Liraglutide Increases the Catabolism of Apolipoprotein B100-Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression

Abstract

OBJECTIVE Dyslipidemia observed in type 2 diabetes (T2D) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles, which all have apolipoprotein B100 (apoB100) as a major apolipoprotein. This prompted us to study the effect of the GLP-1 agonist liraglutide on the metabolism of apoB100-containing lipoproteins. RESEARCH DESIGN AND METHODS We performed an in vivo kinetic study with stable isotopes (L-[1-C-13]leucine) in 10 patients with T2D before and after 6 months of treatment with liraglutide (1.2 mg/day). We also evaluated in mice the effect of liraglutide on the expression of genes involved in apoB100-containing lipoprotein clearance. RESULTS In patients with T2D, liraglutide treatment significantly reduced plasma apoB100 (0.93 +/- 0.13 vs. 1.09 +/- 0.11 g/L, P = 0.011) and fasting triglycerides (1.76 +/- 0.37 vs. 2.48 +/- 0.69 mmol/L, P = 0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL1-apoB100 (4.11 +/- 1.91 vs. 2.96 +/- 1.61 pools/day, P = 0.005), VLDL2-apoB100 (5.17 +/- 2.53 vs. 2.84 +/- 1.65 pools/day, P = 0.008), and IDL-apoB100 (5.27 +/- 2.77 vs. 3.74 +/- 1.85 pools/day, P = 0.017) and in catabolism of LDL-apoB100 (0.72 +/- 0.22 vs. 0.56 +/- 0.22 pools/day, P = 0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced proprotein convertase subtilisin/kexin type 9 (PCSK9), retinol-binding protein 4 (RBP4), and tumor necrosis factor-alpha (TNF-alpha) gene expression in adipose tissue and decreased PCSK9 mRNA and increased LDL receptor protein expression in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver. CONCLUSIONS Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL1, VLDL2, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100-containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2D.