Abstract
Liver cholestasis is a chronic liver disease and a major health problem worldwide. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of bile duct structures. Here we investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of recombination signal binding protein for immunoglobulin kappa j region (Rbpj), which represents a key regulator of Notch signalling, induces severe cholestasis through impaired intra-hepatic bile duct (IHBD) maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with the change of several signalling pathways including a Kyoto Encyclopedia of Genes and Genomes (KEGG) gene set representing the Hippo pathway, further yes-associated protein (YAP) activation and upregulation of SRY (sex determining region Y)-box 9 (SOX9), which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that in vivo Rbpj depletion is followed by YAP activation, which influences the transdifferentiation of hepatocytes and thereby contributing to liver regeneration.
Highlights
Chronic liver disease (CLD) is characterised by a permanent damage of liver cells followed by activation of repair mechanisms and represent a major health problem worldwide
The body weight was monitored for up to 36 weeks and reduced body weight of Rbpj−/− mice was observed at every monitored time point (Figure 1B)
In order to verify the efficiency of Rbpj deletion in the liver, we performed quantitative real-time polymerase chain reaction and Western blotting
Summary
Chronic liver disease (CLD) is characterised by a permanent damage of liver cells followed by activation of repair mechanisms and represent a major health problem worldwide. Liver disease affecting bile acid regulation is called cholestatic liver disease. It can be caused by drugs, autoimmune damage of bile ducts, genetic defects and developmental disorders. Liver-specific Rbpj deletion in mice causes impaired intrahepatic bile duct development, severe cholestasis, hepatic necrosis and fibrosis [15,16]. Through the capability of a cellular plasticity, the liver is able to generate intra-hepatic bile ducts (IHBD) independent of Notch signalling. From our study of in vitro cholestatic liver injury, we could show that upregulation of Sox expression upon induction of cholestasis is independent of Notch signalling.
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