Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice
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...
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2017-08-01
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doaj-0ecf5b9e1964429e9ec61034a86fb6892020-12-08T00:56:38ZengNature Publishing GroupScientific Reports2045-23222017-08-017111110.1038/s41598-017-08583-wInhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in miceJoost Willebrords0Bruno Cogliati1Isabel Veloso Alves Pereira2Tereza Cristina da Silva3Sara Crespo Yanguas4Michaël Maes5Veronica Mollica Govoni6Andressa Lima7Daniele Aparecida Felisbino8Elke Decrock9Marina Sayuri Nogueira10Inar Alves de Castro11Isabelle Leclercq12Luc Leybaert13Robim Marcelino Rodrigues14Mathieu Vinken15Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit BrusselDepartment of Pathology, School of Veterinary Medicine and Animal Science, University of São PauloDepartment of Pathology, School of Veterinary Medicine and Animal Science, University of São PauloDepartment of Pathology, School of Veterinary Medicine and Animal Science, University of São PauloDepartment of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit BrusselDepartment of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit BrusselDepartment of Pathology, School of Veterinary Medicine and Animal Science, University of São PauloDepartment of Pathology, School of Veterinary Medicine and Animal Science, University of São PauloDepartment of Pathology, School of Veterinary Medicine and Animal Science, University of São PauloDepartment of Basic Medical Sciences, Physiology Group, Ghent UniversityDepartment of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São PauloDepartment of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São PauloLaboratory of hepatogastroenterology, Institut de Recherche Expérimentale et clinique, Université catholique de LouvainDepartment of Basic Medical Sciences, Physiology Group, Ghent UniversityDepartment of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit BrusselDepartment of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit BrusselAbstract 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 TAT-Gap19 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 non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis.https://doi.org/10.1038/s41598-017-08583-w |
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DOAJ |
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English |
format |
Article |
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DOAJ |
author |
Joost Willebrords Bruno Cogliati Isabel Veloso Alves Pereira Tereza Cristina da Silva Sara Crespo Yanguas Michaël Maes Veronica Mollica Govoni Andressa Lima Daniele Aparecida Felisbino Elke Decrock Marina Sayuri Nogueira Inar Alves de Castro Isabelle Leclercq Luc Leybaert Robim Marcelino Rodrigues Mathieu Vinken |
spellingShingle |
Joost Willebrords Bruno Cogliati Isabel Veloso Alves Pereira Tereza Cristina da Silva Sara Crespo Yanguas Michaël Maes Veronica Mollica Govoni Andressa Lima Daniele Aparecida Felisbino Elke Decrock Marina Sayuri Nogueira Inar Alves de Castro Isabelle Leclercq Luc Leybaert Robim Marcelino Rodrigues Mathieu Vinken Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice Scientific Reports |
author_facet |
Joost Willebrords Bruno Cogliati Isabel Veloso Alves Pereira Tereza Cristina da Silva Sara Crespo Yanguas Michaël Maes Veronica Mollica Govoni Andressa Lima Daniele Aparecida Felisbino Elke Decrock Marina Sayuri Nogueira Inar Alves de Castro Isabelle Leclercq Luc Leybaert Robim Marcelino Rodrigues Mathieu Vinken |
author_sort |
Joost Willebrords |
title |
Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice |
title_short |
Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice |
title_full |
Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice |
title_fullStr |
Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice |
title_full_unstemmed |
Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice |
title_sort |
inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-08-01 |
description |
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 TAT-Gap19 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 non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis. |
url |
https://doi.org/10.1038/s41598-017-08583-w |
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