Hepcidin knockout mice as a model of iron-overload associated liver disease

Background and aims: Hepcidin is the central regulator of iron homeostasis. Disrupted hepcidin signalling results in hereditary hemochromatosis and iron overload in chronic liver disorders. While the association between iron overload and development of end-stage liver disease is well established, our understanding of the underlying pathomechanisms is hampered by the lack of a suitable animal model. To circumvent this problem, we studied hepcidin-knockout (KO) mice as a model of iron-overload associated liver damage. Methods: 6 month-old hepcidin-KO and -wild type (WT) mice fed 3% iron carbonyl-containing diet (Fe-diet) since four weeks of age were compared to age-matched WT and KO animals kept on standard diet. The liver phenotype was quantified serologically as well as morphometrically based on hematoxylin & eosin, Prussian blue and Sirius red stainings. Liver iron content was determined by atomic mass absorption. Results: The iron overload seen in hepcidin-KO mice on standard diet was even more pronounced when they were fed Fe-diet. Among Fe-fed males, hepcidin KO mice (compared to WTs) exhibited (i) increased iron liver contents (2893 vs. 1960; p<0,025); (ii) elevated AST and serum iron levels (AST: KO 139, WT 79, p<0,006; serum iron: KO 95, WT 51, p<0,0001); (iii) increased liver inflammation and hepatocellular apoptosis. Fe-fed females displayed a milder phenotype than males with significantly lower liver iron content and largely inconspicuous liver enzyme levels. Unexpectedly, Fe-fed hepcidin KO females, but not males exhibited signs of beginning liver fibrosis. Conclusions: Iron-fed hepcidin knockout mice represent an intriguing model of iron overload-associated liver damage as well as liver fibrosis development.

fibrosis - hemochromatosis - hepcidin - iron