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Identification of erythroferrone as an erythroid regulator of iron metabolism

Nature Genetics 46, 678–684 (2014) | Download Citation

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Abstract

Recovery from blood loss requires a greatly enhanced supply of iron to support expanded erythropoiesis. After hemorrhage, suppression of the iron-regulatory hormone hepcidin allows increased iron absorption and mobilization from stores. We identified a new hormone, erythroferrone (ERFE), that mediates hepcidin suppression during stress erythropoiesis. ERFE is produced by erythroblasts in response to erythropoietin. ERFE-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss. ERFE expression is greatly increased in Hbbth3/+ mice with thalassemia intermedia, where it contributes to the suppression of hepcidin and the systemic iron overload characteristic of this disease.

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Change history

  • 13 June 2014

    In the version of this article initially published online, the key in Figure 5b was incorrect. The dotted line with open squares represents data from Fam132b+/- mice. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The authors thank V. Gabayan for her invaluable work with mouse breeding. Flow cytometry was performed in the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center (JCCC) and the Center for AIDS Research Flow Cytometry Core Facility, which is supported by US National Institutes of Health (NIH) awards CA-16042 and AI-28697 and by the JCCC, the UCLA AIDS Institute and the David Geffen School of Medicine at UCLA. The UCLA Vector Core is supported by the JCCC from US NIH grant P30-CA-016042 and the CURE: Digestive Disease Research Core Center from US NIH grant P30-DK-041301. This research was supported by US NIH grant R01-DK-065029 to T.G. and grants R01-DK-090554 and 5R01-DK-095112 to S.R. and by the American Society of Hematology scholar award to L.K.

Author information

Affiliations

  1. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Léon Kautz
    • , Grace Jung
    • , Erika V Valore
    • , Elizabeta Nemeth
    •  & Tomas Ganz

  2. Department of Pediatrics, Division of Hematology-Oncology, Weill Cornell Medical College, New York, New York, USA.

    • Stefano Rivella

  3. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.

    • Stefano Rivella

  4. Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Tomas Ganz

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Contributions

L.K. designed and performed the experiments, analyzed the data and wrote the manuscript. G.J. assisted with experiments. S.R. provided Hbbth3/+ mouse samples for preliminary experiments and E.V.V. prepared a key reagent. E.N. and T.G. conceived the project and wrote the manuscript.

Competing interests

E.N. and T.G. are shareholders and scientific advisors of Intrinsic LifeSciences and Merganser Biotech and are consultants for Xenon Pharmaceuticals. S.R. receives laboratory support from Isis, Bayer and Merganser Biotech and is a shareholder of Merganser Biotech. The remaining authors declare no competing financial interests.

Corresponding author

Correspondence to Tomas Ganz.

Integrated supplementary information

Supplementary figures

  1. 1.

    Serum iron levels after erythropoietic stimulation.

  2. 2.

    Smad5 phosphorylation and Id1 mRNA expression in response to erythropoietic stimulation.

  3. 3.

    Hepcidin suppression by increased erythropoietic activity is independent of the effect of the BMP pathway.

  4. 4.

    Serum EPO levels after erythropoietic stimulation.

  5. 5.

    Erythroferrone is induced by EPO in human erythroblasts.

  6. 6.

    Erythroferrone Fam132b mRNA expression is not influenced by the hypoxia pathway.

  7. 7.

    Erythroferrone FAM132B mRNA expression is not influenced by systemic inflammation.

  8. 8.

    Six-week-old ERFE-deficient mice have normal iron stores and hepcidin expression but have reduced hemoglobin levels compared to wild-type mice.

  9. 9.

    ERFE-deficient mice have normal mean corpuscular volume (MCV) and serum iron concentrations.

  10. 10.

    ERFE-deficient mice have normal hemoglobin, iron stores and hepcidin at 3 and 24 weeks of age.

  11. 11.

    Serum iron concentrations in ERFE-deficient mice in response to phlebotomy.

  12. 12.

    ERFE is not required for erythroblast differentiation during stress erythropoiesis.

  13. 13.

    ERFE-deficient mice show lower MCV and hematocrit levels during recovery from anemia.

  14. 14.

    Saa1 and Id1 expression in ERFE-treated mice.

  15. 15.

    Ablation of ERFE in thalassemic mice decreases serum iron concentrations, erythrocyte mean corpuscular volume and mean corpuscular hemoglobin concentrations.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Table 2 and Supplementary Figures 1–15

Excel files

  1. 1.

    Supplementary Table 1

    Mouse Fam132b promoter analysis 3k.

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DOI

https://doi.org/10.1038/ng.2996

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