Apolipoprotein B100 Metabolism in Autosomal-Dominant Hypercholesterolemia Related to Mutations inPCSK9

Abstract

Objective— We have reported further heterogeneity in familial autosomal-dominant hypercholesterolemia (FH) related to mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene previously named neural apoptosis regulated convertase 1 (Narc-1). Our aim was to define the metabolic bases of this new form of hypercholesterolemia. Methods and Results— In vivo kinetics of apolipoprotein B100-containing lipoproteins using a 14-hour primed constant infusion of [²H₃] leucine was conducted in 2 subjects carrying the mutation S127R in PCSK9, controls subjects, and FH subjects with known mutations on the low-density lipoprotein (LDL) receptor gene (LDL-R). Apo B100 production, catabolism, and transfer rates were estimated from very LDL (VLDL), intermediate-density lipoprotein (IDL), and LDL tracer enrichments by compartmental analysis. PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold). The 2 subjects also showed a decrease in VLDL and IDL conversion (10% to 30% of the controls). LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls but still higher than LDL-R–mutated subjects. Conclusion— These results showed that the effect of the S127R mutation of PCSK9 on plasma cholesterol homeostasis is mainly related to an overproduction of apolipoprotein B100. Kinetic study using [²H₃] leucine was conducted in 2 subjects with PCSK9 mutation and in controls. Patients exhibited a dramatic increase in the production rate of apolipoprotein B100 in VLDL, IDL, and LDL, a decrease in VLDL and IDL conversion rate, and a slight decrease in LDL fractional catabolic rate.