Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

doi:10.1073/pnas.0501652102

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

Departments of ^*Molecular Genetics, ^†Biochemistry, and ^‡Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046

Communicated by Joseph L. Goldstein, University of Texas Southwestern Medical Center, Dallas, TX, March 2, 2005 (received for review February 8, 2005)

Abstract

PCSK9 encodes proprotein convertase subtilisin/kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg/dl in Pcsk9 ^–/– mice versus 96 mg/dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9 ^–/– mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.

Footnotes

↵ § To whom correspondence should be addressed at: Departments of Molecular Genetics and Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room L5-238, Dallas, TX 75390-9046. E-mail: jay.horton{at}utsouthwestern.edu.
Author contributions: S.R., D.E.C., R.G., N.N.A., Y.B., Y.-A.M., and J.D.H. designed research; S.R., D.E.C., R.G., N.N.A., Y.B., Y.-A.M., and J.D.H. performed research; S.R., Y.-A.M., and J.D.H. analyzed data; Y.K.H. and R.E.H. contributed new reagents/analytic tools; and S.R. and J.D.H. wrote the paper.
Abbreviations: ARH, autosomal recessive hypercholesterolemia; Apo, apolipoprotein; LDLR, low-density lipoprotein receptor; LRP, LDLR-related protein; PCSK9, proprotein convertase subtilisin/kexin type 9a; SREBP, sterol regulatory element-binding protein; RAP, receptor-associated protein; VLDL, very low-density lipoprotein; HDL, high-density lipoprotein.