基于FXR-胆汁酸轴探讨灵芝多糖对雷公藤甲素诱导肝损伤的保护作用OA

OBJECTIVE To explore the hepatoprotective effect of Ganoderma lucidum polysaccha-ride(GLP)against triptolide(TP)-induced liver injury and its modulation of the farnesoid X receptor(FXR)-bile acid metabolism axis.METHODS Data from the DrugBank database and literature(up to February 2025)were mined to analyze the current application status of FXR agonists in liver diseases.A screening process was built to get hepatoprotective traditional Chinese herbs and ingredients that target FXR and have no clear hepatotoxicity.Molecular docking was used to evaluate the binding ability of hepatoprotective ingredients with FXR.GLP was chosen as the representative ingredient.After its molecular weight distribution and monosaccharide composition were figured out,the TP liver injury model was set up.C57BL/6J male mice were randomly divided into control group,model group,and model+GLP 100 mg·kg-1 group.GLP was given by intragastric gavage(ig)once a day for 7 days.On day 8,the model group and the model+GLP group were given TP 1 mg·kg-1 by intraperitoneal injection(ip).After induction for 24 h,the TP-induced liver injury mouse model was established.ELISA was performed to measure the levels of aspartate aminotransferase(AST),alanine aminotransferase(ALT),alkaline phosphatase(ALP),and total bile acid(TBA)in plasma.RT-qPCR was performed to measure the mRNA levels of FXR,small heterodimer partner(SHP),cholesterol 7α-hydroxylase(Cyp7a1),and cytochrome P450 family 8 subfamily B member 1(Cyp8b1)in liver tissue.Western blotting was performed to measure the protein expression levels of FXR and CYP8B1 in liver tissue.Metabolomics was performed to measure the levels of cholic acid(CA),deoxycholic acid(DCA),taurocholic acid(TCA),tauroursodeoxycholic acid(TUDCA),taurochenodeoxycholic acid(TCDCA),and taurodeoxycho-lic acid(TDCA)in plasma.Spearman correlation analysis was performed to evaluate the correlations between bile acids and FXR pathway genes and liver function indicators.RESULTS 28 FXR agonists were obtained by database mining.34 hepatoprotective traditional Chinese herbs targeting FXR were obtained.28 hepatoprotective ingredients targeting FXR were obtained.The binding energy range of 27 hepatoprotective ingredients with FXR was from-9.578 to-2.887 kcal·mol-1.This range was obtained by molecular docking.Animal experiments showed that compared with the control group,the plasma levels of AST,ALT,and TBA in the model group were significantly increased.The mRNA expression levels of FXR and SHP in liver tissue were significantly decreased,while the mRNA expres-sion level of Cyp8b1 was significantly increased.The protein expression level of FXR in liver tissue was significantly decreased,while the protein expression level of CYP8B1 was significantly increased.Plasma metabolomics analysis showed that the metabolic profiles of the control and model groups were significantly separated,and TUDCA,TCDCA,and TDCA in the model group were significantly increased.Compared with the model group,the plasma levels of AST,ALT,ALP,and TBA in the model+GLP group were significantly decreased.The mRNA expression levels of FXR and SHP in liver tissue were significantly increased,while the mRNA expression level of Cyp8b1 was significantly decreased.The protein expression level of FXR in liver tissue was significantly increased,while the protein expres-sion level of CYP8B1 was significantly decreased.Plasma metabolomics analysis showed that the metabolic profile of the model+GLP group was shifted toward that of the control group,and TUDCA and TDCA in the model+GLP group were significantly decreased.Spearman correlation analysis showed that bile acid levels were significantly negatively correlated with the expression of FXR and SHP genes,and significantly positively correlated with CYP8B1 gene expression.CONCLUSION GLP can reverse TP-induced liver injury and bile acid metabolism disorder in mice by regulating the FXR-bile acid metabolic axis.