 |
 |
 |
 |
 |
 |
Jin Kyung Suh, M.D., Ph.D., In-sang Jeon, M.D.
Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea
Correspondence to: In-sang Jeon
Department of Pediatrics, College of Medicine, Gachon University, 21 Namdongdaero 774 beongil, Namdong-gu, Incheon 21565,Korea
Tel: +82-32-460-8382 Fax: +82-32-460-3224
E-mail: isjeon@gilhospital.com
Department of Pediatrics, College of Medicine, Gachon University, 21 Namdongdaero 774 beongil, Namdong-gu, Incheon 21565,Korea
Tel: +82-32-460-8382 Fax: +82-32-460-3224
E-mail: isjeon@gilhospital.com
Received March 26, 2018; Revised April 3, 2018; Accepted April 9, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Abstract
- Iron is critical for almost all living organisms because it serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism. Disruption of iron homeostasis is associated with a wide range of diseases. Thus mammals have developed sophisticated mechanisms to maintain optimal range of iron concentration. Iron regulation involves processes at the systemic and cellular levels. These processes are regulated by hepcidin and iron regulatory proteins. Hepcidin modulates systemic iron homeostasis with ability to impede cellular iron export via interaction with the iron export protein, ferroportin. Whereas, iron regulatory proteins control cellular iron homeostasis by translational regulation of proteins which involve iron metabolism. Recent advances in the study of iron metabolism have shown promising results that hepcidin-targeted strategies may help to improve the diagnosis and treatment of iron related diseases. Although these strategies are now under development, ongoing studies can help to elucidate its application possibilities.
- Keywords: Iron metabolism, Iron metabolism disorders, Hepcidin
- References
- Ganz T. Systemic iron homeostasis. Physiol Rev 2013;93: 1721-41.
- Anderson GJ, Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr 2017;106(Suppl 6):1559s-66s.
- Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005;115:1258-66.
- McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001;291:1755-9.
- Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000;275:19906-12.
- Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000;403:776-81.
- Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999;21:195-9.
- Schade AL, Caroline L. An iron-binding component in human blood plasma. Science 1946;104:340-1.
- Ferris CD, Jaffrey SR, Sawa A, et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1999;1:152-7.
- Chifman J, Laubenbacher R, Torti SV. A systems biology approach to iron metabolism. Adv Exp Med Biol 2014;844:201-25.
- Frazer DM, Anderson GJ. The regulation of iron transport. Biofactors 2014;40:206-14.
- Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell 2010;142:24-38.
- Bainton DF, Finch CA. The diagnosis of iron deficiency anemia. Am J Med 1964;37:62-70.
- Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 2005;37:1264-9.
- Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood 2006;108:1388-94.
- Sharp P. The molecular basis of copper and iron interactions. Proc Nutr Soc 2004;63:563-9.
- Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol 2007;69:69-85.
- Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005;1:191-200.
- Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci U S A 2006;103:13612-7.
- Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 2004;104:4287-93.
- Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 1999;274:20826-32.
- Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood 2004;104:4294-9.
- Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001;276:7811-9.
- Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:7806-10.
- Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-3.
- De Domenico I, Lo E, Ward DM, Kaplan J. Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2. Proc Natl Acad Sci U S A 2009;106:3800-5.
- Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531-9.
- Andriopoulos B Jr, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009;41:482-7.
- Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005;2:399-409.
- Zhang AS, Yang F, Wang J, Tsukamoto H, Enns CA. Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression. J Biol Chem 2009;284:22580-9.
- Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 2008;8:502-11.
- Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009;9:217-27.
- Gao J, Chen J, De Domenico I, et al. Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. Blood 2010;115:3374-81.
- Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006;108:3204-9.
- Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 2004;113:1251-3.
- Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L. Mechanisms of mammalian iron homeostasis. Biochemistry 2012;51:5705-24.
- Leidgens S, Bullough KZ, Shi H, et al. Each member of the poly-r(C)-binding protein 1 (PCBP) family exhibits iron chaperone activity toward ferritin. J Biol Chem 2013;288:17791-802.
- Theil EC. Ferritin: the protein nanocage and iron biomineral in health and in disease. Inorg Chem 2013;52:12223-33.
- Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell 2005;122:789-801.
- Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther 2007;114:345-58.
- Keel SB, Doty RT, Yang Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 2008;319:825-8.
- Hentze MW, Kühn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci U S A 1996;93:8175-82.
- Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 2008;28:197-213.
- Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet 2016;387:907-16.
- Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008;40:569-71.
- Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-23.
- Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986-95.
- Barton JC, Edwards CQ, Acton RT. HFE gene: structure, function, mutations, and associated iron abnormalities. Gene 2015;574:179-92.
- Anderson GJ. Mechanisms of iron loading and toxicity. Am J Hematol 2007;82(12 Suppl):1128-31.
- Laarakkers CM, Wiegerinck ET, Klaver S, et al. Improved mass spectrometry assay for plasma hepcidin: detection and characterization of a novel hepcidin isoform. PLoS One 2013;8:e75518.
- Mahajan G, Sharma S, Chandra J, Nangia A. Hepcidin and iron parameters in children with anemia of chronic disease and iron deficiency anemia. Blood Res 2017;52:212-7.
- Campostrini N, Castagna A, Zaninotto F, et al. Evaluation of hepcidin isoforms in hemodialysis patients by a proteomic approach based on SELDI-TOF MS. J Biomed Biotechnol 2010;2010:329646.
- Arezes J, Nemeth E. Hepcidin and iron disorders: new biology and clinical approaches. Int J Lab Hematol 2015;37 Suppl 1:92-8.
- Ruchala P, Nemeth E. The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci 2014;35:155-61.
- April 2024, 31 (1)
Full Text PDF
Citation
Twitter
Facebook- Cited By Articles
Author ORCID Information-
In-sang Jeon
