Journal of Lipid Research | |
Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase1 | |
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