Liver cell contacts as sensors of disease and targets for drug development

The liver is the largest solid organ in the human body. It is endowed with a plethora of specialized functions to serve as poison control center and metabolic hub of the body. The presence of an elaborate network of cellular contacts, including adherens, tight and gap junctions, is a corner stone in the performance of hepatic functionality. These cell contacts are key players that support liver architecture and hepatic cellular communication in order to control normal liver functioning. In addition, cellular interactions are frequently implicated in liver dysfunctionality. Because of its unique anatomic location and diverse functions, the liver is a frequent target for disease. The present doctoral thesis project revolves around hepatic cellular contacts and consists of 3 studies. The first 2 studies were set up to investigate whether hepatic cell junction components act as sensors of acute and chronic liver disease. In the first study, it was found that bile duct ligation, a well-known surgical procedure that triggers cholestatic and fibrotic insults, increases the expression of adherens junction building stones in murine liver. The second study revealed that liver injury inflicted by paracetamol or carbon tetrachloride is associated with differential changes in the production of adherens, tight and gap junction components. The results described in both studies support the idea of introducing
hepatic cell junctions and their components as diagnostic markers. The third study of this doctoral thesis project puts focus on hepatocellular communication channels
composed of pannexin1 proteins. The opening of pannexin1 channels is considered a key event in inflammation. This carries translational relevance, as pannexin1 channel inhibition could represent an innovative strategy for the treatment of inflammatory disorders. However, therapeutic pannexin1 channel targeting is impeded by the lack of specific, potent and/or in vivo-applicable inhibitors. This doctoral thesis project introduced for the first time nanobody-based inhibitors of pannexin1 channels, which were successfully tested as anti-inflammatory agents in a mouse model of paracetamol overdosing. The results described in this study therefore aid the development and further optimization of novel drugs for the treatment of hepatic inflammatory disorders.