Osteopontin is involved in estrogen-mediated protection against diethylnitrosamine-induced liver injury in mice

Diethylnitrosamine (DEN) is a potent hepatotoxin and hepatocarcinogen in animals and possible in humans. Estrogen has been reported to play a protective role against DEN exposure. Osteopontin (OPN), a downstream molecular of estrogen, plays a role in many pathophysiological processes. In this study, we evaluate the role of OPN in estrogen-mediated hepatoprotection in DEN-treated mice. DEN was administrated intraperitoneally to C57BL/6 and OPN−/− mice. Compared to male mice, female mice exhibited significantly higher hepatic OPN expression with less liver damage 48 h after DEN treatment. Interestingly, enhanced OPN expression was predominantly detected in hepatocytes after DEN treatment. OPN deficiency enhanced the susceptibility to DEN, which was more apparent in females than males. Estrogen-mediated protection against DEN in males was abrogated by OPN deficiency. The protective activities of estrogen could be mimicked by exogenous OPN. Consistent with liver injury, oxidative stress in liver was enhanced with OPN depletion. OPN reduced DEN-induced oxidative stress likely through inhibition of CYP2A5 expression. In conclusion, we demonstrate that OPN may be involved in estrogen-mediated hepatoprotection in DEN-induced liver injury through enhancement of hepatocyte survival and inhibition of DEN biotransformation. Our findings may provide new insight into gender differences in chemical-induced liver injury and related diseases.

► We examine the role of osteopontin in diethylnitrosamine-induced liver injury in mice. ► Estrogen enhances the expression of osteopontin after diethylnitrosamine administration. ► Osteopontin plays a protective role in diethylnitrosamine-induced liver injury. ► Osteopontin is required for the hepatoprotective activity of estrogen against diethylnitrosamine exposure. ► Osteopontin eliminates diethylnitrosamine-induced oxidative stress through inhibiting diethylnitrosamine metabolism.