Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice

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...

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Published in:PloS one 2012-02, Vol.7 (2), p.e31394
Main Authors: Lee, Jinmi, Hong, Seok-Woo, Chae, Seoung Wan, Kim, Dong Hoon, Choi, Ji Hun, Bae, Ji Cheol, Park, Se Eun, Rhee, Eun-Jung, Park, Cheol-Young, Oh, Ki-Won, Park, Sung-Woo, Kim, Sun-Woo, Lee, Won-Young
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
Animal models
Animals
Biology
Body weight
Body Weight - drug effects
Cell culture
Cell Line, Tumor
Cytokines - genetics
Cytokines - metabolism
Diet
Diet, High-Fat
Fatty acids
Fatty liver
Fatty Liver - blood
Fatty Liver - drug therapy
Fatty Liver - genetics
Fatty Liver - pathology
Feeding Behavior - drug effects
FOXO1 protein
Gene expression
Gene Expression Regulation - drug effects
Glucagon-Like Peptide-1 Receptor
Glucose
Glucose - metabolism
Glucose transporter
Hepatocytes
High fat diet
Homeostasis - drug effects
Homeostasis - genetics
House mouse
Humans
Insulin resistance
Kinases
Lipids
Lipogenesis - drug effects
Lipogenesis - genetics
Liver
Liver - drug effects
Liver - enzymology
Liver - pathology
Liver diseases
LKB1 protein
Medicine
Metabolism
Mice
Mice, Inbred C57BL
Mice, Obese
mRNA
Nicotinamide Phosphoribosyltransferase - genetics
Nicotinamide Phosphoribosyltransferase - metabolism
Obesity
Oxidation
Oxidation-Reduction - drug effects
Palmitic acid
Palmitic Acid - pharmacology
Peptides - pharmacology
Peptides - therapeutic use
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Receptors, Glucagon - genetics
Receptors, Glucagon - metabolism
RNA
Rodents
Saturated fatty acids
SIRT1 protein
Sirtuin 1 - genetics
Sirtuin 1 - metabolism
Triglycerides
Triglycerides - blood
Type 2 diabetes
Venoms - pharmacology
Venoms - therapeutic use
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0031394