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J. Biol. Chem., Vol. 279, Issue 27, 28122-28131, July 2, 2004

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Differential Regulation of Human and Mouse Orphan Nuclear Receptor Small Heterodimer Partner Promoter by Sterol Regulatory Element Binding Protein-1^*

Han-Jong Kim, Joon-Young Kim, Ju-Youn Kim¶, Sang-Kyu Park¶, Ji-Ho Seo||, Jae Bum Kim**, In-Kyu Lee||, Kyung-Sup Kim¶, and Hueng-Sik Choi

From the Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Kwangju 500-757, Republic of Korea, ^¶Department of Biochemistry and Molecular Biology, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea, ^||Department of Internal Medicine, School of Medicine, Keimyung University, Taegu 700-712, Republic of Korea, and ^**School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea

Small heterodimer partner (SHP; NR0B2) is an unusual orphan nuclear receptor that lacks a conventional DNA-binding domain and acts as a modulator of transcriptional activities of a number of nuclear receptors. Herein, we report that the human SHP promoter (hSHP) is activated by sterol regulatory element-binding protein-1 (SREBP-1), which regulates the expression of various genes involved in cholesterol and fatty acid synthesis. Overexpression of SREBP-1 activated the human but not mouse SHP promoter, although SREBP-2 had little effect on the SHP promoter in CV-1 cells. Serial deletion reporter assays revealed that SREBP-1-responsive region is located within the sequences from –243 to –120 bp in the hSHP promoter. DNase I footprinting, gel shift assays, and chromatin immunoprecipitation assays demonstrated that SREBP-1 binds directly to the hSHP promoter. Site-directed mutagenesis made it clear that the hSHP promoter activation by SREBP-1 is mostly mediated by the SRE1 (–186 to –195 bp) in the hSHP promoter, which is not conserved in the mouse SHP promoter. Moreover, adenovirus-mediated overexpression of SREBP-1c/ADD-1 induced SHP mRNA expression and repressed CYP7A1 expression in HepG2 cells. Finally, we found that a four-nucleotide deletion (–195CT-GAdel) in the hSHP promoter, which is reported to be associated with altered body weight and insulin secretion in human, coincides with the SRE1. This mutation strongly decreased both basal and SREBP-1 dependent activities of the hSHP promoter, because of the reduced binding of SREBP-1 to the mutated SRE1. Overall, our results demonstrate a differential regulation of human and mouse SHP promoters by SREBP-1. We propose a possible role of SREBP-1 in the species differential regulation of cholesterol and bile acid homeostasis via a novel mechanism of up-regulation of the hSHP gene expression.

Received for publication, December 5, 2003 , and in revised form, April 29, 2004.

^* This work was supported by Korea Science and Engineering Foundation Grant R02-2003-000-10064-0 and Hormone Research Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a postdoctoral fellowship from BK21 program 2003.

Supported by Korean Research Foundation Grant KRF-2001-015-FS0003.

To whom correspondence should be addressed. Tel.: 82-62-530-0503; Fax: 82-62-530-0500; E-mail: hsc{at}chonnam.ac.kr.

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