Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis.
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 Hfe or producing a C282Y mutant Hfe protein 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 cells; however, this model is unproven and controversial. 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.
Nicolas
Gaël
G
Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, Centre National de la Recherche Scientifique, et Université René Descartes, Faculté de Médecine Cochin-Port Royal, 24, rue du Fg St Jacques 75014 Paris, France.
Viatte
Lydie
L
Lou
Dan-Qing
DQ
Bennoun
Myriam
M
Beaumont
Carole
C
Kahn
Axel
A
Andrews
Nancy C
NC
Vaulont
Sophie
S
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D003433:Crosses, Genetic; D015870:Gene Expression; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D019190:Iron Overload / Q000235:genetics* / Q000517:prevention & control; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C103673:HFE protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012333:RNA, Messenger