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Title: NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.
Author: Sancho, Patrícia
Mainez Villoro, Jessica
Crosas Molist, Eva
Roncero, César
Fernández Rodriguez, Conrado M.
Pinedo, Fernando
Huber, Heidemarie
Eferl, Robert
Mikulits, Wolfgang
Fabregat Romero, Isabel
Keywords: Malalties del fetge
Cèl·lules hepàtiques
Liver diseases
Liver cells
Issue Date: 26-Sep-2012
Publisher: Public Library of Science (PLoS)
Abstract: 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.
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It is part of: PLoS One, 2012, vol. 7, num. 9, p. 1-14
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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