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

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

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2754-2761
Number of pages8
JournalJournal of Lipid Research
Volume47
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Keywords

  • Farnesoid X receptor
  • Nuclear receptors
  • Small heterodimer partner

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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