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Originally published In Press as doi:10.1194/jlr.M700443-JLR200 on November 21, 2007 Originally published In Press as doi:10.1194/jlr.M700443-JLR200 on October 5, 2007

Papers In Press, published online ahead of print February 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700443-JLR200
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Journal of Lipid Research, Vol. 49, 399-409, February 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2boxs

Hyun Jeong Jeong*, Hyun-Sook Lee{dagger},§,**, Kyung-Sup Kim{dagger},§,**,{dagger}{dagger}, Yoon-Kyoung Kim*, Dojun Yoon* and Sahng Wook Park1,{dagger},§,**

* Department of Biochemistry, Kwandong University College of Medicine, Kangnung, Kangwon-do 210-701, Korea
{dagger} Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Korea
§ Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea
** Medical Research Center for Chronic Metabolic Disease, Yonsei University College of Medicine, Seoul 120-752, Korea
{dagger}{dagger} Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data.

Published, JLR Papers in Press, November 21, 2007.

1 To whom correspondence should be addressed. e-mail: swpark64{at}yumc.yonsei.ac.kr

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilases that promotes the internalization and degradation of LDL receptor in liver and thereby controls the level of LDL cholesterol in plasma. Here, we show that the expression of PCSK9 in HepG2 cells is completely dependent on the absence or presence of sterols. The minimal promoter region of the PCSK9 gene contains a sterol-regulatory element (SRE), which makes the transcription of PCSK9 dependent on sterols. Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. In vitro-translated nuclear forms of SREBPs showed interactions with SRE, whereas mutations in SRE abolished their binding. In vivo studies in mice showed that Pcsk9 protein and mRNA were decreased significantly by fasting and increased by refeeding. However, supplementation with 2% cholesterol in the diet prevented the increase in Pcsk9. The amounts of Pcsk9 mRNA in livers of refed mice showed correlated regulation by the changes in the nuclear form of Srebp-2. In summary, it is suggested that the expression of PCSK9 is regulated by sterol at the transcriptional level in HepG2 cells and that both SREBP-1 and SREBP-2 can transcriptionally activate PCSK9 via SRE in its proximal promoter region in vitro. However, in vivo, it is suggested that the sterol-dependent regulation of PCSK9 is mediated predominantly by SREBP-2.

Supplementary key words low density lipoprotein receptor • hypercholesterolemia • transcriptional regulation • lovastatin

Abbreviations: DLPS, delipidated serum; EMSA, electrophoretic mobility shift assay; LDLR, low density lipoprotein receptor; Ni-NTA, nickel-nitrilotriacetic acid; PCSK9, proprotein convertase subtilisin/kexin type 9; SRE, sterol-regulatory element; SREBP, sterol-regulatory element binding protein


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