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 (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.
Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
Patricia
P
Sancho
Jèssica
J
Mainez
Eva
E
Crosas-Molist
César
C
Roncero
Conrado M
CM
Fernández-Rodriguez
Fernando
F
Pinedo
Heidemarie
H
Huber
Robert
R
Eferl
Wolfgang
W
Mikulits
Isabel
I
Fabregat
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001706:Biopsy; D002251:Carbon Tetrachloride; D054338:Cell Transdifferentiation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D016174:Hepacivirus / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D019698:Hepatitis C, Chronic / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D002251:Carbon Tetrachloride; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C417743:Cdkn2a protein, mouse; C494087:Stat3 protein, mouse; C422943:Nox4 protein, mouse