Abstract

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.

Article and author information

Author details

  1. Samira Lakhal-Littleton

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    For correspondence
    samira.lakhal-littleton@dpag.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7797-1567
  2. Magda Wolna

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu Jin Chung

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Helen C Christian

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Lisa C Heather

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Marcella Brescia

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Vicky Ball

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Rebeca Diaz

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Ana Santos

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Biggs

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Kieran Clarke

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Benjamin Davies

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3623-600X
  13. Peter A Robbins

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4975-0609

Funding

British Heart Foundation (FS/12/63/29895)

  • Samira Lakhal-Littleton

Vifor Pharma (R19874-CN004)

  • Magda Wolna

The funders funded the salary and research expenses relating to this work for two of the authors, as described above.

Ethics

Animal experimentation: All animal procedures were compliant with and approved under the UK Home Office Animals (Scientific Procedures) Act 1986 (Project Licence number 30/3182). In vivo assessment of cardiac function was carried out under anesthesia (2% Isofluorane) to minimize suffering.

Reviewing Editor

  1. Richard P Harvey, The Victor Chang Cardiac Research Institute, Australia

Publication history

  1. Received: July 19, 2016
  2. Accepted: November 24, 2016
  3. Accepted Manuscript published: November 29, 2016 (version 1)
  4. Version of Record published: December 21, 2016 (version 2)

Copyright

© 2016, Lakhal-Littleton et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Samira Lakhal-Littleton
  2. Magda Wolna
  3. Yu Jin Chung
  4. Helen C Christian
  5. Lisa C Heather
  6. Marcella Brescia
  7. Vicky Ball
  8. Rebeca Diaz
  9. Ana Santos
  10. Daniel Biggs
  11. Kieran Clarke
  12. Benjamin Davies
  13. Peter A Robbins
(2016)
An essential cell-autonomous role for hepcidin in cardiac iron homeostasis
eLife 5:e19804.
https://doi.org/10.7554/eLife.19804

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