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...

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Autores principales:	Patricia Sancho, Jèssica Mainez, Eva Crosas-Molist, César Roncero, Conrado M Fernández-Rodriguez, Fernando Pinedo, Heidemarie Huber, Robert Eferl, Wolfgang Mikulits, Isabel Fabregat
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/75617722b61f41f39952517e7d2fb884
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spelling	oai:doaj.org-article:75617722b61f41f39952517e7d2fb8842021-11-18T08:13:57ZNADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.1932-620310.1371/journal.pone.0045285https://doaj.org/article/75617722b61f41f39952517e7d2fb8842012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23049784/?tool=EBIhttps://doaj.org/toc/1932-6203A 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(-/-)/p19(ARF-/-), Stat3(Δhc)/Mdr2(-/-)) and a model of experimental induced fibrosis (CCl(4)) 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.Patricia SanchoJèssica MainezEva Crosas-MolistCésar RonceroConrado M Fernández-RodriguezFernando PinedoHeidemarie HuberRobert EferlWolfgang MikulitsIsabel FabregatPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e45285 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patricia Sancho Jèssica Mainez Eva Crosas-Molist César Roncero Conrado M Fernández-Rodriguez Fernando Pinedo Heidemarie Huber Robert Eferl Wolfgang Mikulits Isabel Fabregat NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.
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(-/-)/p19(ARF-/-), Stat3(Δhc)/Mdr2(-/-)) and a model of experimental induced fibrosis (CCl(4)) 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.
format	article
author	Patricia Sancho Jèssica Mainez Eva Crosas-Molist César Roncero Conrado M Fernández-Rodriguez Fernando Pinedo Heidemarie Huber Robert Eferl Wolfgang Mikulits Isabel Fabregat
author_facet	Patricia Sancho Jèssica Mainez Eva Crosas-Molist César Roncero Conrado M Fernández-Rodriguez Fernando Pinedo Heidemarie Huber Robert Eferl Wolfgang Mikulits Isabel Fabregat
author_sort	Patricia Sancho
title	NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.
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.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/75617722b61f41f39952517e7d2fb884
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NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.

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