Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice

Authors

  • Víctor Díaz,

    1. Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), and University of Zurich, Switzerland
    2. Department of Health and Human Performance, Faculty of Sports Science, INEF, Technical University of Madrid, Spain
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    • These authors contributed equally to the work.

  • Elena Gammella,

    1. Department of Biomedical Sciences for Health, University of Milano, Italy
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    • These authors contributed equally to the work.

  • Stefania Recalcati,

    1. Department of Biomedical Sciences for Health, University of Milano, Italy
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  • Paolo Santambrogio,

    1. Department of Biomedical Science and Technology, San Raffaele Scientific Institute, Milano, Italy
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  • Arianne Monge Naldi,

    1. Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), and University of Zurich, Switzerland
    2. Clinic for Otolaryngology, Head and Neck Surgery, University Hospital Zurich, Switzerland
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  • Johannes Vogel,

    1. Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), and University of Zurich, Switzerland
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  • Max Gassmann,

    1. Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), and University of Zurich, Switzerland
    2. Universidad Peruana Cayetano Heredia, Lima, Perú
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    • Contribution of both senior authors was equivalent.

  • Gaetano Cairo

    Corresponding author
    1. Department of Biomedical Sciences for Health, University of Milano, Italy
    • Address reprint requests to: Gaetano Cairo, Department of Biomedical Sciences for Health, University of Milano, Via Mangiagalli 31, 20133 Milano, Italy. E-mail: gaetano.cairo@unimi.it

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    • Contribution of both senior authors was equivalent.


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from Ministero Istruzione, Università e Ricerca (PRIN project) and World Anti Doping Agency (to G.C.), Technical University of Madrid, Program Marie Curie, COFUND, (contract UNITE 246565), Swisslife Jubiläumsstiftung (to V.D.), Zurich Center Integrative Human Physiology (ZIHP), Zurich Center Integrative Rodent Physiology (ZIRP) and Swiss National Science Foundation (to M.G.).

Abstract

The liver-derived peptide hepcidin controls the balance between iron demand and iron supply. By inhibiting the iron export activity of ferroportin, hepcidin modulates iron absorption and delivery from the body's stores. The regulation of hepcidin, however, is not completely understood and includes a variety of different signals. We studied iron metabolism and hepcidin expression in mice constitutively overexpressing erythropoietin (Epo) (Tg6 mice), which leads to excessive erythropoiesis. We observed a very strong down-regulation of hepcidin in Tg6 mice that was accompanied by a strong increase in duodenal expression of ferroportin and divalent metal tranporter-1, as well as enhanced duodenal iron absorption. Despite these compensatory mechanisms, Tg6 mice displayed marked circulating iron deficiency and low levels of iron in liver, spleen, and muscle. To elucidate the primary signal affecting hepcidin expression during chronically elevated erythropoiesis, we increased iron availability by either providing iron (thus further increasing the hematocrit) or reducing erythropoiesis-dependent iron consumption by means of splenectomy. Both treatments increased liver iron and up-regulated hepcidin expression and the BMP6/SMAD pathway despite continuously high plasma Epo levels and sustained erythropoiesis. This suggests that hepcidin expression is not controlled by erythropoietic signals directly in this setting. Rather, these results indicate that iron consumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and hepcidin. Analysis of the BMP6/SMAD pathway targets showed that inhibitor of DNA binding 1 (ID1) and SMAD7, but not transmembrane serine protease 6 (TMPRSS6), were up-regulated by increased iron availability and thus may be involved in setting the upper limit of hepcidin. Conclusion: We provide evidence that under conditions of excessive and effective erythropoiesis, liver iron regulates hepcidin expression through the BMP6/SMAD pathway. (Hepatology 2013; 58:2122–2132)

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