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Statins Induce Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9
Author(s) -
Lagace Thomas A.,
Bashmakov Yuriy,
Anderson Norma N.,
McNutt Markey C.,
Grefhorst Aldo,
Ho Y. K.,
Horton Jay D.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1040.4
Subject(s) - pcsk9 , kexin , proprotein convertase , sterol regulatory element binding protein , ldl receptor , endocrinology , medicine , hmg coa reductase , cholesterol , chemistry , simvastatin , familial hypercholesterolemia , statin , reductase , lipoprotein , biology , sterol , biochemistry , enzyme
LDL receptor (LDLR) number is regulated transcriptionally by sterol regulatory element‐binding protein (SREBP)‐2. Studies have shown that inhibitors of HMG‐CoA reductase (statins) used to treat hypercholesterolemia trigger a regulatory response in cells leading to elevated levels of active SREBP‐2, thereby increasing LDLR expression. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a SREBP‐2 regulated protein secreted by the liver, binds to the LDLR and mediates its degradation. Thus, induction of PCSK9 may counter‐balance the effect of statins on liver LDLR protein levels. We demonstrate that simvastatin‐fed rats exhibit elevated levels of nuclear SREBP‐2 in liver and increased transcription of SREBP‐2 target genes, including PCSK9 . This was associated with a >3‐fold increase in circulating PCSK9 levels compared to control rats. In human studies, 13 subjects with moderate to slightly elevated plasma LDL‐cholesterol levels (127 – 238 mg/dl) were administered a statin for 7 days (Lipitor ‐ 40 mg/day), which resulted in a 25% decrease in plasma cholesterol levels. ELISA measurements of circulating PCSK9 concentrations showed a mean increase of 35% in these subjects. These studies demonstrate that circulating PCSK9 levels are reflective of liver SREBP‐2 activity and the induction of PCSK9 by statins may partially offset their efficacy in lowering plasma LDL‐cholesterol levels. Supported by CIHR.