on May 27, 2004
Published online before print May 27, 2004, doi: 10.1161/01.ATV.0000133684.77013.88
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Submitted on December 23, 2003
Accepted on April 8, 2004
Apolipoprotein B100 Metabolism in Autosomal-Dominant Hypercholesterolemia Related to Mutations in PCSK9
Khadija Ouguerrram ;
From INSERM U 539 (K.O., M.C., Y.Z., P.C., T.M., M.K.), Centre de Recherche en Nutrition Humaine de Nantes; and Hôtel Dieu (M.A., M.V., C.B.), Nantes, INSERM U 383, Hôpital Necker-enfants malades, Paris, France.
* To whom correspondence should be addressed. E-mail: mkrempf{at}sante.univ-nantes.fr.
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 (Narc1). 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.
Key words: PCSK9 • hypercholesterolemia • apolipoprotein B100 • kinetic analysis • modeling
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