GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE3-Leiden mice

• Published in: PloS one 2012-11, Vol.7 (11), p.e49152
• Main Authors: Parlevliet, Edwin T, Wang, Yanan, Geerling, Janine J, Schröder-Van der Elst, Janny P, Picha, Kristen, O'Neil, Karyn, Stojanovic-Susulic, Vedrana, Ort, Tatiana, Havekes, Louis M, Romijn, Johannes A, Pijl, Hanno, Rensen, Patrick C N
• Format: Article
• Language: English
• Subjects: Animals; Apolipoprotein E; Apolipoprotein E3 - genetics; Apolipoprotein E3 - metabolism; Apolipoproteins; Apolipoproteins B - metabolism; Binding sites; Biology; Blood Glucose - metabolism; Brain research; Cholesterol; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diet; Down-regulation; Dyslipidemia; Dyslipidemias - blood; Endocrinology; Experiments; Fasting; Fatty liver; Fatty Liver - metabolism; Fatty Liver - therapy; Food; Gene expression; Gene regulation; Genes; Genetic engineering; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose tolerance; High fat diet; Insulin; Insulin - metabolism; Insulin resistance; Internal medicine; Intolerance; Lipid metabolism; Lipids; Lipogenesis; Lipoproteins; Lipoproteins (very low density); Liver; Liver - pathology; Liver diseases; Low density lipoproteins; Male; Medical research; Medicine; Metabolic disorders; Metabolism; Metabolites; Mice; Mice, Transgenic; Peptides; Peptides - chemistry; Peptides - metabolism; Phospholipids; Production management; R&D; Reagents; Receptor density; Receptor mechanisms; Receptors, Glucagon - metabolism; Research & development; Rodents; Steatosis; Sterol regulatory element-binding protein; Transgenic mice; Type 2 diabetes; Venoms - metabolism; Veterinary Science
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0049152

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. 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. 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). 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.