5{alpha}-Bile alcohols function as farnesoid X receptor antagonists
- National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501 (Japan)
- School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo 142-8555 (Japan)
- Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112 (Japan)
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 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, which is distinct from that of other steroids and cholesterol metabolites, we investigated the role of this 5{beta}-configuration in FXR activation. The results showed that the 5{beta}-(A/B cis) bile alcohols 5{beta}-cyprinol and bufol are potent FXR agonists, whereas their 5{alpha}-(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 orientation of bile salts in agonist/antagonist function.
- OSTI ID:
- 20795863
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 339, Issue 1; Other Information: DOI: 10.1016/j.bbrc.2005.11.027; PII: S0006-291X(05)02541-6; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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