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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Bile Acids and Salts / biosynthesis*
-
Cells, Cultured
-
Cholesterol / metabolism
-
Cholesterol 7-alpha-Hydroxylase / genetics
-
Cholesterol 7-alpha-Hydroxylase / metabolism
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Feedback / physiology
-
Gene Expression Regulation, Enzymologic / physiology
-
Homeostasis / physiology*
-
Humans
-
Kidney / cytology
-
Liver X Receptors
-
Mice
-
Orphan Nuclear Receptors
-
Promoter Regions, Genetic / physiology
-
Receptors, Cytoplasmic and Nuclear / genetics*
-
Receptors, Cytoplasmic and Nuclear / metabolism*
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transcription, Genetic / physiology
Substances
-
Bile Acids and Salts
-
DNA-Binding Proteins
-
Liver X Receptors
-
NR1H3 protein, human
-
NR5A2 protein, human
-
Nr1h3 protein, mouse
-
Orphan Nuclear Receptors
-
Receptors, Cytoplasmic and Nuclear
-
Repressor Proteins
-
Transcription Factors
-
nuclear receptor subfamily 0, group B, member 2
-
farnesoid X-activated receptor
-
Cholesterol
-
Cholesterol 7-alpha-Hydroxylase