5α-Bile alcohols function as farnesoid X receptor antagonists

Tomoko Nishimaki-Mogami, Yosuke Kawahara, Norimasa Tamehiro, Takemi Yoshida, Kazuhide Inoue, Yasuo Ohno, Taku Nagao, Mizuho Une

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

The farnesoid X receptor (FXR) is a bile acid/alcohol-activated nuclear receptor that regulates lipid homeostasis. Unlike other steroid receptors, FXR binds bile acids in an orientation that allows the steroid nucleus A ring to face helix 12 in the receptor, a crucial domain for coactivator-recruitment. Because most naturally occurring bile acids and alcohols contain a cis-oriented A ring, which is distinct from that of other steroids and cholesterol metabolites, we investigated the role of this 5β-configuration in FXR activation. The results showed that the 5β-(A/B cis) bile alcohols 5β-cyprinol and bufol are potent FXR agonists, whereas their 5α-(A/B trans) counterparts antagonize FXR transactivation and target gene expression. Both isomers bound to FXR, but their ability to induce coactivator-recruitment and thereby induce transactivation differed. These findings suggest a critical role for the A-ring orientation of bile salts in agonist/antagonist function.

Original languageEnglish
Pages (from-to)386-391
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume339
Issue number1
DOIs
Publication statusPublished - Jan 6 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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