Plasma PCSK9 correlates with apoB-48-containing triglyceride-rich lipoprotein production in men with insulin resistance

Abstract

Intestinal triglyceride (TG)-rich lipoproteins (TRLs) are important in the pathogenesis of atherosclerosis in insulin resistance (IR). We investigated the association of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations with apoB-48-containing TRL metabolism in 148 men displaying various degrees of IR by measuring in vivo kinetics of TRL apoB-48 during a constant-fed state after a primed-constant infusion of L-[5,5,5-D3]leucine. Plasma PCSK9 concentrations positively correlated with TRL apoB-48 pool size (r = 0.31, P = 0.0002) and production rate (r = 0.24, P = 0.008) but not the fractional catabolic rate (r = -0.04, P = 0.6). Backward stepwise multiple linear regression analysis identified PCSK9 concentrations as a positive predictor of TRL apoB-48 production rate (standard β = +0.20, P = 0.007) independent of BMI, age, T2D/metformin use, dietary fat intake during the kinetic study, and fasting concentrations of TGs, insulin, glucose, LDL cholesterol, or C-reactive protein. We also assessed intestinal expression of key genes involved in chylomicron processing from duodenal samples of 71 men. Expression of PCSK9 and HMG-CoAR genes was positively associated (r = 0.43, P = 0.002). These results support PCSK9 association with intestinal secretion and plasma overaccumulation of TRL apoB-48 in men with IR.

Keywords: apolipoprotein B-48; cholesterol; proprotein convertase subtilisin/kexin type 9.

Fig. 1.

Radar plot presenting the associations between PCSK9 (●, PCSK9 plasma concentrations, n = 148; ◆, PCSK9 intestinal expression, n = 71) and anthropometric and fasting biochemical characteristics of the subjects. Radar lines represent Pearson’s correlation coefficient. Correlations between intestinal expression of PCSK9 and anthropometric and fasting biochemical characteristics of the subjects were adjusted for the expression of the reference gene G6PD. All P values were adjusted for multiple testing using the adaptive Holm–Bonferroni method. Black-filled marks identify significant association (P < 0.05), and white-filled marks represent nonsignificant association (P > 0.05). C, cholesterol.

Fig. 2.

Pearson’s correlations between fasting PCSK9 concentrations and postprandial TRL apoB-48 PS (A), FCR (B), and PR (C) in n = 148 men with various degrees of IR. P values were adjusted for multiple testing using the adaptive Holm–Bonferroni method.

Fig. 3.

Radar plot presenting the associations between the intestinal expression of PCSK9 (♦) and intestinal expression of key genes involved in cholesterol and chylomicron metabolism in n = 71 men. Radar lines represent Pearson’s correlation coefficient. Correlations were adjusted for the expression of the reference gene G6PD. P values were adjusted for multiple testing using the adaptive Holm–Bonferroni method. Black-filled marks identify significant association (P < 0.05), and white-filled marks represent nonsignificant association.