Syndecan‐1 limits the progression of liver injury and promotes liver repair in acetaminophen‐induced liver injury in mice

摘要

Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. Although mechanisms that trigger APAPinduced liver injury (AILI) are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injuryin vivo remains unknown. Here, we examined the role of syndecan1, the major cellsurface HSPG of hepatocytes, in AILI. Ablation of syndecan1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times postAPAP overdose were unaffected by syndecan1, suggesting that syndecan1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan1 null (Sdc1/ ) mice were traced to a deficiency in protein kinase B (Akt) activation in hepatocytes, which led to a delayed increase in glycogen synthase kinase3?(GSK3?mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK3?and caspases protected mice from AILI. Moreover, administration of purified syndecan1, HS, or engineered heparan compounds containing 2O sulfate groups rescuedSdc1/ mice from AILI by potentiating Akt signaling and inhibiting GSK3?mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared toN acetylcysteine.Conclusion : These results demonstrate that 2O sulfated domains in syndecan1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in AILI. We propose that syndecan1 is a critical endogenous factor that controls the balance between prosurvival signaling and apoptosis in hepatocytes in APAP liver disease. (Hepatology 2017;66:16011615).