While connexin-based gap junctions have been historically considered as goal keepers of tissue physiology, connexin hemichannels and pannexin channels have lately gained considerable attention as drivers of pathological processes, including cell death and inflammation. The objective of this doctoral thesis project was to investigate the role of the latter 2 channel types, in particular hemichannels consisting of connexin32 (Cx32) and connexin43 (Cx43) as well as pannexin channels built up by pannexin1 (Panx1), in liver disease. Focus was hereby put on non-alcoholic steatohepatitis (NASH), which is a highly prevalent type of chronic liver disease worldwide and that is characterized by hepatocellular lipid accumulation, oxidative stress and inflammation. In a first study, it was found that diet-induced NASH in whole body Cx32-/- mice results in more pronounced liver damage, inflammation and oxidative stress, thus suggesting a protective effect of overall Cx32 signaling. A second study showed that specific pharmacological inhibition of Cx32 and Cx43 hemichannels alleviates the clinical manifestation of NASH in mice as evidenced by reduced liver inflammation and oxidative stress. The third study demonstrated reduced liver damage, inflammation and oxidative stress in whole body Panx1-/- mice upon diet-based induction of NASH. Collectively, the outcome of these studies confirms the claimed pathological role of connexin hemichannel and pannexin channel signaling, and opens new perspectives for the clinical treatment of NASH.
|Award date||29 Jan 2018|
|Place of Publication||Brussels|
|Publication status||Unpublished - 2018|