Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase.
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/RXRalpha specifically binds to the FAS IR-1 and that the FAS promoter is activated approximately 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.
Matsukuma
Karen E
KE
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
Bennett
Mary K
MK
Huang
Jiansheng
J
Wang
Li
L
Gil
Gregorio
G
Osborne
Timothy F
TF
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004247:DNA; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated