on June 3, 2004
Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134621.14315.43
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134621.14315.43
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Submitted on April 28, 2004
Accepted on May 18, 2004
Statins Upregulate PCSK9, the Gene Encoding the Proprotein Convertase Neural Apoptosis-Regulated Convertase-1 Implicated in Familial Hypercholesterolemia
Geneviève Dubuc ;
From the Laboratory of Hyperlipidemia and Atherosclerosis Research Group (G.D., H.W., J.D., L.B.) and the Laboratory of Biochemical Neuroendocrinology (A.C., N.G.S., A.P.), Clinical Research Institute of Montreal, Quebec, Canada.
* To whom correspondence should be addressed. E-mail: prata{at}ircm.qc.ca.
Objective--Neural apoptosis-regulated convertase (NARC)-1 is the newest member of the proprotein convertase family implicated in the cleavage of a variety of protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2 other known genes implicated in ADH encode the low-density lipoprotein receptor and apolipoprotein B. As an approach toward the elucidation of the physiological role(s) of NARC-1, we studied its transcriptional regulation.
Methods and Results--Using quantitative RT-PCR, we assessed NARC-1 regulation under conditions known to regulate genes involved in cholesterol metabolism in HepG2 cells and in human primary hepatocytes. We found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by cholesterol depletion but insensitive to liver X receptor activation. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element (SRE) and an Sp1 site.
Conclusions--PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism. In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.
Key words: cholesterol • QPCR • SRE • HepG2 • primary hepatocytes
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