GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice

PLoS One. 2012;7(11):e49152. doi: 10.1371/journal.pone.0049152. Epub 2012 Nov 2.

Abstract

Objective: In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism.

Experimental approach: The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined.

Results: CNTO3649 and exendin-4 reduced fasting plasma glucose (up to -30% and -28% respectively) and insulin (-43% and -65% respectively). In addition, these agents reduced VLDL-TG production (-36% and -54% respectively) and VLDL-apoB production (-36% and -43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (-39% and -55% respectively), cholesterol (-30% and -55% respectively), and phospholipids (-23% and -36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob).

Conclusion: GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein E3 / genetics
  • Apolipoprotein E3 / metabolism*
  • Apolipoproteins B / metabolism
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Dyslipidemias / blood
  • Exenatide
  • Fatty Liver / metabolism*
  • Fatty Liver / therapy
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor
  • Insulin / metabolism
  • Lipogenesis
  • Liver / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Peptides / chemistry
  • Peptides / metabolism
  • Receptors, Glucagon / metabolism*
  • Venoms / metabolism

Substances

  • Apolipoprotein E3
  • Apolipoproteins B
  • Blood Glucose
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide

Grants and funding

This research was supported by a grant from Janssen Research & Development, the Netherlands Heart Foundation (NHS grant 2007B81 to PCNR), and the Dutch Diabetes Foundation (DFN grant 2007.00.010). PCNR is an Established Investigator of the Netherlands Heart Foundation (grant 2009T038). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.