title: Accelerated CCl4-induced liver fibrosis in Hjv-/- mice, associated with an oxidative burst and precocious profibrogenic gene expression.
abstract: Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/-) mice and wild type (wt) controls were intoxicated with CCl(4). Hjv-/- mice developed earlier (by 2-4 weeks) and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I)-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv-/- animals. Even though livers of naïve Hjv-/- mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2-3 fold vs. wt, p<0.05) levels of α1-(I)-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Giada
authors.initials: G
authors.lastname: Sebastiani
authors.forename: Kostas
authors.initials: K
authors.lastname: Gkouvatsos
authors.forename: Carmen
authors.initials: C
authors.lastname: Maffettone
authors.forename: Graziella
authors.initials: G
authors.lastname: Busatto
authors.forename: Maria
authors.initials: M
authors.lastname: Guido
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins; D000071020:Hemochromatosis Protein; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride