Cytoglobin deficiency enhances liver injury and fibrogenesis during cholestasis in mice

Cytoglobin (Cygb), the fourth member of globin family, was originally discovered in rat hepatic stellate cells, which are dominantly involved in liver fibrosis. Cholestasis is a common hepatic disease and can lead to hepatic fibrosis and cirrhosis if it persistently occurs. Since there is no report showing the involvement of Cygb in cholestasis-associated hepatic pathophysiology, we aimed to investigate the role of Cygb in this aspect by using Cygb knockout (KO) mice. Cholestasis was induced in KO male mice and wild-type (WT) controls by bile duct ligation (BDL) with 4 to 8 mice for each group. Mice were sacrificed at 3, 7 days (short-term) and 14, 21 days (long-term) after BDL. Liver injury and fibrosis were evaluated by several parameters. At short-term treatment, KO mice showed severe biliary infraction with high level of alanine aminotransferase compared with WT. Fibrosis, which was assessed through the amount of collagen and αSMA expression at mRNA and protein level, was developed dominantly in KO mice after long-term treatment. Both Ki67, the proliferative maker, and TUNEL, the apoptotic maker, emerged in hepatocytes of KO mice aberrantly comparing to WT ones. These phenomena were associated with activated apoptosis pathway and inhibited growth arrest-related genes in hepatocytes in cholestasis. Conclusion: Cygb deficiency enhances liver injury and fibrogenesis in mice subjected to BDL.