Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia.
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.


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.
Dubuc
Geneviève
G
Laboratory of Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Quebec, Canada.
Chamberland
Ann
A
Wassef
Hanny
H
Davignon
Jean
J
Seidah
Nabil G
NG
Bernier
Lise
L
Prat
Annik
A
D000077556:Alitretinoin; D000818:Animals; D000069059:Atorvastatin; D001483:Base Sequence; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis* / Q000494:pharmacology; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000071518:Liver X Receptors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D012045:Regulatory Sequences, Nucleic Acid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D019821:Simvastatin / Q000494:pharmacology; D016329:Sp1 Transcription Factor / Q000502:physiology; D013045:Species Specificity; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology
D004268:DNA-Binding Proteins; D006538:Heptanoic Acids; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011725:Pyridines; D011758:Pyrroles; D011804:Quinolines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497390:SREBF2 protein, human; D016329:Sp1 Transcription Factor; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C003585:22-hydroxycholesterol; D000077556:Alitretinoin; C012258:mevastatin; D014212:Tretinoin; C015367:mevalonolactone; C007997:25-hydroxycholesterol; D002784:Cholesterol; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C108475:pitavastatin; D008798:Mevalonic Acid