Abstract
Hereditary hemochromatosis is a prevalent genetic disorder of iron hyperabsorption leading to hyperferremia, tissue iron deposition and complications including cirrhosis, hepatocarcinoma, cardiomyopathy and diabetes. Most individuals affected with hereditary hemochromatosis are homozygous with respect to a missense mutation that disrupts the conformation of HFE, an atypical HLA class I molecule (ref. 1; OMIM 235200). Mice lacking Hfe2,3,4 or producing a C282Y mutant Hfe protein3 develop hyperferremia and have high hepatic iron levels. In both humans and mice, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. It has been suggested that HFE modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells5,6; however, this model is unproven and controversial7,8. Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE. Although expression of mouse Hamp is normally greater during iron overload, Hfe−/− mice have inappropriately low expression of Hamp. We crossed Hfe−/− mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe−/− mice. This argues against the crypt programming model and suggests that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease.
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Acknowledgements
We thank B. Grandchamp for discussions, J. Bauchet and N. Sorhaindo for technical assistance and L. Montross for maintaining and shipping Hfe−/− mice. This work was supported by the Institut National de la Sante et de la Recherche Medicale, the Ministère de la Recherche, the Howard Hughes Medical Institute and the US National Institutes of Health. G.N. was funded by the Fondation pour la Recherche Médicale and the Association Hémochromatose France.
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Nicolas, G., Viatte, L., Lou, DQ. et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 34, 97–101 (2003). https://doi.org/10.1038/ng1150
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DOI: https://doi.org/10.1038/ng1150
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