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J. Biol. Chem., Vol. 281, Issue 2, 807-812, January 13, 2006

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Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Promoter by Nuclear Receptors Liver Receptor Homologue-1 and Small Heterodimer Partner

A MECHANISM FOR DIFFERENTIAL REGULATION OF CHOLESTEROL SYNTHESIS AND UPTAKE^*

Shrimati Datta1, Li Wang, David D. Moore¶, and Timothy F. Osborne2

From the Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, Departments of Medicine and Pharmacology, University of Kansas Medical Center, Kansas City, Kansas 66160, and ^¶Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas 77030

Cholesterol homeostasis in mammals involves pathways for biosynthesis, cellular uptake, and hepatic conversion to bile acids. Key genes for all three pathways are regulated by negative feedback control. Uptake and biosynthesis are directly regulated by cholesterol through its inhibition of the proteolytic activation of the sterol regulatory element binding proteins. The conversion of cholesterol into bile acids in the liver is regulated through the bile acid-dependent induction of the negatively acting small heterodimer partner nuclear receptor. In this report, we have shown that the small heterodimer partner also directly regulates cholesterol biosynthesis through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase but has no effect on low density lipoprotein receptor expression. This has significant metabolic significance, as it provides both a mechanism to independently regulate cholesterol synthesis from uptake (an essential regulatory feature known to occur in vivo) and a pathway for direct regulation of cholesterol biosynthesis by bile acids. This latter feature ensures that the early phase of bile acid synthesis (pre-cholesterol) is in metabolic communication with the later stages of the pathway to properly regulate whole pathway flux. This highlights an important regulatory feature that is shared with other key branched, multienzyme pathways, such as glycolysis, where pathway outflow through pyruvate kinase is regulated by the concentration of a key early intermediate, fructose 1,6-bisphosphate.

Received for publication, October 11, 2005 , and in revised form, November 4, 2005.

^* This work was supported in part by Grant HL48044 from the National Institutes of Health (to T. F. O.). 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 Present address: Dept. of Immunology, The Scripps Research Institute, La Jolla, CA 92037.

² To whom correspondence should be addressed: Molecular Biology and Biochemistry 3244 McGaugh Hall University of California, Irvine, Irvine, CA 92697-3900. Tel.: 949-Fax: 949-824-8551; E-mail: tfosborn{at}uci.edu.

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