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

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.