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Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2004 Aug; Vol. 24 (8), pp. 1448-53. Date of Electronic Publication: 2004 May 27. - Publication Year :
- 2004
-
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.<br />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.<br />Conclusions: 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.
- Subjects :
- Adult
Amino Acid Substitution
Apolipoprotein B-100
Cholesterol Esters metabolism
Female
Genes, Dominant
Humans
Hyperlipoproteinemia Type II metabolism
Lipid Metabolism
Lipoproteins metabolism
Lipoproteins, IDL
Lipoproteins, LDL metabolism
Lipoproteins, VLDL metabolism
Liver metabolism
Male
Middle Aged
Proprotein Convertase 9
Proprotein Convertases
Serine Endopeptidases chemistry
Serine Endopeptidases physiology
Apolipoproteins B biosynthesis
Hyperlipoproteinemia Type II genetics
Mutation, Missense
Point Mutation
Serine Endopeptidases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 24
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 15166014
- Full Text :
- https://doi.org/10.1161/01.ATV.0000133684.77013.88