title: Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells.
abstract: Mutations in Proprotein Convertase Subtilisin Kexin 9 (PCSK9) have been associated with autosomal dominant hypercholesterolemia. In vivo kinetic studies indicate that LDL catabolism was impaired and apolipoprotein B (apoB)-containing lipoprotein synthesis was enhanced in two patients presenting with the S127R mutation on PCSK9. To understand the physiological role of PCSK9, we overexpressed human PCSK9 in mouse and cellular models as well as attenuated the endogenous expression of PCSK9 in HuH7 hepatoma cells using RNA interference. Here, we show that PCSK9 dramatically impairs the expression of the low density lipoprotein receptor (LDLr) and, in turn, LDL cellular binding as well as LDL clearance from the plasma compartment in C57BL6/J mice but not in LDLr-deficient mice, establishing a definitive role for PCSK9 in the modulation of the LDLr metabolic pathway. In contrast to data obtained in S127R-PCSK9 patients presenting with increased apoB production, our study indicates that wild-type PCSK9 does not significantly alter the production and/or secretion of VLDL apoB in either cultured cells or mice. Finally, we show that unlike PCSK9 overexpression in mice, the S127R mutation in patients led to increased VLDL apoB levels, suggesting a potential gain of function for S127R-PCSK9 in humans.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U539, Centre Hospitalier Universitaire, Hôtel Dieu, Nantes, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Lalanne
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.forename: Marcelo J A
authors.initials: MJ
authors.lastname: Amar
authors.forename: Maud
authors.initials: M
authors.lastname: Chétiveaux
authors.forename: Yassine
authors.initials: Y
authors.lastname: Zaïr
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Jarnoux
authors.forename: Khadija
authors.initials: K
authors.lastname: Ouguerram
authors.forename: José
authors.initials: J
authors.lastname: Friburg
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.forename: Michel
authors.initials: M
authors.lastname: Krempf
authors.forename: Philippe
authors.initials: P
authors.lastname: Costet
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D020868:Gene Silencing; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D001055:Apolipoproteins B; D002352:Carrier Proteins; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; C106092:microsomal triglyceride transfer protein; D008049:Lipase; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases