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 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 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.
Highlights
Disruption of iron homeostasis and accumulation of excess iron in tissues is associated with oxidative stress, cell injury and disease [1]
We show that excessive hepatic iron deposition potentiates chemically-induced liver fibrogenesis by promoting an oxidative burst and premature induction of profibrogenic cytokines
To assess the effects of iron overload in liver fibrogenesis, Hjv2/2 and isogenic wt animals were subjected to treatment with CCl4 over a period of up to 6 weeks
Summary
Disruption of iron homeostasis and accumulation of excess iron in tissues is associated with oxidative stress, cell injury and disease [1]. Hereditary hemochromatosis is characterized by chronic hyperabsorption and gradual deposition of iron within liver hepatocytes, while enterocytes and macrophages fail to retain iron due to inappropriately low expression of hepcidin [2,3,4]. This liverderived circulating peptide controls iron fluxes by binding to and promoting degradation of the iron exporter ferroportin. An early onset variant, is mostly caused by mutations in hemojuvelin (Hjv) [10], a BMP co-receptor that is essential for signaling to hepcidin [11]
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