J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M300215-JLR200 on September 29, 2003 Originally published In Press as doi:10.1194/jlr.M300215-JLR200 on September 16, 2003

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Journal of Lipid Research, Vol. 45, 132-138, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation

Tomofumi Fujino*, Mizuho Une1,{dagger}, Tsuneo Imanaka§, Kazuhide Inoue* and Tomoko Nishimaki-Mogami*

* Division of Biosignaling, National Institute of Health Sciences, Tokyo, Japan
{dagger} Division of Medicinal Chemistry Programs for Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
§ Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan

1 To whom correspondence should be addressed. e-mail: mune{at}hiroshima-u.ac.jp

The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that plays a major role in bile acid and cholesterol metabolism. To obtain an insight into the structure-activity relationships of FXR ligands, we investigated the functional roles of structural elements in the physiological ligands chenodeoxycholic acid [CDCA; (3{alpha},7{alpha})], cholic acid [CA; (3{alpha},7{alpha},12{alpha})], deoxycholic acid [DCA; (3{alpha},12{alpha})], and lithocholic acid (3{alpha}) in regard to FXR activation in a cell-based FXR response element-driven luciferase assay and an in vitro coactivator association assay. Conversion of the carboxyl group of CDCA or CA to an alcohol did not greatly diminish their ability to activate FXR. In contrast, the 7ß-epimers of the alcohols were inactive, indicating that the bile alcohols retained the ligand properties of the original bile acids and that the 7ß-hydroxyl group diminished their FXR-activating effect. Similarly, hydroxyl epimers of DCA exhibited decreased activity compared with DCA, indicating a negative effect of 3ß- or 12ß-hydroxyl groups. Introduction of an alkyl group at the 7ß- or 3ß-position of CDCA resulted in diminished FXR activation in the following order of alkyl groups: 7-ethyl = 7-propyl > 3-methyl > 7-methyl.

These results indicate that bulky substituents, whether hydroxyl groups or alkyl residues, at the ß-position of cholanoids decrease their ability to activate FXR.

Abbreviations: CA, cholic acid (3{alpha},7{alpha},12{alpha}-trihydroxy-5ß-cholanoic acid); CDCA, chenodeoxycholic acid (3{alpha},7{alpha}-dihydroxy-5ß-cholanoic acid); CYP7A1, cholesterol 7{alpha}-hydroxylase; CYP8B1, sterol 12{alpha}-hydroxylase; DCA, deoxycholic acid (3{alpha},12{alpha}-dihydroxy-5ß-cholanoic acid); FXR, farnesoid X receptor; LCA, lithocholic acid (3{alpha}-hydroxy-5ß-cholanoic acid); LRH-1, liver receptor homolog-1; RXR, retinoid X receptor; SHP, small heterodimer partner; SRC-1, steroid receptor coactivator-1; UCA, ursocholic acid (3{alpha},7ß,12{alpha}-trihydroxy-5ß-cholanoic acid); UDCA, ursodeoxycholic acid (3{alpha},7ß-dihydroxy-5ß-cholanoic acid)

Supplementary key words bile alcohols • steroid receptor coactivator-1 • cholesterol 7{alpha}-hydroxylase • CV-1 cell • farnesoid X receptor


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T. Nishimaki-Mogami, M. Une, T. Fujino, Y. Sato, N. Tamehiro, Y. Kawahara, K. Shudo, and K. Inoue
Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor
J. Lipid Res., August 1, 2004; 45(8): 1538 - 1545.
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