Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells.
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.
Lalanne
Florent
F
Institut National de la Santé et de la Recherche Médicale U539, Centre Hospitalier Universitaire, Hôtel Dieu, Nantes, France.
Lambert
Gilles
G
Amar
Marcelo J A
MJ
Chétiveaux
Maud
M
Zaïr
Yassine
Y
Jarnoux
Anne-Laure
AL
Ouguerram
Khadija
K
Friburg
José
J
Seidah
Nabil G
NG
Brewer
H Bryan
HB
Krempf
Michel
M
Costet
Philippe
P
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
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