NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.
A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats...
| Autores: | , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2012 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/36383 |
| Acesso em linha: | https://hdl.handle.net/2445/36383 |
| Access Level: | acceso abierto |
| Palavra-chave: | Malalties del fetge Cèl·lules hepàtiques Fibroblasts Liver diseases Liver cells |
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NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.Sancho, PatríciaMainez Villoro, JessicaCrosas Molist, EvaRoncero, CesáreoFernández Rodriguez, Conrado M.Pinedo, FernandoHuber, HeidemarieEferl, RobertMikulits, WolfgangFabregat Romero, IsabelMalalties del fetgeCèl·lules hepàtiquesFibroblastsLiver diseasesLiver cellsFibroblastsA role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2−/−/p19ARF−/−, Stat3Δhc/Mdr2−/−) and a model of experimental induced fibrosis (CCl4) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-β pathway activation. In vitro TGF-β-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-β is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-β-induced epithelial-mesenchymal transition (EMT), but was required for TGF-β-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-β-induced death of hepatocytes.Public Library of Science (PLoS)2013201320122013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/36383Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: http://dx.doi.org/10.1371/journal.pone.0045285PLoS One, 2012, vol. 7, num. 9, p. 1-14http://dx.doi.org/10.1371/journal.pone.0045285info:eu-repo/grantAgreement/EC/FP7/202047cc-by (c) Sancho, Patrícia et al., 2012http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/363832026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| title |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| spellingShingle |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. Sancho, Patrícia Malalties del fetge Cèl·lules hepàtiques Fibroblasts Liver diseases Liver cells Fibroblasts |
| title_short |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| title_full |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| title_fullStr |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| title_full_unstemmed |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| title_sort |
NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. |
| dc.creator.none.fl_str_mv |
Sancho, Patrícia Mainez Villoro, Jessica Crosas Molist, Eva Roncero, Cesáreo Fernández Rodriguez, Conrado M. Pinedo, Fernando Huber, Heidemarie Eferl, Robert Mikulits, Wolfgang Fabregat Romero, Isabel |
| author |
Sancho, Patrícia |
| author_facet |
Sancho, Patrícia Mainez Villoro, Jessica Crosas Molist, Eva Roncero, Cesáreo Fernández Rodriguez, Conrado M. Pinedo, Fernando Huber, Heidemarie Eferl, Robert Mikulits, Wolfgang Fabregat Romero, Isabel |
| author_role |
author |
| author2 |
Mainez Villoro, Jessica Crosas Molist, Eva Roncero, Cesáreo Fernández Rodriguez, Conrado M. Pinedo, Fernando Huber, Heidemarie Eferl, Robert Mikulits, Wolfgang Fabregat Romero, Isabel |
| author2_role |
author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malalties del fetge Cèl·lules hepàtiques Fibroblasts Liver diseases Liver cells Fibroblasts |
| topic |
Malalties del fetge Cèl·lules hepàtiques Fibroblasts Liver diseases Liver cells Fibroblasts |
| description |
A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2−/−/p19ARF−/−, Stat3Δhc/Mdr2−/−) and a model of experimental induced fibrosis (CCl4) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-β pathway activation. In vitro TGF-β-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-β is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-β-induced epithelial-mesenchymal transition (EMT), but was required for TGF-β-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-β-induced death of hepatocytes. |
| publishDate |
2012 |
| dc.date.none.fl_str_mv |
2012 2013 2013 2013 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/36383 |
| url |
https://hdl.handle.net/2445/36383 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.pone.0045285 PLoS One, 2012, vol. 7, num. 9, p. 1-14 http://dx.doi.org/10.1371/journal.pone.0045285 info:eu-repo/grantAgreement/EC/FP7/202047 |
| dc.rights.none.fl_str_mv |
cc-by (c) Sancho, Patrícia et al., 2012 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by (c) Sancho, Patrícia et al., 2012 http://creativecommons.org/licenses/by/3.0/es |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
14 p. application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Public Library of Science (PLoS) |
| publisher.none.fl_str_mv |
Public Library of Science (PLoS) |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Ciències Fisiològiques) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| reponame_str |
Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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15,811543 |