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

J Hepatol. 2011 Jun;54(6):1214-23. doi: 10.1016/j.jhep.2010.09.032. Epub 2010 Oct 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cytokines / metabolism
  • DNA Primers / genetics
  • Dipeptidyl Peptidase 4 / deficiency
  • Dipeptidyl Peptidase 4 / genetics
  • Dipeptidyl Peptidase 4 / metabolism
  • Enzyme Activation / drug effects
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide 1 / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Inflammation Mediators / metabolism
  • Lipids / blood
  • Lipogenesis / drug effects
  • Lipogenesis / physiology*
  • Liver / drug effects*
  • Liver / metabolism*
  • Male
  • Metabolic Networks and Pathways / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred F344
  • Rats, Transgenic


  • Cytokines
  • DNA Primers
  • Inflammation Mediators
  • Lipids
  • RNA, Messenger
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Prkaa2 protein, rat
  • AMP-Activated Protein Kinases
  • Dipeptidyl Peptidase 4