Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis

Nat Genet. 2003 May;34(1):97-101. doi: 10.1038/ng1150.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics*
  • Crosses, Genetic
  • Gene Expression
  • Hemochromatosis / genetics*
  • Hemochromatosis / metabolism
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Iron Overload / genetics*
  • Iron Overload / prevention & control
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation, Missense
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Antimicrobial Cationic Peptides
  • HAMP protein, human
  • HFE protein, human
  • Hamp protein, mouse
  • Hemochromatosis Protein
  • Hepcidins
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • RNA, Messenger

Associated data

  • OMIM/235200
  • OMIM/606464