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 journalArticle

161 Citations (Scopus)

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 2011

Fingerprint

Lipogenesis
AMP-Activated Protein Kinases
Glucagon-Like Peptide 1
Liver
Fats
Dipeptidyl Peptidase 4
Hepatocytes
Food
Insulin Resistance
Enzymes
Phosphorylation
Carnitine O-Palmitoyltransferase
Glucose Clamp Technique
High Fat Diet
Protein Kinases
Signal Transduction
Triglycerides
Up-Regulation
Fatty Acids
Down-Regulation

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

Ben-Shlomo, S., Zvibel, I., Shnell, M., Shlomai, A., Chepurko, E., Halpern, Z., ... Fishman, S. (2011). Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. Journal of Hepatology, 54(6), 1214-1223. https://doi.org/10.1016/j.jhep.2010.09.032

Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. / Ben-Shlomo, Shani; Zvibel, Isabel; Shnell, Mati; Shlomai, Amir; Chepurko, Elena; Halpern, Zamir; Barzilai, Nir; Oren, Ran; Fishman, Sigal.

In: Journal of Hepatology, Vol. 54, No. 6, 06.2011, p. 1214-1223.

Research output: Contribution to journalArticle

Ben-Shlomo, S, Zvibel, I, Shnell, M, Shlomai, A, Chepurko, E, Halpern, Z, Barzilai, N, Oren, R & Fishman, S 2011, 'Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase', Journal of Hepatology, vol. 54, no. 6, pp. 1214-1223. https://doi.org/10.1016/j.jhep.2010.09.032
Ben-Shlomo, Shani ; Zvibel, Isabel ; Shnell, Mati ; Shlomai, Amir ; Chepurko, Elena ; Halpern, Zamir ; Barzilai, Nir ; Oren, Ran ; Fishman, Sigal. / Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. In: Journal of Hepatology. 2011 ; Vol. 54, No. 6. pp. 1214-1223.
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AU - Zvibel, Isabel

AU - Shnell, Mati

AU - Shlomai, Amir

AU - Chepurko, Elena

AU - Halpern, Zamir

AU - Barzilai, Nir

AU - Oren, Ran

AU - Fishman, Sigal

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