Parenteral vs. oral iron: Influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice

McDonald, C.J., Wallace, D.F., Ostini, L., & Subramaniam, V.N. (2014) Parenteral vs. oral iron: Influence on hepcidin signaling pathways through analysis of Hfe/Tfr2-null mice. American Journal of Physiology - Gastrointestinal and Liver Physiology, 306(2), G132-G139.

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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.

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12 citations in Scopus
8 citations in Web of Science®
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ID Code: 99832
Item Type: Journal Article
Refereed: No
Keywords: liver, hepatocyte, iron metabolism, Kupffer cell, bone morphogenetic protein 6
DOI: 10.1152/ajpgi.00256.2013
ISSN: 1522-1547
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: © 2014 the American Physiological Society
Deposited On: 13 Oct 2016 03:49
Last Modified: 29 Mar 2017 03:26

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