The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression

Cell Metab. 2008 Mar;7(3):205-14. doi: 10.1016/j.cmet.2007.11.016.

Abstract

Hemochromatosis is caused by mutations in HFE, a protein that competes with transferrin (TF) for binding to transferrin receptor 1 (TFR1). We developed mutant mouse strains to gain insight into the role of the Hfe/Tfr1 complex in regulating iron homeostasis. We introduced mutations into a ubiquitously expressed Tfr1 transgene or the endogenous Tfr1 locus to promote or prevent the Hfe/Tfr1 interaction. Under conditions favoring a constitutive Hfe/Tfr1 interaction, mice developed iron overload attributable to inappropriately low expression of the hormone hepcidin. In contrast, mice carrying a mutation that interferes with the Hfe/Tfr1 interaction developed iron deficiency associated with inappropriately high hepcidin expression. High-level expression of a liver-specific Hfe transgene in Hfe-/- mice was also associated with increased hepcidin production and iron deficiency. Together, these models suggest that Hfe induces hepcidin expression when it is not in complex with Tfr1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / metabolism*
  • Binding Sites
  • Erythropoiesis
  • Gene Expression Regulation
  • Genotype
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Homeostasis
  • Iron / deficiency
  • Iron / metabolism*
  • Iron Overload / genetics
  • Iron Overload / metabolism*
  • Iron Overload / physiopathology
  • Liver / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation, Missense
  • Phenotype
  • Protein Binding
  • RNA, Messenger / metabolism
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism*
  • Signal Transduction* / genetics
  • Transferrin / metabolism

Substances

  • Antimicrobial Cationic Peptides
  • Hamp protein, mouse
  • Hemochromatosis Protein
  • Hepcidins
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Transferrin
  • Tfrc protein, mouse
  • Transferrin
  • Iron