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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/0ecf5b9e1964429e9ec61034a86fb689 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:0ecf5b9e1964429e9ec61034a86fb689 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:0ecf5b9e1964429e9ec61034a86fb6892021-12-02T16:06:32ZInhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice10.1038/s41598-017-08583-w2045-2322https://doaj.org/article/0ecf5b9e1964429e9ec61034a86fb6892017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08583-whttps://doaj.org/toc/2045-2322Abstract 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.Joost WillebrordsBruno CogliatiIsabel Veloso Alves PereiraTereza Cristina da SilvaSara Crespo YanguasMichaël MaesVeronica Mollica GovoniAndressa LimaDaniele Aparecida FelisbinoElke DecrockMarina Sayuri NogueiraInar Alves de CastroIsabelle LeclercqLuc LeybaertRobim Marcelino RodriguesMathieu VinkenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 |
| 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. |
| format |
article |
| 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 |
| 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 Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/0ecf5b9e1964429e9ec61034a86fb689 |
| work_keys_str_mv |
AT joostwillebrords inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT brunocogliati inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT isabelvelosoalvespereira inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT terezacristinadasilva inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT saracrespoyanguas inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT michaelmaes inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT veronicamollicagovoni inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT andressalima inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT danieleaparecidafelisbino inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT elkedecrock inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT marinasayurinogueira inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT inaralvesdecastro inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT isabelleleclercq inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT lucleybaert inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT robimmarcelinorodrigues inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice AT mathieuvinken inhibitionofconnexinhemichannelsalleviatesnonalcoholicsteatohepatitisinmice |
| _version_ |
1718384947463454720 |