Protective role of Cytoglobin in liver injury and fibrogenesis in bile duct ligation-induced cholestatic mice; possible involvement of nitric oxide

This study clarified the role of Cytoglobin (Cygb), the fourth globin in mammals expressed in rat hepatic stellate cells, in bile duct ligation (BDL)-induced cholestatic liver disease. BDL augmented inflammatory reactions as... [ view full abstract ]

This study clarified the role of Cytoglobin (Cygb), the fourth globin in mammals expressed in rat hepatic stellate cells, in bile duct ligation (BDL)-induced cholestatic liver disease. BDL augmented inflammatory reactions as revealed by increased infiltrating neutrophils, CD68⁺-macrophages, and chemokine mRNA expression in Cygb^-/- mice compared to wild-type mice. In Cygb^-/- mice, impairment of bile canaliculi indicated by the loss of CD10 expression and down-regulation of bile salt transporters increased serum total bile acid and gave rise to massive apoptotic and necrotic hepatocytes, resulting in reduced animal survival. In Cygb^-/- mouse liver, all of nitric oxide (NO) metabolites and oxidative stress were increased. Treatment with NO inhibitor, N^G-nitro-L-arginine methyl ester, restrained all above phenotypes and restored CD10 expression in BDL Cygb^-/- mice, while administration of NO donor, sodium nitroprusside, aggravated liver damage in BDL-wild type mice to the same extent of BDL-Cygb^-/- mice. N-acetylcysteine had a negligible effect in all groups. In mice of BDL for 1–3 weeks, expression of fibrosis-related markers, including collagen 1A1 and tissue inhibitor of metalloproteinases 1, was significantly increased in Cygb^-/- mice. In contrast, Cygb overexpressing mice were obviously protected from liver injury in acute phase and fibrosis developing in chronic phase. Thus, Cygb protects BDL mice from liver injury in early phase and fibrosis development in late phase, presumably via regulating NO metabolism. The development of drugs that modulate Cygb function and consequently NO metabolism is anticipated for the human cholestatic liver disease, a field of unmet medical needs.