Involvement of SIRT1 in amelioration of schistosomiasis-induced hepatic fibrosis by genistein

Previous study revealed that genistein alleviate the extent of hepatic fibrosis in schistosomiasis-infected mice, however, the potential mechanism is still incomplete. Present study was, therefore, carried out to investigate the underlying mechanism of ameliorating schistosomiasis-induced hepatic fibrosis by genistein. alpha-smooth muscle actin (alpha-SMA) expression, as a critical fibrotic marker, was markedly upregulated in Schistosoma japonicum (S. japonicum) egg-induced liver fibrosis, and gradually inhibited by genistein administration in infected mice. Contrary to the changes of alpha-SMA expression, hepatic SIRT1 expression and activity was greatly inhibited in mice upon S. japonicum infection, and the repression was reversed in liver tissues after receiving 25 mg/kg genistein. 50 mg/kg genistein treatment gave rise to the higher SIRT1 expression and activity than that of the control group. In hepatic stellate cells (HSCs), genistein (5, 10, 20 mu M) treatment resulted in the increases of SIRT1 expression and activity in concentration-dependent manner. Moreover, to mimic the fibrogenesis in vivo, macrophage was treated with soluble egg antigen (SEA) to obtain macrophage-conditioned medium (M phi CM), which was used to stimulate HSCs. Intriguingly, SIRT1 overexpression decreased fibrosis associated gene expression in HSCs exposed to M phi CM or not. Additionally, M phi CM gave rise to high levels of alpha-SMA and p-Smad3 and the increments were reversed upon genistein treatment in HSCs. Furthermore, EX527, SIRT1 specific inhibitor, abrogated the inhibitory effects of genistein on HSCs activation. Together, the results support the notion that the strong elevation of SIRT1 expression and activity may represent a potential mechanism of protection against schistosomiasis-induced hepatic fibrosis by genistein.