title: SIRT1 mediates the effect of GLP-1 receptor agonist exenatide on ameliorating hepatic steatosis.
abstract: GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD(+)-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1(+/-) mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1(+/-) mice. In addition, the protein expression of SIRT1 and phosphorylated AMPK was upregulated, whereas lipogenic-related protein, including SREBP-1c and PNPLA3, was downregulated in the WT group after exenatide treatment. However, none of these changes were observed in SIRT1(+/-) mice. In HepG2 cells, exendin-4-reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNA interference. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting the GLP-1 receptor agonist could serve as a potential drug for nonalcoholic fatty liver disease (NAFLD), especially in type 2 diabetes combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Zonglan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Zeng
authors.affiliation: Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China wjianp@mail.sysu.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Weng
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D000077270:Exenatide; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D034622:RNA Interference; D018027:Receptors, Glucagon / Q000819:agonists*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014688:Venoms / Q000627:therapeutic use*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1