Hepcidin knockout mice as a model of iron-overload associated liver disease
Hepcidin is the central regulatory hormone of iron metabolism. Disrupted hepcidin signalling is seen in hereditary hemochromatosis (HH) which leads to iron overload. While the association between iron overload and development of end-stage liver disease is well established, the precise underlying mechanisms remain to be defined. To develop iron overload model similar to human HH, we analyzed hepcidin knockout (KO) and wild type (WT) mice were fed with iron-rich diet for 5 or 11 months and compared them to age matched mice kept on standard chow. Harvested livers and serum samples were used for evaluation of liver injury and fibrosis. To determine the iron localization, a subcellular fractionation and electron microscopy was performed. Hepcidin KOs kept on standard diet developed spontaneous hepatic iron overload, which was even more pronounced in KOs fed iron-rich chow who reached levels similar to the ones observed in HH patients. Elevated serum liver enzymes, serum iron levels, mild hepatocellular inflammation and apoptosis were observed in hepcidin KOs fed iron-rich diet. After 11 months of iron-rich chow, hepcidin KOs developed moderate liver fibrosis. The liver injury was accompanied by a marked lysosomal iron overload and lysosomal fragility with release of cathepsins into the cytoplasm. Increased LC3-II and p62 levels pointed towards an activated autophagy which likely contributes to the lysosomal iron overload. On the other hand, large indigestible iron complexes were found in hepcidin knockout mice fed iron-rich diet thereby suggesting a defect in protein degradation as it is observed in lysosomal storage diseases. In conclusion, hepcidin KO mice represent an attractive animal model which mimics both iron overload and associated liver injury observed in humans with HH.
Subject headings[LCSH]: Animal Models
[MeSH]: Hemochromatosis | Hepcidins | Iron overload | Liver diseases | Mice, Knockout
[DDC subject group]: DDC 610 / Medicine & health
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DOI & citation
Please use this identifier to cite or link to this item: http://dx.doi.org/10.18725/OPARU-2987