Abstract

Farnesoid X receptor (FXR) and G-protein-coupled bile acid receptor 1 (GPBAR1) are two important bile acid (BA) receptors. As non-BAs drug template for GPBAR1, none of the natural oleanane-type triterpenes have been reported as FXR ligands, despite FXR and GPBAR1 having similar binding pockets for BAs. Here, we report the natural triterpene hedragonic acid that has been isolated from the stem and root of Celastrus orbiculatus Thunb. (COT) as an effective agonist for FXR. Both biochemical amplified luminescent proximity homogeneous assay and cell-based reporter assays showed that hedragonic acid regulated the transcriptional activity of FXR. Circular dichroism spectroscopy further suggested the conformational changes of FXR upon the binding of hedragonic acid. Interestingly, the crystal structure of hedragonic acid–bound FXR revealed a unique binding mode with hedragonic acid occupying a novel binding pocket different from the classic binding position. The structural comparison between hedragonic acid–bound FXR and oleanolic acid–bound GPBAR1 explained the molecular basis for the selectivity of oleanane-type triterpenes for FXR. Moreover, hedragonic acid treatment protected mice from liver injury induced by acetaminophen overdose and decreased hepatic inflammatory responses in an FXR-dependent manner, suggesting that hedragonic acid might be one of the major components of COT for its multifunctional pharmaceutical uses. In conclusion, our results provide novel structure templates for drug design based on natural triterpenes by targeting FXR and/or GPBAR1 with pharmaceutical values.