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J. Biol. Chem., Vol. 283, Issue 39, 26332-26339, September 26, 2008

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Regulation of Cholesterologenesis by the Oxysterol Receptor, LXR^*

Yongjun Wang, Pamela M. Rogers, Chen Su, Gabor Varga, Keith R. Stayrook, and Thomas P. Burris¹

From the Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808 and Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285

Cholesterol is required for normal cellular and physiological function, yet dysregulation of cholesterol metabolism is associated with diseases such as atherosclerosis. Cholesterol biosynthesis is regulated by end product negative feedback inhibition where the levels of sterols and oxysterols regulate the expression of cholesterologenic enzymes. Sterol regulatory element-binding protein-2 is responsive to both sterols and oxysterols and has been shown to mediate the transcriptional response of the cholesterologenic enzymes to these lipids. Here, we show that the nuclear hormone receptor for oxysterols, the liver X receptor (LXR), regulates cholesterol biosynthesis by directly silencing the expression of two key cholesterologenic enzymes (lanosterol 14-demethylase (CYP51A1), and squalene synthase (farnesyl diphosphate farnesyl transferase 1)) via novel negative LXR DNA response elements (nLXREs) located in each of these genes. Examination of the CYP51A1 gene revealed that both the SRE and nLXRE are required for normal oxysterol-dependent repression of this gene. Thus, these data suggest that LXR plays an important role in the regulation of cholesterol biosynthesis.

Received for publication, June 24, 2008 , and in revised form, July 31, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK080201 (to T. P. B.). This work was also supported by an award from the American Heart Association (to T. P. B.). 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: The Scripps Research Institute, 5353 Parkside Dr., Jupiter FL 33458. Tel.: 561-799-8100; E-mail: tburris{at}scripps.edu.

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