title: Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, and Sackler School of Medicine, Tel Aviv, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Ben-Shlomo
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
authors.forename: Mati
authors.initials: M
authors.lastname: Shnell
authors.forename: Amir
authors.initials: A
authors.lastname: Shlomai
authors.forename: Elena
authors.initials: E
authors.lastname: Chepurko
authors.forename: Zamir
authors.initials: Z
authors.lastname: Halpern
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Ran
authors.initials: R
authors.lastname: Oren
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic
chemical_list: D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D008055:Lipids; D012333:RNA, Messenger; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; C543928:Prkaa2 protein, rat; D055372:AMP-Activated Protein Kinases; D018819:Dipeptidyl Peptidase 4