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Journal of Lipid Research, Vol. 47, 2754-2761, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase¹

Karen E. Matsukuma^*, Mary K. Bennett^*, Jiansheng Huang, Li Wang, Gregorio Gil and Timothy F. Osborne^2,*

^* Department of Molecular Biology and Biochemistry, University of California, Irvine, CA
Departments of Medicine and Pharmacology, University of Kansas Medical Center, Kansas City, KS
Department of Biochemistry, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA

¹ This paper is dedicated to the memory of Professor Edward K. Wagner, who died during the preparation of the manuscript.

Published, JLR Papers in Press, September 6, 2006.

² To whom correspondence should be addressed. e-mail: tim.osborne{at}uci.edu

We discovered a nuclear receptor element in the FAS promoter consisting of an inverted repeat spaced by one nucleotide (IR-1) and located 21 bases downstream of a direct repeat sequenced by 4 nucleotides (DR-4) oxysterol liver X receptor response element. An IR-1 is present in promoters of several genes of bile acid and lipid homeostasis and binds farnesoid X receptor/retinoid X receptor (FXR/RXR) heterodimers to mediate bile acid-dependent transcription. We show that FXR/RXR specifically binds to the FAS IR-1 and that the FAS promoter is activated 10-fold by the addition of a synthetic FXR agonist in transient transfection assays. We also demonstrate that endogenous FXR binds directly to the murine FAS promoter in the hepatic genome using a tissue-based chromatin immunoprecipitation procedure. Furthermore, we show that feeding wild-type mice a chow diet supplemented with the natural FXR agonist chenodeoxycholic acid results in a significant induction of FAS mRNA expression. Thus, we have identified a novel IR-1 in the FAS promoter and demonstrate that it mediates FXR/bile acid regulation of the FAS gene. These findings provide the first evidence for direct regulation of lipogenesis by bile acids and also provide a mechanistic rationale for previously unexplained observations regarding bile acid control of FAS expression.

Supplementary key words farnesoid X receptor • nuclear receptors • small heterodimer partner

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