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Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice

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 UGent, et al. (2017) SCIENTIFIC REPORTS. 7.
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
FATTY LIVER-DISEASE, GAP-JUNCTION PROTEIN, ATP RELEASE, INFLAMMATION, RAT, PATHOGENESIS, CHANNELS, ACID, HEPATOCYTES, EXPRESSION
journal title
SCIENTIFIC REPORTS
Sci. Rep.
volume
7
article number
8268
pages
11 pages
Web of Science type
Article
Web of Science id
000407570000145
ISSN
2045-2322
DOI
10.1038/s41598-017-08583-w
language
English
UGent publication?
yes
classification
A1
additional info
the first two authors contributed equally to this work
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8540472
handle
http://hdl.handle.net/1854/LU-8540472
date created
2017-12-06 10:42:59
date last changed
2018-01-05 15:35:26
@article{8540472,
  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.},
  articleno    = {8268},
  author       = {Willebrords, Joost and Cogliati, Bruno and Pereira, Isabel Veloso Alves and da Silva, Tereza Cristina and Crespo Yanguas, Sara and Maes, Micha{\"e}l and Govoni, Veronica Mollica and Lima, Andressa and Felisbino, Daniele Aparecida and Decrock, Elke and Nogueira, Marina Sayuri and de Castro, Inar Alves and Leclercq, Isabelle and Leybaert, Luc and Rodrigues, Robim Marcelino and Vinken, Mathieu},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {FATTY LIVER-DISEASE,GAP-JUNCTION PROTEIN,ATP RELEASE,INFLAMMATION,RAT,PATHOGENESIS,CHANNELS,ACID,HEPATOCYTES,EXPRESSION},
  language     = {eng},
  pages        = {11},
  title        = {Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice},
  url          = {http://dx.doi.org/10.1038/s41598-017-08583-w},
  volume       = {7},
  year         = {2017},
}

Chicago
Willebrords, Joost, Bruno Cogliati, Isabel Veloso Alves Pereira, Tereza Cristina da Silva, Sara Crespo Yanguas, Michaël Maes, Veronica Mollica Govoni, et al. 2017. “Inhibition of Connexin Hemichannels Alleviates Non-alcoholic Steatohepatitis in Mice.” Scientific Reports 7.
APA
Willebrords, Joost, Cogliati, B., Pereira, I. V. A., da Silva, T. C., Crespo Yanguas, S., Maes, M., Govoni, V. M., et al. (2017). Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice. SCIENTIFIC REPORTS, 7.
Vancouver
1.
Willebrords J, Cogliati B, Pereira IVA, da Silva TC, Crespo Yanguas S, Maes M, et al. Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice. SCIENTIFIC REPORTS. 2017;7.
MLA
Willebrords, Joost, Bruno Cogliati, Isabel Veloso Alves Pereira, et al. “Inhibition of Connexin Hemichannels Alleviates Non-alcoholic Steatohepatitis in Mice.” SCIENTIFIC REPORTS 7 (2017): n. pag. Print.