GLP-1 Receptor Activation Inhibits VLDL Production and Reverses Hepatic Steatosis by Decreasing Hepatic Lipogenesis in High-Fat-Fed APOE*3-Leiden Mice

Abstract

ObjectiveIn 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 ApproachThe 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.ResultsCNTO3649 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).ConclusionGLP-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.

Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

“…Rats with chronically elevated plasma GLP-1 levels showed decreased expression of lipogenic enzymes and reduced hepatic TG content ( 37 ). In line with this, continuous subcutaneous infusion of exendin-4, a GLP-1 receptor agonist, decreased hepatic VLDL-TG production in mice ( 8 ). Importantly, also central GLP-1 infusion decreased hepatic TG content and expression of lipogenic enzymes in mice, suggesting that GLP-1 can at least in part affect hepatic TG metabolism via a central mechanism ( 38,39 ).…”

Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction

“…Exendin-4 as a GLP-1 receptor agonist can decrease LDL, apolipoprotein B, TG, and increase HDL. Research by Parlevliet et al [18] indicated that this drug could reduce hepatic steatosis and ameliorate dyslipidemia by decreasing serum levels of VLDL and TG. The corresponding results are in agreement with the present study showing that exendin-4 can reduce harmful lipid factors and increase the serum level of HDL.

Figure 2.Treatment of NMRI mice with exendin-4 altered hepatic lipid and enzymatic profiles in the serum.

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Cardiovascular Actions of Incretin-Based Therapies

“…Although chronic administration of GLP-1R agonists in rodent models of dyslipidemia also reduces the levels of circulating lipoproteins, whether these findings reflect direct or indirect actions on liver, intestine, or other tissues remains unclear. 48,49 Furthermore, the specific GLP-1R + cell types mediating these effects on intestinal and hepatic lipoprotein metabolism require further elucidation. Because intracerebroventricular exendin-4 administration (0.023 or 0.23 nmol) reduced hepatic TAG secretion after an overnight fast in C57BL/6 mice fed a high-fat diet for 4 weeks, 7 and acute intracerebroventricular GLP-1 administration rapidly lowered hepatic TAG content in hyperinsulinemic mice fed a high-fat diet, 50 the importance of central GLP-1R signaling for the control of lipid metabolism requires further investigation.…”