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  • Title: 5Alpha-bile alcohols function as farnesoid X receptor antagonists.
    Author: Nishimaki-Mogami T, Kawahara Y, Tamehiro N, Yoshida T, Inoue K, Ohno Y, Nagao T, Une M.
    Journal: Biochem Biophys Res Commun; 2006 Jan 06; 339(1):386-91. PubMed ID: 16300737.
    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 5beta-configuration in FXR activation. The results showed that the 5beta-(A/B cis) bile alcohols 5beta-cyprinol and bufol are potent FXR agonists, whereas their 5alpha-(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.
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