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

Shani Ben-Shlomo, Isabel Zvibel, Mati Shnell, Amir Shlomai, Elena Chepurko, Zamir Halpern, Nir Barzilai, Ran Oren, Sigal Fishman

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

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 β-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 non-alcoholic fatty liver diseases.

Original languageEnglish (US)
Pages (from-to)1214-1223
Number of pages10
JournalJournal of Hepatology
Volume54
Issue number6
DOIs
StatePublished - Jun 1 2011

Keywords

  • AMPK
  • Dipeptidylpetidase 4
  • Glucagon-like peptide 1
  • Gluconeogenesis
  • Incretins
  • Inflammatory cytokines
  • Lipogenesis
  • Liver

ASJC Scopus subject areas

  • Hepatology

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