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Haematologica 2018 Volume 103(10):1616-1626
1Iron Metabolism Laboratory, QIMR Berghofer Medical Research Institute, Herston; 2School of Medicine, The University of Queensland, St Lucia; 3School of Biomedical Sciences, Queensland University of Technology, Gardens Point and 4School of Chemistry and Molecular Bioscience, The University of Queensland, St Lucia, Australia.
Ferrata Storti Foundation
Iron Metabolism & its Disorders
Circulating iron levels influence the regulation of hepcidin following stimulated erythropoiesis
Cornel S.G. Mirciov,1,2 Sarah J. Wilkins,1 Grace C. C. Hung,1
Sheridan L. Helman,1,3 Gregory J. Anderson1,2,4 and David M. Frazer1,2
ABSTRACT
The stimulation of erythrocyte formation increases the demand for iron by the bone marrow and this in turn may affect the levels of circulating diferric transferrin. As this molecule influences the pro- duction of the iron regulatory hormone hepcidin, we hypothesized that erythropoiesis-driven changes in diferric transferrin levels could con- tribute to the decrease in hepcidin observed following the administration of erythropoietin. To examine this, we treated mice with erythropoietin and examined diferric transferrin at various time points up to 18 hours. We also investigated the effect of altering diferric transferrin levels on ery- thropoietin-induced inhibition of Hamp1, the gene encoding hepcidin. We detected a decrease in diferric transferrin levels 5 hours after erythro- poietin injection and prior to any inhibition of the hepatic Hamp1 mes- sage. Diferric transferrin returned to control levels 12 hours after erythro- poietin injection and had increased beyond control levels by 18 hours. Increasing diferric transferrin levels via intravenous iron injection pre- vented the inhibition of Hamp1 expression by erythropoietin without altering hepatic iron concentration or the expression of Erfe, the gene encoding erythroferrone. These results suggest that diferric transferrin likely contributes to the inhibition of hepcidin production in the period shortly after injection of erythropoietin and that, under the conditions examined, increasing diferric transferrin levels can overcome the inhibito- ry effect of erythroferrone on hepcidin production. They also imply that the decrease in Hamp1 expression in response to an erythropoietic stim- ulus is likely to be mediated by multiple signals.
Introduction
Hepcidin is a key regulator of body iron homeostasis. This 25-amino acid peptide is produced predominantly by hepatocytes and is secreted into the circulation where it binds to the iron export protein ferroportin on the surface of body cells.1 This inter- action causes the ferroportin/hepcidin complex to be internalized and degraded, inhibiting iron release and allowing hepcidin to regulate critical processes such as dietary iron absorption and the recycling of erythrocyte iron by macrophages.
The production of hepcidin is tightly regulated. The main stimuli triggering changes in hepcidin synthesis are the level of iron in the body, referred to as the stores regulator, and the adequacy of iron supply to the erythroid marrow, termed the erythroid regulator.2,3 The molecular basis of the stores regulator has been rela- tively well characterized. As body iron stores increase, non-parenchymal cells in the liver secrete bone morphogenetic protein 6 (BMP6), which binds to the BMP receptor complex on the surface of hepatocytes and stimulates hepcidin expression by activating the SMAD signaling pathway.4-6 This increase in hepcidin production inhibits dietary iron absorption, limiting further increases in body iron stores, and tissue iron release, and resulting in the storage of excess iron within macrophages and hepatocytes. Various other molecules, such as hemojuvelin and transmem-
Correspondence:
david.frazer@qimrberghofer.edu.au
Received: December 29, 2017. Accepted: June 11, 2018. Pre-published: June 14, 2018.
doi:10.3324/haematol.2017.187245
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1616
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