Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe

Gastroenterology. 2011 Nov;141(5):1907-14. doi: 10.1053/j.gastro.2011.06.077. Epub 2011 Jul 13.


Background & aims: HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes.

Methods: Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling.

Results: Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading.

Conclusions: These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / metabolism*
  • Bone Morphogenetic Protein 6 / metabolism
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Iron / metabolism
  • Iron, Dietary / pharmacology*
  • Liver / drug effects
  • Liver / metabolism
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • Models, Animal
  • RNA, Messenger / metabolism
  • Receptors, Transferrin / deficiency*
  • Receptors, Transferrin / genetics
  • Signal Transduction / physiology*
  • Smad1 Protein / metabolism*
  • Smad5 Protein / metabolism*
  • Smad8 Protein / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Antimicrobial Cationic Peptides
  • Bmp6 protein, mouse
  • Bone Morphogenetic Protein 6
  • Hamp protein, mouse
  • Hemochromatosis Protein
  • Hepcidins
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Idb1 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Iron, Dietary
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Transferrin
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • Smad8 Protein
  • Smad9 protein, mouse
  • TFR2 protein, mouse
  • Iron