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Papers In Press, published online ahead of print March 1, 2005
J. Lipid Res., doi:10.1194/jlr.M400396-JLR200
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U539, INSERM, Nantes 44000
Corresponding Author: philippe.costet{at}nantes.inserm.fr
Mutations in Proprotein Convertase Subtilisin Kexin 9 (PCSK9) have recently been associated with Autosomal Dominant Hypercholesterolemia (ADH). In vivo kinetic studies indicate that LDL catabolism is impaired and that apolipoprotein (apo) B containing lipoprotein synthesis is enhanced in two patients presenting with the S127R mutation on PCSK9. To understand PCSK9 physiological role, 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 LDL receptor and in turn LDL cellular binding as well as LDL clearance from the plasma compartment in C57BL6/J 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 PCSK9-S127R 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 both cultured cells and mice. Finally, we show that unlike PCSK9 overexpression in mice, the S127R mutation in patients lead to increased VLDL apoB levels, suggesting a potential gain of function for S127R PCSK9 in humans.
Revised on February 23, 2005
Accepted on February 28, 2005
Wild-type PCSK9 inhibits LDL clearance but does not affect apoB containing lipoprotein production in mouse and cultured cells
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