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A more recent version of this article appeared on February 1, 2008 Originally published In Press as doi:10.1194/jlr.M700443-JLR200 on October 5, 2007

Papers In Press, published online ahead of print November 21, 2007
J. Lipid Res., doi:10.1194/jlr.M700443-JLR200
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Submitted on October 4, 2007
Revised on October 31, 2007
Accepted on November 19, 2007

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

Hyun Jeong Jeong, Hyun-Sook Lee, Kyung-Sup Kim, Yoon-Kyoung Kim, Dojun Yoon, and Sahng Wook Park

Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul 120752

Corresponding Author: swpark64{at}yumc.yonsei.ac.kr

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


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A. Grefhorst, M. C. McNutt, T. A. Lagace, and J. D. Horton
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[Abstract] [Full Text] [PDF]


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