An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

Author:

Lakhal-Littleton Samira1ORCID,Wolna Magda1,Chung Yu Jin1,Christian Helen C1,Heather Lisa C1,Brescia Marcella1,Ball Vicky1,Diaz Rebeca2,Santos Ana2,Biggs Daniel2,Clarke Kieran1,Davies Benjamin2ORCID,Robbins Peter A1ORCID

Affiliation:

1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom

2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

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.

Funder

British Heart Foundation

Wellcome Trust

Vifor Pharma

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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