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Originally published In Press as doi:10.1194/jlr.M400396-JLR200 on March 1, 2005

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Journal of Lipid Research, Vol. 46, 1312-1319, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells

Florent Lalanne1,*, Gilles Lambert1,*, Marcelo J. A. Amar{dagger}, Maud Chétiveaux*, Yassine Zaïr*, Anne-Laure Jarnoux*, Khadija Ouguerram*, José Friburg*, Nabil G. Seidah§, H. Bryan Brewer, Jr.{dagger}, Michel Krempf* and Philippe Costet2,*

* Institut National de la Santé et de la Recherche Médicale U539, Centre Hospitalier Universitaire, Hôtel Dieu, Nantes, France
{dagger} Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
§ Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute, Montreal, Quebec, Canada

Published, JLR Papers in Press, March 1, 2005. DOI 10.1194/jlr.M400396-JLR200

1 F. Lalanne and G. Lambert contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: philippe.costet{at}univ-nantes.fr

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.

Abbreviations: apoB, apolipoprotein B; DiI, 3,3'-dioctadecylindocarbocyanine iodide; FCR, fractional catabolic rate; FH, familial hypercholesterolemia; FPLC, fast-protein liquid chromatography; HDL-C, high density lipoprotein-cholesterol; IDL, intermediate density lipoprotein; KO, knockout; LDLr, low density lipoprotein receptor; MTP, microsomal transfer protein; PCSK9, Proprotein Convertase Subtilisin Kexin 9; RIPA, radioimmunoprecipitation buffer; siRNA, short, interfering RNA; SR-BI, scavenger receptor class B type I; TC, total cholesterol; TG, triglyceride

Supplementary key words Proprotein Convertase Subtilisin Kexin 9 • low density lipoprotein • apolipoprotein B


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