Nrf2 protects hepatocytes against oxidative liver injury and has a role in liver regeneration via stem cell activation.

Background: Aim of this study was to elucidate the hepatic defence mechanisms employed against oxidative stress. In particular, the specific role of the redox-sensitive transcription factor Nrf2, the major regulator implicated in the endogenous defence system against oxidative stress, was investigated.

Methods: We used the DDC-model that leads to oxidative liver damage resulting in chronic cholestatic liver injury and therefore resembles human diseases like sclerosing cholangitis and forms of metabolic liver diseases. Therefore, Nrf2-knockout and hepatic Keap1-knockout mice, which have a hepatocyte specific overactive Nrf2, were feed on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet and analysed over time by oxyblot-technique, TBARS-assay, western-blot, real time-PCR and immunohistochemistry.

Results: Nrf2-KO mice showed significant more lymphocyte infiltration as wild type mice. Over time significantly more necrosis, apoptosis and cholestasis became evident in Nrf2-knockout mice. This was associated with stronger periportal oval cell activation. In contrast, mice with hepatocyte specific knockout of Keap1, the inhibitor of Nrf2, showed significant less oxidative liver damage, and less lymphocyte infiltration. Interestingly, Keap1-liver knockout leads to enhanced stem cell proliferation in response to DDC feeding.

Conclusion: We show that Nrf2-dependent signalling pathway is crucial to protect liver from oxidative damage induced by DDC feeding. These findings indicate that the use of Nrf2-inducers might be considered as a novel therapeutic strategy to combat oxidative stress-related hepatic diseases. We show here first data connecting oxidative stress with stem cell activation and regeneration.