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 journalArticle

18 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

Fingerprint

Cholestanols
Bile Acids and Salts
Transcriptional Activation
Steroids
Steroid Receptors
Cytoplasmic and Nuclear Receptors
Metabolites
Gene expression
Isomers
Homeostasis
Chemical activation
Cholesterol
Alcohols
Lipids
Gene Expression

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Nishimaki-Mogami, T., Kawahara, Y., Tamehiro, N., Yoshida, T., Inoue, K., Ohno, Y., ... Une, M. (2006). 5α-Bile alcohols function as farnesoid X receptor antagonists. Biochemical and Biophysical Research Communications, 339(1), 386-391. https://doi.org/10.1016/j.bbrc.2005.11.027

5α-Bile alcohols function as farnesoid X receptor antagonists. / Nishimaki-Mogami, Tomoko; Kawahara, Yosuke; Tamehiro, Norimasa; Yoshida, Takemi; Inoue, Kazuhide; Ohno, Yasuo; Nagao, Taku; Une, Mizuho.

In: Biochemical and Biophysical Research Communications, Vol. 339, No. 1, 06.01.2006, p. 386-391.

Research output: Contribution to journalArticle

Nishimaki-Mogami, T, Kawahara, Y, Tamehiro, N, Yoshida, T, Inoue, K, Ohno, Y, Nagao, T & Une, M 2006, '5α-Bile alcohols function as farnesoid X receptor antagonists', Biochemical and Biophysical Research Communications, vol. 339, no. 1, pp. 386-391. https://doi.org/10.1016/j.bbrc.2005.11.027
Nishimaki-Mogami, Tomoko ; Kawahara, Yosuke ; Tamehiro, Norimasa ; Yoshida, Takemi ; Inoue, Kazuhide ; Ohno, Yasuo ; Nagao, Taku ; Une, Mizuho. / 5α-Bile alcohols function as farnesoid X receptor antagonists. In: Biochemical and Biophysical Research Communications. 2006 ; Vol. 339, No. 1. pp. 386-391.
@article{6b7402038e4b46348a800c9b09a4b97b,
title = "5α-Bile alcohols function as farnesoid X receptor antagonists",
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.",
author = "Tomoko Nishimaki-Mogami and Yosuke Kawahara and Norimasa Tamehiro and Takemi Yoshida and Kazuhide Inoue and Yasuo Ohno and Taku Nagao and Mizuho Une",
year = "2006",
month = "1",
day = "6",
doi = "10.1016/j.bbrc.2005.11.027",
language = "English",
volume = "339",
pages = "386--391",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

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

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

VL - 339

SP - 386

EP - 391

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -