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Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing

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Abstract

The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5–7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.

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Acknowledgments

We thank Dr. Alan Spatz, Dr. Naciba Benlimame and Lilian Canetti for assistance with histology. This work was supported by a grant from the Canadian Institutes for Health Research (CIHR; MOP-86515). AD is a recipient of a doctoral fellowship from the Fonds de la Recherche en Santé du Quebéc (FRSQ). KG is a recipient of doctoral awards from the J. Latsis and A. Onassis Public Benefit Foundations. KP holds a Chercheur National career award from the FRSQ.

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Authors and Affiliations

  1. Lady Davis Institute for Medical Research, Jewish General Hospital and Department of Medicine, McGill University, Montreal, QC, Canada

    Alina Daba, Konstantinos Gkouvatsos, Giada Sebastiani & Kostas Pantopoulos

  2. Division of Gastroenterology, Royal Victoria Hospital, McGill University Health Center, Montreal, QC, Canada

    Giada Sebastiani

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  1. Alina Daba
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  2. Konstantinos Gkouvatsos
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  3. Giada Sebastiani
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  4. Kostas Pantopoulos
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Correspondence to Kostas Pantopoulos.

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Daba, A., Gkouvatsos, K., Sebastiani, G. et al. Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing. J Mol Med 91, 95–102 (2013). https://doi.org/10.1007/s00109-012-0937-5

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  • DOI: https://doi.org/10.1007/s00109-012-0937-5

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