p38α deficiency restrains liver regeneration after partial hepatectomy triggering oxidative stress and liver injury

p38 alpha MAPK negatively regulates the G(1)/S and G(2)/M cell cycle transitions. However, liver-specific p38 alpha deficiency impairs cytokinesis and reduces hepatocyte proliferation during cirrhosis and aging in mice. In this work, we have studied how p38 alpha down-regulation affects hepatocyte proliferation after partial hepatectomy, focusing on mitotic progression, cytokinesis and oxidative stress. We found that p38 alpha deficiency triggered up-regulation of cyclins A1, B1, B2, and D1 under basal conditions and after hepatectomy. Moreover, p38 alpha-deficient hepatocytes showed enhanced binucleation and increased levels of phospho-histone H3 but impaired phosphorylation of MNK1 after hepatectomy. The recovery of liver mass was transiently delayed in mice with p38 alpha-deficient hepatocytes vs wild type mice. We also found that p38 alpha deficiency caused glutathione oxidation in the liver, increased plasma aminotransferases and lactate dehydrogenase activities, and decreased plasma protein levels after hepatectomy. Interestingly, p38 alpha silencing in isolated hepatocytes markedly decreased phospho-MNK1 levels, and silencing of either p38 alpha or Mnk1 enhanced binucleation of hepatocytes in culture. In conclusion, p38 alpha deficiency impairs mitotic progression in hepatocytes and restrains the recovery of liver mass after partial hepatectomy. Our results also indicate that p38 alpha regulates cytokinesis by activating MNK1 and redox modulation.