title: Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
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.
  
  
  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.
  
  
  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.
authors.affiliation: INSERM U 539, Centre de Recherche en Nutrition Humaine de Nantes, France.
authors.forename: Khadija
authors.initials: K
authors.lastname: Ouguerram
authors.forename: Maud
authors.initials: M
authors.lastname: Chetiveaux
authors.forename: Yassine
authors.initials: Y
authors.lastname: Zair
authors.forename: Philippe
authors.initials: P
authors.lastname: Costet
authors.forename: Marianne
authors.initials: M
authors.lastname: Abifadel
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Thierry
authors.initials: T
authors.lastname: Magot
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis*; D002788:Cholesterol Esters / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002788:Cholesterol Esters; D008074:Lipoproteins; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases