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J. Biol. Chem., Vol. 282, Issue 8, 5225-5236, February 23, 2007

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Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin^*

From the Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

This report provides the first evidence that human P450 4F2 (CYP4F2) is induced by statins, which are widely used to treat hypercholesterolemia. Real time PCR and immunoblots indicate that lovastatin treatment increases expression of the endogenous CYP4F2 gene in human primary hepatocytes and HepG2 cells. The effects of lovastatin on gene expression are often mediated through sterol regulatory element-binding proteins (SREBPs). Immunoblots indicate that lovastatin-treated human hepatocytes display increased proteolytic processing of SREBP-2. In HepG2 cells, co-administration of a potent suppressor of SREBP-2 activation, 25-hydroxycholesterol, inhibits CYP4F2 mRNA induction by lovastatin. HepG2 cells transfected with an expression vector for the active nuclear form of SREBP-1a (nSREBP-1a) also display elevated endogenous CYP4F2 expression. Luciferase reporters containing the CYP4F2 proximal promoter are transactivated by nSREBPs (-1a, -1c, and -2) or a dominant positive form of the SREBP cleavage-activating protein (SCAP), which facilitates activation of endogenous SREBPs. Lovastatin-induced reporter expression is inhibited by overexpressed Insig-1, which prevents proteolytic activation of endogenous SREBPs. Electrophoretic mobility shift assays with in vitro translated nSREBP-1a identified two SREBP binding sites at –169/–152 and –109/–92, relative to the CYP4F2 transcription start site. Mutations in each site abolish SREBP binding. Chromatin immunoprecipitation experiments indicate that more SREBP-1 is associated with the CYP4F2 promoter after overexpression of nSREBP-1a. Transfection studies and mutagenesis indicate that the –109/–92 region is the primary site responsible for the effects of statins. Collectively, these results demonstrate that SREBPs transactivate CYP4F2 transcription and that CYP4F2 induction by statins is mediated by SREBP-2.

Received for publication, August 25, 2006 , and in revised form, December 1, 2006.

^* This work was supported by National Institutes of Health Grant HD004445 (to E. F. J.). 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.

¹ To whom correspondence should be addressed: Mail Drop MEM255, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-7918; Fax: 858-784-7978; E-mail: Johnson{at}scripps.edu.

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