title: Parenteral vs. oral iron: influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice.
abstract: Treatment for iron deficiency anemia can involve iron supplementation via dietary or parenteral routes that result in different cellular iron distributions. The effect of the administered iron on the iron regulatory system and hepcidin in the liver has not been well studied. Hepcidin, the liver-expressed central iron-regulatory peptide, is itself regulated through the bone morphogenetic protein (BMP)/SMAD signaling pathway. Specifically, Bmp6 expression is upregulated in response to iron and induces hepcidin through phosphorylation of Smad1/5/8. The hemochromatosis-associated proteins Hfe and transferrin receptor 2 (Tfr2) are known upstream regulators of hepcidin, although their precise roles are still unclear. To investigate the mechanisms of this regulation and the roles of the Hfe and Tfr2, we subjected wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice to iron loading via dietary or parenteral routes. Systematic analysis demonstrated that Tfr2 is required for effective upregulation of Bmp6 in response to hepatocyte iron, but not nonparenchymal iron. Hfe is not required for Bmp6 upregulation, regardless of iron localization, but rather, is required for efficient downstream transmission of the regulatory signal. Our results demonstrate that Hfe and Tfr2 play separate roles in the regulatory responses to iron compartmentalized in different cell types and further elucidates the regulatory mechanisms controlling iron homeostasis.
authors.affiliation: Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Rd., Herston, Brisbane, QLD 4006, Australia. Nathan.Subramaniam@qimr.edu.au.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: McDonald
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wallace
authors.forename: Lesa
authors.initials: L
authors.lastname: Ostini
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D004396:Coloring Agents; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000235:genetics / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000502:physiology*; D007263:Infusions, Parenteral; D007501:Iron / Q000008:administration & dosage* / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D011990:Receptors, Transferrin / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D055418:Bone Morphogenetic Protein 6; D004396:Coloring Agents; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D051785:Smad Proteins; C503641:TFR2 protein, mouse; D007501:Iron
keywords: Kupffer cell; bone morphogenetic protein 6; hepatocyte; iron metabolism; liver