Accelerated CCl4-Induced Liver Fibrosis in Hjv-/- Mice, Associated with an Oxidative Burst and Precocious Profibrogenic Gene Expression

作者：Sebastiani, Giada^*; Gkouvatsos, Kostas; Maffettone, Carmen; Busatto, Graziella; Guido, Maria; Pantopoulos, Kostas

来源：PLos One, 2011, 6(9): e25138.

DOI：10.1371/journal.pone.0025138

• DIETARY IRON OVERLOAD
• NF-KAPPA-B
• HEPATIC IRON
• MEDICAL PROGRESS
• RODENT MODEL
• ANIMAL-MODEL
• EXCESS IRON
• LONG-TERM
• HEMOCHROMATOSIS
• ACTIVATION

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 CCl4. 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 alpha 1-(I)-collagen, the profibrogenic cytokines TGF-beta 1, 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 naive Hjv-/- mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards alpha-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2-3 fold vs. wt, p<0.05) levels of alpha 1-(I)-collagen, TGF-beta 1, 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.

• 出版日期2011-9-22
• 单位McGill; 河北医科大学