to regulate FoXO1 activity and FoXO1 target gene transcription. In this review, we summarize how different post-translational modifications regulate FoXO1 physiological function, which may provide new insights for drug design and development.
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Affiliation(s)
- Xiaojun Zhang
- Department of Cardiology, Shandong Rongjun General Hospital, Jinan, 250013, People's Republic of China
| | - Lusheng Jiang
- Department of Emergency, Shandong Rongjun General Hospital, Jinan, 250013, People's Republic of China
| | - Huimin Liu
- Blood Purification Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People's Republic of China
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The Role of Hepatic Fat Accumulation in Glucose and Insulin Homeostasis-Dysregulation by the Liver. J Clin Med 2021; 10:jcm10030390. [PMID: 33498493 PMCID: PMC7864173 DOI: 10.3390/jcm10030390] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 11/17/2022] Open
Abstract
Accumulation of hepatic triacylglycerol (TG) is associated with obesity and metabolic syndrome, which are important pathogenic factors in the development of type 2 diabetes. In this narrative review, we summarize the effects of hepatic TG accumulation on hepatic glucose and insulin metabolism and the underlying molecular regulation in order to highlight the importance of hepatic TG accumulation for whole-body glucose metabolism. We find that liver fat accumulation is closely linked to impaired insulin-mediated suppression of hepatic glucose production and reduced hepatic insulin clearance. The resulting systemic hyperinsulinemia has a major impact on whole-body glucose metabolism and may be an important pathogenic step in the development of type 2 diabetes.
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Zhang C, Seong KM, Sun W, Mittapalli O, Qiu B, Clark JM, Pittendrigh BR. The insulin signaling pathway in Drosophila melanogaster: A nexus revealing an "Achilles' heel" in DDT resistance. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2021; 171:104727. [PMID: 33357549 DOI: 10.1016/j.pestbp.2020.104727] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/28/2020] [Accepted: 10/10/2020] [Indexed: 06/12/2023]
Abstract
Insecticide resistance is an ongoing challenge in agriculture and disease vector control. Here, we demonstrate a novel strategy to attenuate resistance. We used genomics tools to target fundamental energy-associated pathways and identified a potential "Achilles' heel" for resistance, a resistance-associated protein that, upon inhibition, results in a substantial loss in the resistance phenotype. Specifically, we compared the gene expression profiles and structural variations of the insulin/insulin-like growth factor signaling (IIS) pathway genes in DDT-susceptible (91-C) and -resistant (91-R) Drosophila melanogaster (Drosophila) strains. A total of eight and seven IIS transcripts were up- and down-regulated, respectively, in 91-R compared to 91-C. A total of 114 nonsynonymous mutations were observed between 91-C and 91-R, of which 51.8% were fixed. Among the differentially expressed transcripts, phosphoenolpyruvate carboxykinase (PEPCK), down-regulated in 91-R, encoded the greatest number of amino acid changes, prompting us to perform PEPCK inhibitor-pesticide exposure bioassays. The inhibitor of PEPCK, hydrazine sulfate, resulted in a 161- to 218-fold decrease in the DDT resistance phenotype (91-R) and more than a 4- to 5-fold increase in susceptibility in 91-C. A second target protein, Glycogen synthase kinase 3β (GSK3β-PO), had one amino acid difference between 91-C and 91-R, and the corresponding transcript was also down-regulated in 91-R. A GSK3β-PO inhibitor, lithium chloride, likewise reduced the resistance but to a lesser extent than did hydrazine sulfate for PEPCK. We demonstrate the potential role of IIS genes in DDT resistance and the potential discovery of an "Achilles' heel" against pesticide resistance in this pathway.
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Affiliation(s)
- Can Zhang
- Department of Eco-Engineering, Guangdong Eco-Engineering Polytechnic, Guangzhou 510520, China; Department of Entomology, Michigan State University, East Lansing, MI 48824, USA
| | - Keon Mook Seong
- Department of Entomology, Michigan State University, East Lansing, MI 48824, USA; Department of Applied Biology, College of Ecology and Environment, Kyungpook National University, Sangju, Republic of Korea
| | - Weilin Sun
- Department of Entomology, Michigan State University, East Lansing, MI 48824, USA
| | | | - Baoli Qiu
- Department of Entomology, South China Agricultural University, Guangzhou 510640, China
| | - John M Clark
- Department of Veterinary and Animal Sciences, University of Massachusetts-Amherst, Amherst, MA, USA
| | - Barry R Pittendrigh
- Department of Entomology, Michigan State University, East Lansing, MI 48824, USA.
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Guerra S, Gastaldelli A. The role of the liver in the modulation of glucose and insulin in non alcoholic fatty liver disease and type 2 diabetes. Curr Opin Pharmacol 2020; 55:165-174. [PMID: 33278735 DOI: 10.1016/j.coph.2020.10.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 10/12/2020] [Accepted: 10/19/2020] [Indexed: 12/20/2022]
Abstract
In this review we have discussed how the liver plays a central role in the regulation of glucose metabolism and in insulin clearance. Both non-alcoholic fatty liver disease (NAFLD) and diabetes (T2D) are characterized by high plasma insulin concentrations, hepatic insulin resistance, high hepatic glucose production (HGP), in particular gluconeogenesis (GNG), that are increased proportionally to fasting hyperglycemia, while postprandial hyperglycemia is due to impaired suppression of HGP by insulin, and reduced hepatic glycogen storage. The liver acts also as a modulator of peripheral insulin since most of insulin secreted by the pancreas is cleared by the liver during the first pass. Hepatokines and hepatic lipids can act in either autocrine or paracrine way and can be responsible of the changes in insulin sensitivity and alterations in glucose metabolism.
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Affiliation(s)
- Sara Guerra
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy; Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy; Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy.
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Saeed NM, Mansour AM, Allam S. Lycopene induces insulin signaling and alleviates fibrosis in experimental model of non-alcoholic fatty liver disease in rats. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Kim DH, Ha S, Choi YJ, Dong HH, Yu BP, Chung HY. Altered FoxO1 and PPARγ interaction in age-related ER stress-induced hepatic steatosis. Aging (Albany NY) 2020; 11:4125-4144. [PMID: 31246177 PMCID: PMC6628996 DOI: 10.18632/aging.102042] [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] [Received: 02/28/2019] [Accepted: 06/17/2019] [Indexed: 01/05/2023]
Abstract
Chronic kidney disease (CKD) is one of the most powerful predictors of premature cardiovascular disease (CVD), with heightened susceptibility to vascular intimal and medial calcification associated with a high cardiovascular mortality. Abnormal mineral metabolism of calcium (Ca) and phosphate (P) and underlying (dys)regulated hormonal control in CKD-mineral and bone disorder (MBD) is often accompanied by bone loss and increased vascular calcification (VC). While VC is known to be a multifactorial process and a major risk factor for CVD, the view of primary triggers and molecular mechanisms complexity has been shifting with novel scientific knowledge over the last years. In this review we highlight the importance of calcium-phosphate (CaP) mineral crystals in VC with an integrated view over the complexity of CKD, while discuss past and recent literature aiming to highlight novel horizons on this major health burden. Exacerbated VC in CKD patients might result from several interconnected mechanisms involving abnormal mineral metabolism, dysregulation of endogenous calcification inhibitors and inflammatory pathways, which function in a feedback loop driving disease progression and cardiovascular outcomes. We propose that novel approaches targeting simultaneously VC and inflammation might represent valuable new prognostic tools and targets for therapeutics and management of cardiovascular risk in the CKD population.
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Affiliation(s)
- Dae Hyun Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea
| | - Sugyeong Ha
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea
| | - Yeon Ja Choi
- Department of Biopharmaceutical Engineering, Division of Chemistry and Biotechnology, Dongguk University, Gyeongju 38066, Korea
| | - H Henry Dong
- Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Byung Pal Yu
- Department of Physiology, The University of Texas Health Science Center at San Antonio, TX 78229, USA
| | - Hae Young Chung
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea
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Hosseini Khorami SA, Mutalib MSA, Feili Shiraz M, Abdullah JA, Rejali Z, Ali RM, Khaza'ai H. Genetic determinants of obesity heterogeneity in type II diabetes. Nutr Metab (Lond) 2020; 17:55. [PMID: 32670384 PMCID: PMC7346329 DOI: 10.1186/s12986-020-00476-6] [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: 03/21/2020] [Accepted: 07/01/2020] [Indexed: 11/23/2022] Open
Abstract
Background Although obesity is considered as the main cause of Type II diabetes (T2DM), non-obese individuals may still develop T2DM and obese individuals may not. Method The mRNA expression of PI3K/AKT axis from 100 non-obese and obese participants with insulin sensitivity and insulin resistance states were compared in this study toward the understanding of obesity heterogeneity molecular mechanism. Result In present study, there was no statistically significant difference in gene expression levels of IRS1 and PTEN between groups, whereas PI3K, AKT2 and GLUT4 genes were expressed at a lower level in obese diabetic group compared to other groups and were statistically significant. PDK1 gene was expressed at a higher level in non-obese diabetic group compared to obese diabetic and non-obese non-diabetics groups. No statistically significant difference was identified in gene expression pattern of PI3K/AKT pathway between obese non-diabetics and non-obese non-diabetics. Conclusion The components of PI3K/AKT pathway which is related to the fasting state, showed reduced expression in obese diabetic group due to the chronic over-nutrition which may induced insensitivity and reduced gene expression. The pathogenesis of insulin resistance in the absence of obesity in non-obese diabetic group could be due to disturbance in another pathway related to the non-fasting state like gluconeogenesis. Therefore, the molecular mechanism of insulin signalling in non-obese diabetic individuals is different from obese diabetics which more investigations are required to study insulin signalling pathways in greater depth, in order to assess nutritional factors, contribute to insulin resistance in obese diabetic and non-obese diabetic individuals.
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Affiliation(s)
| | - Mohd Sokhini Abd Mutalib
- Department of Nutrition and Dietetic, University Putra Malaysia, 43400 Serdang, Selangor Malaysia
| | - Mohammad Feili Shiraz
- Department of Artificial Intelligence and Computer Engineering, Faculty of Electrical Engineering, Computer and IT, Qazvin Branch, Islamic Azad University, Qazvin, Iran
| | | | - Zulida Rejali
- Department of Obstetrics and Gynaecology, University Putra Malaysia, 43400 Serdang, Selangor Malaysia
| | - Razana Mohd Ali
- Department of Pathology, University Putra Malaysia, 43400 Serdang, Selangor Malaysia
| | - Huzwah Khaza'ai
- Department of Biomedical Science, University Putra Malaysia, 43400 Serdang, Selangor Malaysia
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Transcriptional Regulation in Non-Alcoholic Fatty Liver Disease. Metabolites 2020; 10:metabo10070283. [PMID: 32660130 PMCID: PMC7408131 DOI: 10.3390/metabo10070283] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.
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Rosso C, Caviglia GP, Younes R, Ribaldone DG, Fagoonee S, Pellicano R, Bugianesi E. Molecular mechanisms of hepatic fibrosis in chronic liver diseases. MINERVA BIOTECNOL 2020; 32. [DOI: 10.23736/s1120-4826.20.02619-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sookoian S, Pirola CJ, Valenti L, Davidson NO. Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology. Hepatology 2020; 72:330-346. [PMID: 32170962 PMCID: PMC7363530 DOI: 10.1002/hep.31229] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/12/2020] [Accepted: 03/06/2020] [Indexed: 12/16/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane-bound O-acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17-beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell-based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low-density lipoprotein assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
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Affiliation(s)
- Silvia Sookoian
- University of Buenos Aires, School of Medicine, Institute of Medical Research ALanari, Ciudad Autónoma de Buenos Aires, Argentina.,National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute of Medical Research (IDIM), Department of Clinical and Molecular Hepatology, Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J. Pirola
- University of Buenos Aires, School of Medicine, Institute of Medical Research ALanari, Ciudad Autónoma de Buenos Aires, Argentina.,National Scientific and Technical Research Council (CONICET)−University of Buenos Aires, Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Ciudad Autónoma de Buenos Aires, Argentina
| | - Luca Valenti
- Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca Granda OspedalePoliclinico Milano, Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy
| | - Nicholas O. Davidson
- Departments of Medicine and Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Zhang Y, Yuan T, Su Z, Wang X, Wang Y, Ni Y, Zuo Y, Gu H. Reduced methylation of PP2Ac promotes ethanol-induced lipid accumulation through FOXO1 phosphorylation in vitro and in vivo. Toxicol Lett 2020; 331:65-74. [PMID: 32492475 DOI: 10.1016/j.toxlet.2020.05.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/21/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022]
Abstract
Although disturbance of the methionine cycle and sequent decrease in hepatic methylation capacity are known to be important factors in the development of alcoholic liver injury, the underlying mechanisms are not fully understood. Here, we investigated the importance of the methylation of protein phosphatase 2A (PP2A) in alcoholic liver disease (ALD). We found that the severity of ethanol-induced liver injury and the extent of demethylation of PP2A catalytic C subunit (PP2Ac) were reduced after treatment with betaine, a methyl donor involved in the methionine-homocysteine cycle. These results suggest that PP2Ac methylation is decreased due to a broad decrease in hepatic methylation capacity after exposure to ethanol. Moreover, we found that the reduction in PP2Ac methylation led to increased degradation of the regulatory Bα subunit, thus promoting the phosphorylation and nuclear exclusion of Forkhead box O1 (FOXO1) and reducing FOXO1 transcriptional activity. Ultimately, the reduced activity of FOXO1 led to increased expression of TXNIP, which caused hepatic lipid accumulation. Our findings suggest that the reduction of PP2A methylation, a result of decrease hepatic methylation capacity, played an important role in ethanol-induced lipid accumulation via down-regulation of PP2A/Bα and FOXO1 phosphorylation.
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Affiliation(s)
- Yali Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
| | - Tianli Yuan
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Zhangyao Su
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Xi Wang
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Yilun Wang
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Yao Ni
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Yue Zuo
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
| | - Haohao Gu
- Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China
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Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats. Clin Sci (Lond) 2020; 133:2415-2430. [PMID: 31769484 DOI: 10.1042/cs20190863] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/12/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND With an increasing prevalence of obesity and metabolic syndrome, exploring the effects and delineating the mechanisms of possible therapeutic agents are of critical importance. We examined the effects of SGLT2 inhibitor-dapagliflozin on insulin resistance, hepatic gluconeogenesis, hepatic injury and pancreatic ER stress in high-fat diet-induced obese rats. MATERIALS AND METHODS Male Wistar rats were fed with normal diet (ND) or high-fat diet for 16 weeks. Then high-fat rats were given vehicle (HF) or dapagliflozin (1 mg/kg/day; HFDapa) or metformin (30 mg/kg/day; HFMet) for another 4 weeks. RESULTS We found that dapagliflozin ameliorated high-fat diet-induced insulin resistance. The fasting plasma glucose level was comparable among groups, although dapagliflozin treatment led to substantial glycosuria. Hepatic gluconeogenic enzymes, PEPCK, G6Pase and FBPase, expression was not different in HF rats compared with ND rats. Meanwhile, dapagliflozin-treated group exhibited the elevation of these enzymes in parallel with the rise of transcription factor CREB, co-factor PGC1α and upstream regulator SIRT1. Hepatic oxidative stress, inflammation and NAFLD activity score as well as hepatic and pancreatic ER stress and apoptosis in obese rats were attenuated by dapagliflozin. CONCLUSION We conclude that dapagliflozin improved obesity-related insulin resistance, hepatic and pancreatic injury independent of fasting plasma glucose level. Of note, dapagliflozin-induced glycosuria apparently triggered the up-regulation of hepatic gluconeogenic enzymes to prevent hypoglycemia.
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Lucchinetti E, Lou PH, Wawrzyniak P, Wawrzyniak M, Scharl M, Holtzhauer GA, Krämer SD, Hersberger M, Rogler G, Zaugg M. Novel Strategies to Prevent Total Parenteral Nutrition-Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes. Mol Nutr Food Res 2020; 65:e1901270. [PMID: 32359213 DOI: 10.1002/mnfr.201901270] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/09/2020] [Indexed: 12/15/2022]
Abstract
Total parenteral nutrition (TPN) is a life-saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN-associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut-originating incretins as well as the potentially toxicity of phytosterols and pro-inflammatory fatty acids mainly released from soybean oil-based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti-inflammatory n-3 to pro-inflammatory n-6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN-associated adverse effects.
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Affiliation(s)
- Eliana Lucchinetti
- Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada
| | - Phing-How Lou
- Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada
| | - Paulina Wawrzyniak
- Division of Clinical Chemistry and Biochemistry, Children's Hospital Zurich, Zurich, 8032, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Gregory A Holtzhauer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Stefanie D Krämer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Martin Hersberger
- Division of Clinical Chemistry and Biochemistry, Children's Hospital Zurich, Zurich, 8032, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Michael Zaugg
- Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada.,Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada
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