Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease
Biochimica et Biophysica Acta - Molecular Basis of Disease
Acute liver failure; Hepatotoxicity; Inflammation; Non-alcoholic steatohepatitis; Pannexin
© 2017 Elsevier B.V. Pannexins are transmembrane proteins that form communication channels connecting the cytosol of an individual cell with its extracellular environment. A number of studies have documented the presence of pannexin1 in liver as well as its involvement in inflammatory responses. In this study, it was investigated whether pannexin1 plays a role in acute liver failure and non-alcoholic steatohepatitis, being prototypical acute and chronic liver pathologies, respectively, both featured by liver damage, oxidative stress and inflammation. To this end, wild-type and pannexin1−/− mice were overdosed with acetaminophen for 1, 6, 24 or 48 h or were fed a choline-deficient high-fat diet for 8 weeks. Evaluation of the effects of genetic pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, lipid accumulation, protein adduct formation, oxidative stress and inflammation. In parallel, in order to elucidate molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. The results of this study show that pannexin1−/− diseased mice present less liver damage and oxidative stress, while inflammation was only decreased in pannexin1−/− mice in which non-alcoholic steatohepatitis was induced. A multitude of genes related to inflammation, oxidative stress and xenobiotic metabolism were differentially modulated in both liver disease models in wild-type and in pannexin1−/− mice. Overall, the results of this study suggest that pannexin1 may play a role in the pathogenesis of liver disease.
Willebrords, J., Maes, M., Pereira, I., da Silva, T., Govoni, V., Lopes, V., Crespo Yanguas, S., Shestopalov, V., Nogueira, M., de Castro, I., Farhood, A., Mannaerts, I., van Grunsven, L., Akakpo, J., Lebofsky, M., Jaeschke, H., Cogliati, B., & Vinken, M. (2018). Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864 (3). http://dx.doi.org/10.1016/j.bbadis.2017.12.013