Hepcidin and Ferroportin: The New Players in Iron Metabolism

ABSTRACT

Systemic iron homeostasis is regulated by the interaction of the peptide hormone, hepcidin and the iron exporter, ferroportin. Mutations in FPN1, the gene that encodes ferroportin, result in iron-overload disease that shows dominant inheritance and variation in phenotype. The inheritance of ferroportin-linked disorders can be explained by the finding that ferroportin is a multimer and the product of the mutant allele participates in multimer formation. The nature of the ferroportin mutant can explain the variation in phenotype, which is due to either decreased iron export activity or decreased ability to be downregulated by hepcidin. Iron export through ferroportin is determined by the concentration of ferroportin in plasma membrane, which is the result of both synthetic and degradation events. Ferroportin degradation can occur by hepcidin-dependent and hepcidin-independent internalization. Ferroportin expression is regulated transcriptionally and posttranslationally.

KEYWORDS

Ferroportin - iron - hepcidin - genetics

REFERENCES

• 1 Nicolas G, Bennoun M, Devaux I et al.. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.  Proc Natl Acad Sci U S A. 2001;  98 (15) 8780-8785
• 2 Nicolas G, Bennoun M, Porteu A et al.. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.  Proc Natl Acad Sci U S A. 2002;  99 (7) 4596-4601
• 3 Roy CNMH, Mak H H, Akpan I, Losyev G, Zurakowski D, Andrews N C. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation.  Blood. 2007;  109 (9) 4038-4044
• 4 Weinstein D A, Roy C N, Fleming M D, Loda M F, Wolfsdorf J I, Andrews N C. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease.  Blood. 2002;  100 (10) 3776-3781
• 5 Finberg K E, Heeney M M, Campagna D R et al.. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).  Nat Genet. 2008;  40 (5) 569-571
• 6 Nemeth E, Tuttle M S, Powelson J et al.. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.  Science. 2004;  306 (5704) 2090-2093
• 7 Liu X B, Yang F, Haile D J. Functional consequences of ferroportin 1 mutations.  Blood Cells Mol Dis. 2005;  35 (1) 33-46
• 8 Donovan A, Brownlie A, Zhou Y et al.. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter.  Nature. 2000;  403 (6771) 776-781
• 9 McKie A T, Marciani P, Rolfs A et al.. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.  Mol Cell. 2000;  5 (2) 299-309
• 10 Troadec M B, Warner D, Wallace J et al.. Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria.  Blood. 2011;  117 (20) 5494-5502
• 11 Donovan A, Lima C A, Pinkus J L et al.. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis.  Cell Metab. 2005;  1 (3) 191-200
• 12 Montosi G, Donovan A, Totaro A et al.. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.  J Clin Invest. 2001;  108 (4) 619-623
• 13 Pietrangelo A, Montosi G, Totaro A et al.. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene.  N Engl J Med. 1999;  341 (10) 725-732
• 14 Mao J, McKean D M, Warrier S, Corbin J G, Niswander L, Zohn I E. The iron exporter ferroportin 1 is essential for development of the mouse embryo, forebrain patterning and neural tube closure.  Development. 2010;  137 (18) 3079-3088
• 15 Pietrangelo A. The ferroportin disease.  Blood Cells Mol Dis. 2004;  32 (1) 131-138
• 16 De Domenico I, Ward D M, Nemeth E et al.. The molecular basis of ferroportin-linked hemochromatosis.  Proc Natl Acad Sci U S A. 2005;  102 (25) 8955-8960
• 17 Schimanski L M, Drakesmith H, Merryweather-Clarke A T et al.. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.  Blood. 2005;  105 (10) 4096-4102
• 18 Rice A E, Mendez M J, Hokanson C A, Rees D C, Björkman P J. Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter.  J Mol Biol. 2009;  386 (3) 717-732
• 19 Wallace D F, Harris J M, Subramaniam V N. Functional analysis and theoretical modeling of ferroportin reveals clustering of mutations according to phenotype.  Am J Physiol Cell Physiol. 2010;  298 (1) C75-C84
• 20 McDonald C J, Wallace D F, Ostini L, Bell S J, Demediuk B, Subramaniam V N. G80S-linked ferroportin disease: classical ferroportin disease in an Asian family and reclassification of the mutant as iron transport defective.  J Hepatol. 2011;  54 (3) 538-544
• 21 Drakesmith H, Schimanski L M, Ormerod E et al.. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.  Blood. 2005;  106 (3) 1092-1097
• 22 Cunat S, Giansily-Blaizot M, Bismuth M CHU Montpellier AOI 2004 Working Group et al. Global sequencing approach for characterizing the molecular background of hereditary iron disorders.  Clin Chem. 2007;  53 (12) 2060-2069
• 23 De Domenico I, Ward D M, Musci G, Kaplan J. Evidence for the multimeric structure of ferroportin.  Blood. 2007;  109 (5) 2205-2209
• 24 McGregor J A, Shayeghi M, Vulpe C D et al.. Impaired iron transport activity of ferroportin 1 in hereditary iron overload.  J Membr Biol. 2005;  206 (1) 3-7
• 25 Pignatti E, Mascheroni L, Sabelli M, Barelli S, Biffo S, Pietrangelo A. Ferroportin is a monomer in vivo in mice.  Blood Cells Mol Dis. 2006;  36 (1) 26-32
• 26 Schimanski L M, Drakesmith H, Talbott C et al.. Ferroportin: lack of evidence for multimers.  Blood Cells Mol Dis. 2008;  40 (3) 360-369
• 27 Yeh K Y, Yeh M, Mims L, Glass J. Iron feeding induces ferroportin 1 and hephaestin migration and interaction in rat duodenal epithelium.  Am J Physiol Gastrointest Liver Physiol. 2009;  296 (1) G55-G65
• 28 Zohn I E, De Domenico I, Pollock A et al.. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease.  Blood. 2007;  109 (10) 4174-4180
• 29 De Domenico I, Vaughn M B, Yoon D, Kushner J P, Ward D M, Kaplan J. Zebrafish as a model for defining the functional impact of mammalian ferroportin mutations.  Blood. 2007;  110 (10) 3780-3783
• 30 De Domenico I, Lo E, Ward D M, Kaplan J. Human mutation D157G in ferroportin leads to hepcidin-independent binding of Jak2 and ferroportin down-regulation.  Blood. 2010;  115 (14) 2956-2959
• 31 Chaston T, Chung B, Mascarenhas M et al.. Evidence for differential effects of hepcidin in macrophages and intestinal epithelial cells.  Gut. 2008;  57 (3) 374-382
• 32 Paradkar P N, De Domenico I, Durchfort N, Zohn I, Kaplan J, Ward D M. Iron depletion limits intracellular bacterial growth in macrophages.  Blood. 2008;  112 (3) 866-874
• 33 Ramey G, Deschemin J C, Durel B, Canonne-Hergaux F, Nicolas G, Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes.  Haematologica. 2010;  95 (3) 501-504
• 34 Nemeth E, Preza G C, Jung C L, Kaplan J, Waring A J, Ganz T. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study.  Blood. 2006;  107 (1) 328-333
• 35 De Domenico I, Nemeth E, Nelson J M et al.. The hepcidin-binding site on ferroportin is evolutionarily conserved.  Cell Metab. 2008;  8 (2) 146-156
• 36 Fernandes A, Preza G C, Phung Y et al.. The molecular basis of hepcidin-resistant hereditary hemochromatosis.  Blood. 2009;  114 (2) 437-443
• 37 De Domenico I, Lo E, Ward D M, Kaplan J. Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2.  Proc Natl Acad Sci U S A. 2009;  106 (10) 3800-3805
• 38 De Domenico I, Ward D M, Langelier C et al.. The molecular mechanism of hepcidin-mediated ferroportin down-regulation.  Mol Biol Cell. 2007;  18 (7) 2569-2578
• 39 Osaki S, Johnson D A, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum.  J Biol Chem. 1966;  241 (12) 2746-2751
• 40 Dowdy R P, Matrone G. A copper-molybdenum complex: its effects and movement in the piglet and sheep.  J Nutr. 1968;  95 (2) 197-201
• 41 Lee G R, Nacht S, Lukens J N, Cartwright G E. Iron metabolism in copper-deficient swine.  J Clin Invest. 1968;  47 (9) 2058-2069
• 42 Patel B N, David S. A novel glycosylphosphatidylinositol-anchored form of ceruloplasmin is expressed by mammalian astrocytes.  J Biol Chem. 1997;  272 (32) 20185-20190
• 43 Osaki S, Johnson D A, Frieden E. The mobilization of iron from the perfused mammalian liver by a serum copper enzyme, ferroxidase I.  J Biol Chem. 1971;  246 (9) 3018-3023
• 44 Sarkar J SV, Seshadri V, Tripoulas N A, Ketterer M E, Fox P L. Role of ceruloplasmin in macrophage iron efflux during hypoxia.  J Biol Chem. 2003;  278 (45) 44018-44024
• 45 Lahey M E, Gubler C J, Chase M S, Cartwright G E, Wintrobe M M. Studies on copper metabolism. II. Hematologic manifestations of copper deficiency in swine.  Blood. 1952;  7 (11) 1053-1074
• 46 Harris E D. The iron-copper connection: the link to ceruloplasmin grows stronger.  Nutr Rev. 1995;  53 (6) 170-173
• 47 Vulpe C D, Kuo Y M, Murphy T L et al.. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse.  Nat Genet. 1999;  21 (2) 195-199
• 48 Harris Z L, Klomp L W, Gitlin J D. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis.  Am J Clin Nutr. 1998;  67 (5, Suppl) 972S-977S
• 49 Bernstein S E. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia.  J Lab Clin Med. 1987;  110 (6) 690-705
• 50 Hamill R L, Woods J C, Cook B A. Congenital atransferrinemia. A case report and review of the literature.  Am J Clin Pathol. 1991;  96 (2) 215-218
• 51 De Domenico I, Ward D M, di Patti M C et al.. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin.  EMBO J. 2007;  26 (12) 2823-2831
• 52 Delaby C, Pilard N, Puy H, Canonne-Hergaux F. Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression.  Biochem J. 2008;  411 (1) 123-131
• 53 Marro S, Chiabrando D, Messana E et al.. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter.  Haematologica. 2010;  95 (8) 1261-1268
• 54 Park B Y, Chung J. Effects of various metal ions on the gene expression of iron exporter ferroportin-1 in J774 macrophages.  Nurs Res Pract. 2008;  2 (4) 317-321
• 55 Zoller H, Theurl I, Koch R, Kaser A, Weiss G. Mechanisms of iron mediated regulation of the duodenal iron transporters divalent metal transporter 1 and ferroportin 1.  Blood Cells Mol Dis. 2002;  29 (3) 488-497
• 56 Jacolot S, Férec C, Mura C. Iron responses in hepatic, intestinal and macrophage/monocyte cell lines under different culture conditions.  Blood Cells Mol Dis. 2008;  41 (1) 100-108
• 57 Knutson M D, Vafa M R, Haile D J, Wessling-Resnick M. Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages.  Blood. 2003;  102 (12) 4191-4197
• 58 Troadec M B, Ward D M, Lo E, Kaplan J, De Domenico I. Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux.  Blood. 2010;  116 (22) 4657-4664
• 59 Harada N, Kanayama M, Maruyama A et al.. Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages.  Arch Biochem Biophys. 2011;  508 (1) 101-109
• 60 Abboud S, Haile D J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism.  J Biol Chem. 2000;  275 (26) 19906-19912
• 61 Muckenthaler M U, Galy B, Hentze M W. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network.  Annu Rev Nutr. 2008;  28 197-213
• 62 Mok H, Mendoza M, Prchal J T, Balogh P, Schumacher A. Dysregulation of ferroportin 1 interferes with spleen organogenesis in polycythaemia mice.  Development. 2004;  131 (19) 4871-4881
• 63 Zhang D L, Hughes R M, Ollivierre-Wilson H, Ghosh M C, Rouault T A. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression.  Cell Metab. 2009;  9 (5) 461-473