J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on December 1, 2006

Papers In Press, published online ahead of print September 6, 2006
J. Lipid Res., doi:10.1194/jlr.M600342-JLR200
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Submitted on July 26, 2006
Revised on September 5, 2006
Accepted on September 5, 2006

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

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

Molecular Biology and Biochemistry, UC Irvine, Irvine, CA 92697-3900

Corresponding Author: tfosborn{at}uci.edu

We discovered a nuclear receptor element in the fatty acid synthase (FAS) promoter consisting of an inverted repeat spaced by one nucleotide (IR-1) and located 21 bases downstream of a DR-4 oxysterol liver X receptor (LXR) response element. An IR-1 is present in promoters of several genes of bile acid and lipid homeostasis and binds FXR/RXR heterodimers to mediate bile acid-dependent transcription. We show that FXR/RXRa specifically binds to the FAS IR-1 and that the FAS promoter is activated approximately ten-fold by 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.


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