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Science 306 (5704): 2090-2093

Copyright © 2004 by the American Association for the Advancement of Science

Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization

Elizabeta Nemeth,1 Marie S. Tuttle,2 Julie Powelson,2 Michael B. Vaughn,2 Adriana Donovan,3 Diane McVey Ward,2 Tomas Ganz,1* Jerry Kaplan2*

Abstract: Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.

1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
2 Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT, USA.
3 Department of Hematology, Children's Hospital, Boston, MA, USA.

* To whom correspondence should be addressed. E-mail: TGanz{at}mednet.ucla.edu (T.G.); jerry.kaplan{at}path.utah.edu (J.K.)


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Deletion of HIF-2{alpha} in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice.
M. Mastrogiannaki, P. Matak, S. Delga, J.-C. Deschemin, S. Vaulont, and C. Peyssonnaux (2012)
Blood 119, 587-590
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Obesity and iron deficiency in chronic kidney disease: the putative role of hepcidin.
P. A. Sarafidis, A. Rumjon, H. L. MacLaughlin, and I. C. Macdougall (2012)
Nephrol. Dial. Transplant. 27, 50-57
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Superinfection in malaria: Plasmodium shows its iron will.
S. Portugal, H. Drakesmith, and M. M. Mota (2011)
EMBO Rep. 12, 1233-1242
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Effects of iron supplementation on serum hepcidin and serum erythropoietin in low-birth-weight infants.
S. Berglund, B. Lonnerdal, B. Westrup, and M. Domellof (2011)
Am J Clin Nutr 94, 1553-1561
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The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders.
T. Ganz and E. Nemeth (2011)
Hematology 2011, 538-542
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Hepcidin in Human Iron Disorders: Diagnostic Implications.
J. J. C. Kroot, H. Tjalsma, R. E. Fleming, and D. W. Swinkels (2011)
Clin. Chem. 57, 1650-1669
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Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo.
I. Theurl, A. Schroll, M. Nairz, M. Seifert, M. Theurl, T. Sonnweber, H. Kulaksiz, and G. Weiss (2011)
Haematologica 96, 1761-1769
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Fetal regulation of iron transport during pregnancy.
L. Gambling, C. Lang, and H. J. McArdle (2011)
Am J Clin Nutr 94, 1903S-1907S
   Abstract »    Full Text »    PDF »
Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.
E. G. Farrow, X. Yu, L. J. Summers, S. I. Davis, J. C. Fleet, M. R. Allen, A. G. Robling, K. R. Stayrook, V. Jideonwo, M. J. Magers, et al. (2011)
PNAS 108, E1146-E1155
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