title: GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice.
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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Edwin T
authors.initials: ET
authors.lastname: Parlevliet
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.forename: Janine J
authors.initials: JJ
authors.lastname: Geerling
authors.forename: Janny P
authors.initials: JP
authors.lastname: Schröder-Van der Elst
authors.forename: Kristen
authors.initials: K
authors.lastname: Picha
authors.forename: Karyn
authors.initials: K
authors.lastname: O'Neil
authors.forename: Vedrana
authors.initials: V
authors.lastname: Stojanovic-Susulic
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ort
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Hanno
authors.initials: H
authors.lastname: Pijl
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D001055:Apolipoproteins B / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D050171:Dyslipidemias / Q000097:blood; D000077270:Exenatide; D005234:Fatty Liver / Q000378:metabolism* / Q000628:therapy; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000378:metabolism; D050155:Lipogenesis; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism*; D014688:Venoms / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D001055:Apolipoproteins B; D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide