Glycyrrhetinic Acid And Oleanolic Acid Selectively Modulate Farnesoid X Receptor

Nuclear Hormone Receptors (NHRs) are ligand-regulated transcription factors. NHRs play key roles in physiological functions. They can modulate the expression of the target genes by binding small molecules. Farnesoid X Receptor (FXR) is a member of the superfamily of NHRs and FXR shares common structures with other NHRs. At present, researchers have shown that FXR plays important roles in the metabolism of bile acid, lipoprotein and glucose, liver regeneration, enterobacteria growth and hepatoxin responses. FXR, as a bile acid sensor, keeps the homeostasis of bile acid by regulating the acticity of cholesterol 7 alpha-hydroxylase (CYP7A1). CYP7A1 is the rate-limiting enzyme in the synthesis of bile acid. Cholesterol is converted into bile acid in the liver. Bile acid not only is a physiological reagent which helps the absorption, delivery and distribution of lipid-soluble vitamin and diet fat, but also a signaling molecule that regulates the metabolism of bile acid and cholesterol by activating nuclear hormone receptors. On the other hand, bile acid also has cytotoxicity property. When bile acid reaches abnormal level, it can induce hepatic injury, cholestasis even hepatoma.Triterpenes exist widely in plant kindom, traditional medicines and diets. Over 4000 different triterpenes have been discovered. Glycyrrhetinic acid and oleanolic acid are members of pentacyclic-triterpenes. GA and OA show great benefits in anti-inflammatory, anti-cancer, anti-hyperlipdemia, hepatoprotective and immuno-modulatory effects. In China, GA and OA have been used as medicines to cure infectious diseases and hepatitis.In our study, we firstly determined the effects of GA and OA on the activity of FXR-LBD. According to a luciferase reporter system, we found that GA and OA dose-dependently decreased the activity of FXR-LBD induced by CDCA but had no effect on other nuclear hormone receptors. The decreases were not due to the cytotoxicity induced by GA and OA. Then, we expressed FXR-LBD protein in vitro and determined whether GA and OA could affect the interactions between FXR-LBD protein and co-activator SRC-3 with LXXLL motif. We found that both GA and OA could block the the interactions with SRC-3. Finally, we checked the effects of GA and OA on FXR target genes. GA and OA had no effect on the expression of FXR itself. GA and OA down-regulated the expressions of BSEP and CYP7A1 induced by CDCA but had no repressive effect on OSTβ. GA and OA showed different effects on SHP expression. GA decreased SHP expression induced by CDCA which is consistant with GA down-regulation on SHP-promoter. But OA had no inhibitory effect on SHP expression.Both GA and OA could specifically down-regulate the activity of FXR-LBD. It is therefore possible that GA and OA serve as modulators of FXR. This study provides a new potential mechanism for the beneficial effects of GA and OA on liver deseases.