Effects of Sedi Herba (Sedum sarmentosum) on attenuating cholestasis by the activation of the farnesoid x receptor (FXR)-mediated signaling.

Sedum sarmentosum (Sedi Herba) has traditionally been used to treat jaundice and various types of liver disease. This study aimed to clarify the anti-cholestatic efficacy and the mechanism of S. sarmentosum ethyl acetate extract (SDEAE), as well as to screen the potential compounds with FXR activation. SDEAE effectively ameliorated ANIT-induced cholestasis in rats, as evidenced by the ameliorative histopathology of the liver and the significant decrease in biochemical markers (ALT, AST, ALP, GGT, TBIL, DBIL and TBA). The analysis of bile acid profile by LC-MS indicated that SDEAE decreased the toxic bile acid levels (TCA, TMCA and CA). Western blotting indicated that SDEAE activated FXR-associated pathway, thereby upregulating FXR, SHP, BSEP and UGT2B4 expression, and downregulating CYP7A1 and NTCP expression. Twenty-three compounds (7 nor-sesquiterpenoids, 13 flavonoids, 1 lignin, 1 sterol and 1 anthraquinone) were isolated and identified from SDEAE by comparing NMR data with the literature. The HPLC profiles of SDEAE and isolated compounds were also compared. High-content analysis showed that eight compounds (6, 7, 8, 11, 12, 13, 14 and 23) could activate FXR and compound 8 exhibited the most potent activity (p < 0.01). Molecular docking suggested that the main binding modes between these active compounds and FXR were hydrogen bonding and van der Waals forces, and compound 8 had the highest docking score 6.34. The activation of compound 8 on FXR-mediated signaling was validated in L02 cells. After siRNA down-regulation of FXR, compound 8 significantly elevated FXR, SHP, BSEP and UGT2B4 expression, and reduced CYP7A1 and NTCP expression.