TY - JOUR
T1 - Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation
AU - Fujino, Tomofumi
AU - Une, Mizuho
AU - Imanaka, Tsuneo
AU - Inoue, Kazuhide
AU - Nishimaki-Mogami, Tomoko
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/1
Y1 - 2004/1
N2 - 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; (3α,7α)], cholic acid [CA; (3α,7α,12α)], deoxycholic acid [DCA; (3α,12α)], and lithocholic acid (3α) 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 7β-epimers of the alcohols were inactive, indicating that the bile alcohols retained the ligand properties of the original bile acids and that the 7β-hydroxyl group diminished their FXR-activating effect. Similarly, hydroxyl epimers of DCA exhibited decreased activity compared with DCA, indicating a negative effect of 3β- or 12β-hydroxyl groups. Introduction of an alkyl group at the 7β- or 3β-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 β-position of cholanoids decrease their ability to activate FXR.
AB - 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; (3α,7α)], cholic acid [CA; (3α,7α,12α)], deoxycholic acid [DCA; (3α,12α)], and lithocholic acid (3α) 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 7β-epimers of the alcohols were inactive, indicating that the bile alcohols retained the ligand properties of the original bile acids and that the 7β-hydroxyl group diminished their FXR-activating effect. Similarly, hydroxyl epimers of DCA exhibited decreased activity compared with DCA, indicating a negative effect of 3β- or 12β-hydroxyl groups. Introduction of an alkyl group at the 7β- or 3β-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 β-position of cholanoids decrease their ability to activate FXR.
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U2 - 10.1194/jlr.M300215-JLR200
DO - 10.1194/jlr.M300215-JLR200
M3 - Article
C2 - 13130122
AN - SCOPUS:0842347855
VL - 45
SP - 132
EP - 138
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 1
ER -