Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.
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.
Lu
T T
TT
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
Makishima
M
M
Repa
J J
JJ
Schoonjans
K
K
Kerr
T A
TA
Auwerx
J
J
Mangelsdorf
D J
DJ
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
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