J. Lipid Res.
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A more recent version of this article appeared on June 1, 2008

Papers In Press, published online ahead of print March 19, 2008
J. Lipid Res., doi:10.1194/jlr.M800027-JLR200
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Submitted on January 15, 2008
Revised on February 27, 2008
Accepted on March 18, 2008

Plasma PCSK9 preferentially reduces liver LDL receptors in mice

Aldo Grefhorst, Markey C. McNutt, Thomas A. Lagace, and Jay D. Horton

Internal Medicine and Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390-9046

Corresponding Author: jay.horton{at}utsouthwestern.edu

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of low density lipoprotein receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia and loss-of-function mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 µg) to mice by a single injection reduced hepatic LDLRs by ~90% within 30 min and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be ~5 min. Continuous infusion of PCSK9 (32 µg/h) into wild-type mice caused a ~90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9(S386A) and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9’s action on the LDLR is not dependent on catalytic activity in vivo.


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