Therapeutic targeting of GSK3 beta enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C

Objective Impaired adaptive response to oxidative injuries is a fundamental mechanism central to the pathogenesis of chronic hepatitis C (CHC). Glycogen synthase kinase (GSK) 3 beta is an indispensable regulator of the oxidative stress response. However, the exact role of GSK3 beta in CHC is uncertain and was examined. Design GSK3 beta and Nrf2 signalling pathways were examined in JFH1 HCV infected Huh7.5.1 hepatocytes, and also in liver biopsy specimens from CHC patients. Results HCV infection elicited prominent Nrf2 antioxidant response in hepatocytes, marked by elevated expression of the Nrf2-dependent molecule haem oxygenase-1 and subsequent protection from apoptotic cell death. Inhibitory phosphorylation of GSK3 beta seems to be essential and sufficient for HCV-induced Nrf2 response. Mechanistically, GSK3 beta associated and physically interacted with Nrf2 in hepatocytes. In silico analysis revealed that Nrf2 encompasses multiple GSK3 beta phosphorylation consensus motifs, denoting Nrf2 as a cognate substrate of GSK3 beta. In the presence of TGF beta 1, the HCV-induced GSK3 beta phosphorylation was blunted via a protein phosphatase 1-dependent mechanism and the cytoprotective Nrf2 response drastically impaired. This effect was counteracted by lithium, a selective inhibitor of GSK3 beta. In liver biopsy specimens from CHC patients, the expression of phosphorylated GSK3 beta positively correlated with Nrf2 expression and was inversely associated with the degree of liver injury. Moreover, CHC patients who received long-term lithium carbonate therapy primarily for concomitant psychiatric disorders exhibited much less liver injury, associated with enhanced hepatic expression of Nrf2. Conclusions Inhibition of GSK3 beta exerts hepatoprotection in CHC possibly through its direct regulation of Nrf2 antioxidant response.