TY - JOUR
T1 - 5α-Bile alcohols function as farnesoid X receptor antagonists
AU - Nishimaki-Mogami, Tomoko
AU - Kawahara, Yosuke
AU - Tamehiro, Norimasa
AU - Yoshida, Takemi
AU - Inoue, Kazuhide
AU - Ohno, Yasuo
AU - Nagao, Taku
AU - Une, Mizuho
N1 - Funding Information:
This study was supported in part by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and a grant from the Japan Health Sciences Foundation.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/1/6
Y1 - 2006/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=28144454959&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28144454959&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2005.11.027
DO - 10.1016/j.bbrc.2005.11.027
M3 - Article
C2 - 16300737
AN - SCOPUS:28144454959
SN - 0006-291X
VL - 339
SP - 386
EP - 391
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -