Plasma PCSK9 preferentially reduces liver LDL receptors in mice

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

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

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-offunction 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.

Original languageEnglish (US)
Pages (from-to)1303-1311
Number of pages9
JournalJournal of Lipid Research
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2008

Fingerprint

Proprotein Convertases
Subtilisin
LDL Receptors
Liver
Plasmas
Mutation
low density lipoprotein inhibitor
Proprotein Convertase 9
Proteins
Plasma (human)
Enzyme kinetics
Hypercholesterolemia
LDL Cholesterol
Half-Life
Metabolism
Catalyst activity

Keywords

  • LDL-cholesterol
  • Proprotein convertase subtilisin/kexin type 9
  • Sterol-regulatory element binding protein

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Plasma PCSK9 preferentially reduces liver LDL receptors in mice. / Grefhorst, Aldo; McNutt, Markey C.; Lagace, Thomas A.; Horton, Jay D.

In: Journal of Lipid Research, Vol. 49, No. 6, 01.06.2008, p. 1303-1311.

Research output: Contribution to journalArticle

Grefhorst, Aldo ; McNutt, Markey C. ; Lagace, Thomas A. ; Horton, Jay D. / Plasma PCSK9 preferentially reduces liver LDL receptors in mice. In: Journal of Lipid Research. 2008 ; Vol. 49, No. 6. pp. 1303-1311.
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