Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice

Background and aims: Connexins are the molecular constituents of gap junctions and hemichannels. In liver, connexin32 is the predominant connexin species expressed by hepatocytes, whereas non-parenchymal cells typically harbour connexin43. While gap junctions mediate intercellular communication and support liver homeostasis, hemichannels provide a circuit for paracrine signaling and are preferentially opened by pathological stimuli, including inflammation and oxidative stress. The latter are essential features of non-alcoholic steatohepatitis. In this study, it was investigated whether connexin32 and connexin43 hemichannels play a role in non-alcoholic steatohepatitis. Methods: Mice were fed a choline-deficient high-fat diet for 8 weeks. Thereafter, TAT-Gap24 or TAT-Gap19, specific inhibitors of hemichannels composed of connexin32 and connexin43, respectively, were administered for 2 weeks via an abdominal osmotic pump. Subsequently, histopathological examination was carried out and various indicators of inflammation, liver damage and oxidative stress were tested. In addition, whole transcriptome microarray analysis of liver tissue was performed. Channel specificity of TAT-Gap24 and TAT-Gap19 was examined in vitro by fluorescence recovery after photobleaching analysis and measurement of extracellular release of adenosine triphosphate. Results: TAT-Gap24 and TAT-Gap19 reduced adenosine triphosphate release, indicative for hemichannel opening, but did not inhibit gap junctions in cultures of primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of abdominal fat, liver triglycerides and cholesterol, reduced quantities of inflammatory markers and augmented levels of superoxide dismutase. Expression of several genes related to inflammation, oxidative stress and lipid transport were differentially changed. Conclusion: These findings show for the first time the involvement of connexin32 and connexin43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug target in this prevalent chronic liver disease.

Jaar van publicatie:2017

Trefwoorden:connexin, nash, Liver

Auteurs:International

Toegankelijkheid:Open