A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice
- McGill University, Canada
- Ferring Research Institute Inc, United States
- University Hospital Frankfurt, Germany
- Helmholtz Zentrum München, Germany
Abstract
The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in LPS-treated wt mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv-/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wt animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv-/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen, to stimulate ferroportin mRNA translation. Prolonged LPS treatment eliminating ferroportin mRNA permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient combined with iron depletion.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file
Article and author information
Author details
Kostas Pantopoulos
Funding
Canadian Institutes of Health Research (PJT-159730)
- Kostas Pantopoulos
Fonds de Recherche du Québec - Santé
- Edouard Charlebois
Deutsche Forschungsgemeinschaft (SPP 2306)
- Vivek Venkataramani
- Bernhard Michalke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Yelena Ginzburg, Icahn School of Medicine at Mount Sinai, United States
Ethics
Animal experimentation: All experimental procedures were approved by the Animal Care Committee of McGill University (protocol 4966).
Version history
- Preprint posted: November 1, 2021 (view preprint)
- Received: June 23, 2022
- Accepted: August 30, 2022
- Accepted Manuscript published: September 6, 2022 (version 1)
- Version of Record published: September 22, 2022 (version 2)
Copyright
© 2022, Charlebois 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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A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice
eLife 11:e81332.
https://doi.org/10.7554/eLife.81332
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