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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1454.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Statins Upregulate PCSK9, the Gene Encoding the Proprotein Convertase Neural Apoptosis-Regulated Convertase-1 Implicated in Familial Hypercholesterolemia

Geneviève Dubuc; Ann Chamberland; Hanny Wassef; Jean Davignon; Nabil G. Seidah; Lise Bernier; Annik Prat

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.

Correspondence to Annik Prat, Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, 110 W Pine Ave, Montreal, Quebec, Canada H2W 1R7. 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.

The gene PCSK9, encoding NARC-1, has been implicated recently in autosomal dominant hypercholesterolemia. Using real-time polymerase chain reaction, we showed that PCSK9 is regulated by cholesterol in HepG2 cells and in human primary hepatocytes. PCSK9 promoter contains the typical elements for sterol regulation.

Key Words: cholesterol • QPCR • SRE • HepG2 • primary hepatocytes

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