Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase

被引:253
作者
Ben-Shlomo, Shani [1 ]
Zvibel, Isabel [1 ]
Shnell, Mati
Shlomai, Amir [1 ]
Chepurko, Elena [1 ]
Halpern, Zamir [1 ]
Barzilai, Nir [2 ]
Oren, Ran [1 ]
Fishman, Sigal [1 ]
机构
[1] Tel Aviv Sourasky Med Ctr, Sackler Sch Med, Dept Gastroenterol & Hepatol, IL-64239 Tel Aviv, Israel
[2] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10467 USA
关键词
Glucagon-like peptide 1; Dipeptidylpetidase; 4; Liver; Lipogenesis; Gluconeogenesis; Incretins; AMPK; Inflammatory cytokines; INDUCED INSULIN-RESISTANCE; TISSUE GROWTH-FACTOR; LIVER; RAT; STEATOSIS; HEPATOCYTES; METFORMIN; GLP-1; IV; GLUCONEOGENESIS;
D O I
10.1016/j.jhep.2010.09.032
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Glucagon-like peptide-1 (GLP-1), a gut-derived peptide degraded by dipeptidyl peptidase-4 (DPP4), stimulates insulin secretion in response to nutrients, yet its direct effect on the liver is controversial. We investigated the effects of GLP-1 on hepatic fat and glucose metabolism and elucidated its mechanism of action. Methods: Hepatic fat metabolism, including lipogenic enzymes and signal transduction regulators, was assessed in livers of DPP4-deficient rats (DPP4-) with chronically elevated GLP-1 and in GLP-1-treated primary hepatocytes. The effect of chronic elevated GLP-1 on insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp. Results: Normal and high fat diet fed DPP4-rats displayed reduced hepatic triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid beta-oxidation. In vitro studies demonstrated that these effects were directly induced by GLP-1. Mechanistically, GLP-1 increased cAMP in hepatocytes, resulting in the phosphorylation of cAMP-activated protein kinase (AMPK), a suppressor of lipogenesis. Indeed, hepatocytes expressing a dominant negative Ad-DN-AMPK displayed attenuated GLP-1 effects on AMPK phosphorylation and its downstream lipogenic targets. Importantly, normoglycemic DPP4-rats did not display improved hepatic insulin sensitivity in vivo, suggesting a direct effect of GLP-1 on fat metabolism. Finally, DPP4-rats expressed lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient stimuli. Conclusions: GLP-1 suppresses hepatic lipogenesis via activation of the AMPK pathway. GLP-1 inhibitory effects on hepatic fat accumulation and nutrient-induced hepatic proinflammatory response suggest GLP-1 analogs as novel therapies for nonalcoholic fatty liver diseases. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:1214 / 1223
页数:10
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