J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on January 1, 2004 Originally published In Press as doi:10.1194/jlr.M300215-JLR200 on September 29, 2003

Papers In Press, published online ahead of print September 16, 2003
J. Lipid Res., doi:10.1194/jlr.M300215-JLR200
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Submitted on May 23, 2003
Revised on August 18, 2003
Accepted on September 10, 2003

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

Tomofumi Fujino, Mizuho Une, Tsuneo Imanaka, Kazuhide Inoue, and Tomoko Nishimaki-Nogami

Programs for Pharmaceutical Sciences, Graduate School of Biomedical Sciences Hiroshima University, Hiroshima 734-8551

Corresponding Author: 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 physiological ligands, chenodeoxycholic acid (CDCA; [3alpha ,7alpha ]), cholic acid (CA; [3alpha ,7alpha ,12alpha ]), deoxycholic acid (DCA; [3alpha ,12alpha ]) and lithocholic acid (LCA; [3alpha ]) in regard to FXR activation in a cell-based FXRE-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 7beta -epimer of the alcohols were inactive, indicating that the bile alcohols retained the ligand properties of the original bile acids and that the 7beta -hydroxyl group diminished their FXR activating effect. Similarly, hydroxyl epimers of DCA exhibited decreased activity compared to DCA, indicating a negative effect of 3beta - or 12beta -hydroxyl groups. Introduction of an alkyl group at the 7beta - or 3beta -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 beta -position of cholanoids decrease their ability to activate FXR.


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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.
[Abstract] [Full Text] [PDF]


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