Regulation of bile acid synthesis by the nuclear receptor Rev-erb alphaDuez, H., Van Der Veen, J. N., Duhem, C., Pourcet, B., Touvier, T., Fontaine, C., Derudas, B., Bauge, E., Havinga, R., Bloks, V. W., Wolters, H., Van Der Sluijs, F. H., Vennstrom, B., Kuipers, F. & Staels, B., Aug-2008, In : Gastroenterology. 135, 2, p. 689-698 10 p.
Research output: Contribution to journal › Article › Academic › peer-review
Background & Aims: Conversion into bile acids represents an important route to remove excess cholesterol from the body. Rev-erb alpha 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-erb alpha 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-erb alpha. Results: Rev-erb alpha-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-erb alpha-deficient mice, whereas adenovirus-mediated hepatic Rev-erb alpha overexpression induces its expression. Moreover, bile acid feeding resulted in a more pronounced suppression of hepatic CYP7A1 expression in Rev-erb alpha-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-erb alpha-deficient mice. Promoter analysis and chromatin immunoprecipitation experiments demonstrated that SHP and E4BP4 are direct Rev-erb alpha target genes. Finally, the circadian rhythms of liver CYP7A1, SHP, and E4BP4 messenger RNA levels were perturbed in Rev-erb alpha-deficient mice. Conclusions: These data identify a role for Rev-erb alpha in the regulatory loop of bile acid synthesis, likely acting by regulating both hepatic SHP and E4BP4 expression.
|Number of pages||10|
|Publication status||Published - Aug-2008|
- NEGATIVE FEEDBACK-REGULATION, FARNESOID-X-RECEPTOR, CHOLESTEROL 7-ALPHA-HYDROXYLASE, ORPHAN RECEPTOR, MESSENGER-RNA, MICE LACKING, CIRCADIAN TRANSCRIPTION, TRIGLYCERIDE LEVELS, LIPID HOMEOSTASIS, HYDROXYLASE GENE