Journal of lipid research, 2006-12, Vol.47 (12), p.2754-2761
2006
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Details
- Autor(en) / Beteiligte
- Titel
- Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase
- Ist Teil von
- Journal of lipid research, 2006-12, Vol.47 (12), p.2754-2761
- Ort / Verlag
- United States: American Society for Biochemistry and Molecular Biology
- Erscheinungsjahr
- 2006
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2275eISSN: 1539-7262DOI: 10.1194/jlr.M600342-JLR200Titel-ID: cdi_proquest_miscellaneous_68164403
- Format
- –
- Schlagworte
- Animals, Bile Acids and Salts - metabolism, Binding Sites - genetics, Cell Line, DNA - genetics, DNA - metabolism, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Fatty Acid Synthases - genetics, Fatty Acid Synthases - metabolism, Humans, Lipogenesis - physiology, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Promoter Regions, Genetic, Rats, Receptors, Cytoplasmic and Nuclear - genetics, Receptors, Cytoplasmic and Nuclear - metabolism, Recombinant Proteins - genetics, Recombinant Proteins - metabolism, Retinoid X Receptor alpha - genetics, Retinoid X Receptor alpha - metabolism, RNA, Messenger - genetics, RNA, Messenger - metabolism, Sequence Homology, Nucleic Acid, Transcription Factors - genetics, Transcription Factors - metabolism, Transfection