Role And Mechanism Of Heme Oxygenase-1 On Curcumin Mitigating Cholestasis-Induced Hepatic Fibrosis

Curcumin(Cur)is a natural yellow polyphenol extracted from the turmeric and exerts a powerful antioxidant effect by activating the transcription factor Nrf2.Many studies have shown that Cur has a liver-protecting effect,but the mechanism of this effect is not clear.Heme oxygenanse-1(HO-1)is a key enzyme degrades free heme into carbon monoxide,iron and biliver,it can protect cell against inflammation and oxidative damage.The purpose of this study was to:(1)study the effect of curcumin on the liver fibrosis caused by cholestasis;(2)elucidate the intrinsic link between the protective effect of curcumin on liver fibrosis caused by cholestasis and the activity and protein expression of HO-1.In this study,a model of liver fibrosis mice was established by bile duct ligation(BDL).Cur(30 mg/kg)was administered to mice daily for one week after surgery.The results showed that the concentration of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)in the BDL+Cur group were significantly lower than those in the BDL group(P<0.05),indicating that Cur can alleviate liver function damage caused by BDL.At the same time,qPCR results showed that the fibrosis-related genes(collagen type I,α-SMA and TGF-β1)in the BDL+Cur group were significantly lower than those of BDL group(P<0.05),indicating that Cur can alleviate liver fibrosis caused by BDL.In the BDL+Cur group,immunohistochemistry results showed reduction of macrophage and neutrophil infiltration,indicating that Cur can alleviate the inflammation of liver caused by BDL.At the same time,the protein and mRNA expressions of HO-1 in the BDL+Cur group were increased than those in the BDL group,and Cur could promote the nuclear transport of HO-1.Therefore,we speculate Cur may treat BDL-induced liver fibrosis by regulating the expression and activity of HO-1.In order to verify this hypothesis,we used HO-1 activity inhibitor ZnPP.We found that after adding ZnPP,the BDL+Cur+ZnPP group showed obvious inflammatory reaction and more serious liver fibrosis,indicating that the therapeutic effect of Cur on BDL mice can be reversed after inhibiting HO-1 activity;at the same time,curcumin administration could also regulate lipid metabolism disorder caused by BDL modeling,and after ZnPP added.the regulation of curcumin was eliminated.Taken together,the results suggest that Cur can treat liver fibrosis caused by BDL by regulating the expression and activity of HO-1,and its therapeutic effect largely depends on the enzymatic function of HO-1.