Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha

Gastroenterology. 2008 Aug;135(2):689-98. doi: 10.1053/j.gastro.2008.05.035. Epub 2008 May 15.


Background & aims: Conversion into bile acids represents an important route to remove excess cholesterol from the body. Rev-erbalpha is a nuclear receptor that participates as one of the clock genes in the control of circadian rhythmicity and plays a regulatory role in lipid metabolism and adipogenesis. Here, we investigate a potential role for Rev-erbalpha in the control of bile acid metabolism via the regulation of the neutral bile acid synthesis pathway.

Methods: Bile acid synthesis and CYP7A1 gene expression were studied in vitro and in vivo in mice deficient for or over expressing Rev-erbalpha.

Results: Rev-erbalpha-deficient mice display a lower synthesis rate and an impaired excretion of bile acids into the bile and feces. Expression of CYP7A1, the rate-limiting enzyme of the neutral pathway, is decreased in livers of Rev-erbalpha-deficient mice, whereas adenovirus-mediated hepatic Rev-erbalpha overexpression induces its expression. Moreover, bile acid feeding resulted in a more pronounced suppression of hepatic CYP7A1 expression in Rev-erbalpha-deficient mice. Hepatic expression of E4BP4 and the orphan nuclear receptor small heterodimer partner (SHP), both negative regulators of CYP7A1 expression, is increased in Rev-erbalpha-deficient mice. Promoter analysis and chromatin immunoprecipitation experiments demonstrated that SHP and E4BP4 are direct Rev-erbalpha target genes. Finally, the circadian rhythms of liver CYP7A1, SHP, and E4BP4 messenger RNA levels were perturbed in Rev-erbalpha-deficient mice.

Conclusions: These data identify a role for Rev-erbalpha in the regulatory loop of bile acid synthesis, likely acting by regulating both hepatic SHP and E4BP4 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Bile / metabolism
  • Bile Acids and Salts / metabolism*
  • Cell Line, Tumor
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Circadian Rhythm
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Feces / chemistry
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Liver / enzymology
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Time Factors
  • Transfection


  • Basic-Leucine Zipper Transcription Factors
  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Nfil3 protein, mouse
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • nuclear receptor subfamily 0, group B, member 2
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse