Abstract
The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism
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Animals
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Body Weight / drug effects
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Cell Line, Tumor
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Cytokines / genetics
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Cytokines / metabolism
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Diet, High-Fat*
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Exenatide
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Fatty Liver / blood
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Fatty Liver / drug therapy*
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Fatty Liver / genetics
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Fatty Liver / pathology
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Feeding Behavior / drug effects
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Gene Expression Regulation / drug effects
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Glucagon-Like Peptide-1 Receptor
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Glucose / metabolism
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Homeostasis / drug effects
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Homeostasis / genetics
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Humans
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Lipogenesis / drug effects
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Lipogenesis / genetics
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Liver / drug effects
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Liver / enzymology
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Liver / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Obese
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Nicotinamide Phosphoribosyltransferase / genetics
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Nicotinamide Phosphoribosyltransferase / metabolism
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Oxidation-Reduction / drug effects
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Palmitic Acid / pharmacology
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Peptides / pharmacology
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Peptides / therapeutic use*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Glucagon / genetics
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Receptors, Glucagon / metabolism
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Sirtuin 1 / genetics
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Sirtuin 1 / metabolism*
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Triglycerides / blood
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Venoms / pharmacology
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Venoms / therapeutic use*
Substances
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Cytokines
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GLP1R protein, human
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Glp1r protein, mouse
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Glucagon-Like Peptide-1 Receptor
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Peptides
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Receptors, Glucagon
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Triglycerides
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Venoms
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Palmitic Acid
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Exenatide
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, mouse
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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AMP-Activated Protein Kinases
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Sirt1 protein, mouse
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Sirtuin 1
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Glucose