Molecular basis for feedback regulation of bile acid synthesis by nuclear receptos

Timothy T. Lu, Makoto Makishima, Joyce J. Repa, Kristina Schoonjans, Thomas A. Kerr, Johan Auwerx, David J. Mangelsdorf

Research output: Contribution to journalArticle

1092 Scopus citations

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 7α-hydroxylase (CYP7A1). The nuclear receptor LXRα 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.

Original languageEnglish (US)
Pages (from-to)507-515
Number of pages9
JournalMolecular cell
Volume6
Issue number3
DOIs
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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