Molecular Basis for Feedback Regulation of Bile Acid Synthesis by Nuclear Receptors

Mol Cell. 2000 Sep;6(3):507-15. doi: 10.1016/s1097-2765(00)00050-2.

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