Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice

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Willebrords, Joost ; Cogliati, Bruno ; Alves Pereira, Isabel Veloso ; da Silva, Tereza Cristina ; Yanguas, Sara Crespo ; Maes, Michael ; Govoni, Veronica Mollica ; Lima, Andressa ; Felisbino, Daniele Aparecida ; Decrock, Elke ; Nogueira, Marina Sayuri ; de Castro, Inar Alves ; Leclercq, Isabelle ; Leybaert, Luc ; Rodrigues, Robim Marcelino ; Vinken, Mathieu

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, AUG 15 2017.
• Web of Science Citations: 12

Abstract

While gap junctions mediate intercellular communication and support liver homeostasis, connexin hemichannels 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. Mice were fed a choline-deficient high-fat diet or normal 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. 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. TAT-Gap24 and TATGap19 were shown to be hemichannel-specific in cultured primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of liver lipids and inflammatory markers, and augmented levels of superoxide dismutase, which was supported by the microarray results. These findings show the involvement of connexin32 and connexin43 hemichannels in nonalcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis. (AU)

• FAPESP's process: 16/16182-9 - Characterization of connexin 32 and connexin 43 expression in non-alcoholic fatty liver disease in mice
• Grantee: Andressa Lima
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 13/50420-6 - Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease
• Grantee: Mathieu Frederick Alexander Vinken
• Support Opportunities: Research Projects - SPEC Program