title: Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.
abstract: The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1). The nuclear receptor LXRalpha binds oxysterols and mediates feed-forward induction. Here, we show that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH-1; and the promoter-specific repressor, SHP. Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH-1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results reveal an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Lu
authors.forename: M
authors.initials: M
authors.lastname: Makishima
authors.forename: J J
authors.initials: JJ
authors.lastname: Repa
authors.forename: K
authors.initials: K
authors.lastname: Schoonjans
authors.forename: T A
authors.initials: TA
authors.lastname: Kerr
authors.forename: J
authors.initials: J
authors.lastname: Auwerx
authors.forename: D J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005246:Feedback / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C000605213:NR1H3 protein, human; C082631:NR5A2 protein, human; C000605214:Nr1h3 protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2