The role of Caspase‐1 in diet induced chronic liver injury and blood bile barrier regulation

End‐stage chronic liver disease is a major cause of mortality worldwide. Irrespective of the underlying cause, most chronic liver diseases are characterized by fibrosis, hepatocellular necrosis, inflammation, ductular reactions and proliferation of the liver progenitor cells. Vast differences exist between experimental models that mimic these processes, and their identification is fundamental for translational research. However, the underlying differences in the molecular mechanism driving liver injury in different models remains largely unknown due to our inability to visualize the initiation and progression of liver injury in vivo in mice. Recently we have introduced quantitative Liver Intravital Microscopy (qLIM) that enables real‐time assessment of bile transport and blood‐bile barrier (BBlB) integrity in the intact liver of live mice (Pradhan‐Sundd et al., Gastroenterology, 2018) to visualize injury progression in two widely used experimental models of chronic liver injury ‐the choline‐deficient ethionine‐supplemented (CDE) or 3, 5‐diethoxycarbonyl 1, 4‐dihydrocollidine (DDC) diet, respectively. qLIM analysis revealed that chronic liver injury involves physical breach of BBlB, mixing of blood with bile and loss of bile transport across hepatocytes in both CDE and DDC diet fed mice. Mechanistically we showed an association of disruption of the BBlB and loss of various tight junctional proteins with sustained inflammation and apoptotic cell death (Pradhan‐Sundd et al., Gastroenterology, 2018). Thus, we hypothesized that blocking Caspase ‐1 induced inflammatory response can inhibit the loss of BBlB and thus postpone the chronic liver injury initiation in these diet fed mice. Indeed, mice with deletion of caspase‐1 displayed reduced liver injury, ductular reaction, fibrosis, inflammation, and apoptosis after two weeks of CDE and DDC diet. Remarkably, qLIM analysis showed intact blood biliary barrier at day 4 and 6 of CDE and DDC fed mice suggestive of delay in injury initiation. Furthermore, we demonstrate that the recovery from CDE and DDC diet induced liver injury is significantly accelerated in caspase‐1 KO mouse. We also found upregulation several tight junctional claudins in the liver upon caspase ‐1 knockdown. Current investigation is underway to analyse the regulation of tight junctional claudins by Caspase‐1. These findings may lead insight to disease progression and possible treatment of diet induced chronic liver injury.