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

Journal of Lipid Research

Gregorio Gil¹  Karen E. Matsukuma²  Mary K. Bennett²  Timothy F. Osborne²  Jiansheng Huang³  Li Wang³ 

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

关键词: farnesoid X receptor;    nuclear receptors;    small heterodimer partner;   

DOI  :  

来源: DOAJ

【 摘 要 】

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/RXRα 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.

【 授权许可】

Unknown