5α-Bile alcohols function as farnesoid X receptor antagonists

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-recruitm...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2006-01, Vol.339 (1), p.386-391
Main Authors: Nishimaki-Mogami, Tomoko, Kawahara, Yosuke, Tamehiro, Norimasa, Yoshida, Takemi, Inoue, Kazuhide, Ohno, Yasuo, Nagao, Taku, Une, Mizuho
Format: Article
Language:English
Subjects:
Agonist
Antagonist
Bile acid
Bile alcohol
Coactivator
Farnesoid X receptor
Nuclear receptor
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2005.11.027