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Journal of Lipid Research, Vol. 49, 1303-1311, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Plasma PCSK9 preferentially reduces liver LDL receptors in mice^*

Aldo Grefhorst^*, Markey C. McNutt^*, Thomas A. Lagace^* and Jay D. Horton^1,*,

^* From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046
From the Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9046

^* This work was supported by grants from the Perot Family Foundation and the National Institutes of Health (Grants HL-38049 and HL-20948 to A.G.), the Ter Meulen Fund, Royal Netherlands Academy of Arts and Science, The Netherlands (M.C.M.), Medical Scientist Training Grant GM08014 (T.A.L.), and by a fellowship from the Canadian Institutes of Health Research.

Published, JLR Papers in Press, March 19, 2008.

¹ To whom correspondence should be addressed. e-mail: jay.horton{at}utsouthwestern.edu

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL 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 60 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, 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.

Supplementary key words proprotein convertase subtilisin/kexin type 9 • LDL-cholesterol • sterol-regulatory element binding protein

Abbreviations: LDL-C, LDL-cholesterol; LDLR, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SREBP, sterol-regulatory element binding protein; TFR, transferrin receptor

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