Contemporary Views of Iron Homeostasis with Main Focus of Hepcidin - New Hormone Regulator of Iron Metabolism

Main Article Content

Biljana Ilkovska
Bisera Kotevska
Georgi Trifunov


Iron is an essential element of almost all living organisms. It is key functional part of oxygen transporters, depositary molecules and many enzymes which catalyze redox reactions necessary to generate the energy, products of various metabolic intermediates and defense. Studies have shown that a key regulator of iron homeostasis is hepcidin and set the liver as the central authority in the system of iron homeostasis. Hepcidin is cationic peptide composed of 25 amino acids and four disulfide bonds. Recently it was revealed that circulating hepcidin with a relatively high affinity is bound to α2-macroglobulin and with relatively low affinity is bound to albumin. In addition to its role in regulation systemic metabolism of iron, hepcidinot can contribute to host defense. Hepcidinot was originally identified as an antimicrobial peptide and found that it could indirectly contribute to host defense by reducing the concentration of iron in plasma.


Download data is not yet available.

Article Details

How to Cite
Ilkovska B, Kotevska B, Trifunov G. Contemporary Views of Iron Homeostasis with Main Focus of Hepcidin - New Hormone Regulator of Iron Metabolism. Maced Med Electron J [Internet]. 2015 Aug. 12 [cited 2024 Jul. 25];1(1):1-14. Available from:
Basic Medicine


Aisen P, Enns C, Wessling-Resnick M. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol. 2001;33: 940-959. DOI:

Tomas Ganz. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783-8. PMid:12663437 DOI:

Beard JL, Dawson HD. Iron. In: O’Dell BL, Sunde RA, editors. Handbook of Nutritionally Essential Mineral Elements. New York: CRC Press, 1997: pp. 275-334.

Wood RJ, Ronnenberg A.Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, Modern Nutrition in Health And Disease. 10th ed. Baltimore: Lippincott Williams & Wilkins, 2005. pp. 248-70. PMid:16019112

McDowell LR. 2nd ed. Amsterdam: Elsevier Science. Minerals in Animal And Human Nutrition, 2003: p. 660. DOI:

Guggenheim KY. Chlorosis: The rise and disappearance of a nutritional disease. J Nutr.1995;125:1822-5. PMid:7616296 DOI:

Nazanin A, Richard H, Roya K. Review on iron and its importance for human health. J Res Med Sci. 2014; 19(2): 164-174.

Yip R, Dallman PR, Ziegler EE, Filer L. Present knowledge in nutrition. 7th ed. Washington DC: ILSI Press, 1996: pp. 278-92.

Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425-33. PMid:21346250 PMCid:PMC3099567 DOI:

Andrews NC . Forging a field: the golden age of iron biology. Blood. 2008;112(2):219-230. PMid:18606887 PMCid:PMC2442739 DOI:

Laufberger V. Sur la cristallisation de la ferritine. Bulletin de la Societe de chimie biologique. 1937;19:1575-1582.

Worwood M. In: Iron in Biochemistry and Medicine, II. A.a.W. Jacobs M, editor. London: Academic Press, 1980: pp. 204-244.

Addison GM, Beamish MR, Hales CN, Hodgkins M, Jacobs A, Llewellin P. An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. J Clin Pathol. 1972;25:326-329. PMid:5063755 PMCid:PMC477303 DOI:

Jacobs A, Miller F, Worwood M, Beamish MR, Wardrop CA. Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Br Med J. 1972;4:206-208. PMid:5082548 PMCid:PMC1786481 DOI:

Jacobs A, Worwood M. Ferritin in serum. Clinical and biochemical implications. N Engl J Med. 1975;292:951-956. PMid:1090831 DOI:

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: 7811-7819. PMid:11113132 DOI:

Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276: 7806-7810. PMid:11113131

Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480: 147-150. DOI:

Papanikolaou G, Pantopoulos K. Iron metabolism and toxicity. Toxicol Appl Pharmacol. 2005;202:199-211. PMid:15629195 DOI:

Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341: 1986-1995. PMid:10607817 DOI:

Tandara L, Salamunic I. Iron metabolism: current facts and future directions. Biochem Med. 2012; 22(3): 311-328. DOI:

Munoz M, Villar I, Garcia-Erce JA. An update iron physiology. World J Gastroenterol. 2009; 15(37): 4617-4626. PMid:19787824 PMCid:PMC2754509 DOI:

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. PMid:11230685 DOI:

Canonne-Hergaux F, Gruenhied S, Ponka P, et al. Cellular and subcellular localisation of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood. 1999; 93:4406-17. PMid:10361139 DOI:

Andrews, NC. Metal transporters and disease. Curr Opin Chem Biol. 2002;6:181-6. DOI:

Garric MD, Singleton ST, Vargas F, et al. DMT1: Which metals does it transport? Biol Res. 2006; 39: 79-85. DOI:

Conrad ME, Umbreit EG, Moore LN, et al. Separate pathways for cellular uptake of ferric and ferrous iron. Am J Physiol Gastrointest Liver Physiol. 2000;279:767-74. DOI:

Umbreit JN, Conrad, ME, Hainsworth LN, et al. The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin. Am J Physiol Gastrointest Liver Physiol. 2002;282:534-39. PMid:11842004 DOI:

Simovich MJ, Conrad ME, Umbreit JN, et al. Cellular localisation of proteins related to iron absorption and transport. Am J Hematol. 2002;69:164-70. DOI:

Latunde-Dada GO, Takeuchi K, Simpson RJ, McKie AT. Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells. FEBS Lett 2006;580:6865- 870. PMid:17156779 DOI:

Shayeghi, M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789-801. DOI:

Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917-28. PMid:17129779 DOI:

Liu K, Kaffes AJ. Iron deficiency anaemia: a review of diagnosis, investigation and managment. Eur J Gastroenterol Hepatol. 2012;24:109-16. PMid:22157204 DOI:

Ma Y, Yeh M, Yeh K, et al. Iron Imports V: Transport of iron through the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2006;290:417-22. PMid:16474007 DOI:

McKie AT, 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;5:299-309. DOI:

Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306: 2090-2093. PMid:15514116 DOI:

Osaki S, Johnson DA, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem.1966;241(12):2746-51. PMid:5912351 DOI:

Gkouvatsos K, Papanikolaou G, Pantopoulos K. Regulation of iron transport and the role of transferrin. Biochim Byophys Acta. 2012;1820:188-202. PMid:22085723 DOI:

MacGilivray RT, Mendez S, Sinha SK, et al. The complete amino acid sequence of human serum transferring. Proc Natl Acad Sci USA. 1982; 79(8): 2504-2508. DOI:

Thorbecke GJ, Liem HH, Knight S, et al. Sites of formation of the serum proteins transferin and hefnopexin. J Clin Invest. 1973; 52(3):725-731. PMid:4119469 PMCid:PMC302311 DOI:

Baker HM, Anderson BF, Baker EN. Dealing with iron: Common structural principles in proteins that transport iron and heme. Proc Natl Acad Sci USA. 2003;100:3579- 83. PMid:12642662 PMCid:PMC152964 DOI:

í€isen P. Transferin receptor 1. Int J Biochem Cell Biol. 2004; 36: 2137-43. DOI:

Rapisarda C, Puppi J, Hughes RD, et al. Transferrin receptor 2 is crucial for iron sensing in human hepatocytes. Am J Physiol Gastrointest Liver Physiol. 2010;299:G778-83. PMid:20576915 PMCid:PMC2950680 DOI:

Kurz T, Gustafsson B, Brunk UT. Cell sensitivity to oxidative stress is influenced by ferritin autophagy. Free Radic Biol Med. 2011;50:1647-58. DOI:

Harrison PM, Arosio P. The ferritins:molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275(3):161-203. DOI:

Watt RK. Oxido-reduction is not the only mechanism allowing ions traverse the ferritin protein shell. Biochim Biophys Acta. 2010;1800:745-59 DOI:

Alkhateeb A, Connor JR. Nuclear ferritin: A new role for ferritin in cell biology. Biochim Biophys Acta. 2010;1800:793-7. PMid:20347012 DOI:

Bou-Abdallah F, Santambrogio P, Levi S, et al. Unique iron binding and oxidation properties of human ferritin: A comparative analysis with human Hchain ferritin. J Mol Biol. 2005;347:543-54. PMid:15755449 DOI:

Nie GN, Chen G, Sheftel AD, et al. In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin. Blood. 2006;108:2428-34. PMid:16757684 DOI:

Richardson DR, Lane HJR, Becker E, et al. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci USA. 2010; 107:10775-82. PMCid:PMC2890738 DOI:

Ozaki M, Awai T, Kawabata M. Iron release from haemosiderin and production of iron-catalysed hidroxyl radicals in vitro. Biochem J. 1988;250:589-95. PMid:2833249 PMCid:PMC1148895 DOI:

Knutson MD, Oukka M, Koss LM, et al. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA. 2005; 102:1324-8. PMid:15665091 PMCid:PMC547844 DOI:

Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA. 1997; 94:10919-24. DOI:

Detivaud L, Nemeth E, Boudjema K, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels and hepatic function. Blood. 2005;106:746-8. PMid:15797999 DOI:

Weinstein DA, Roy CN, Fleming MD, et al. Inappropriate expression of hepcidin is associated with iron refractory anemia: implication for anemia of chronic disease. Blood. 2002;100:3776-81. PMid:12393428 DOI:

Kemna EH, Tjalsma H, Willems HL, et al. Hepcidin: from discovery to differential diagnosis. Haematologica. 2008;93(1):90-7. PMid:18166790 DOI:

Valore E, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormon convertase furin. Blood Cells Mol Dis. 2008;40:132-38. PMCid:PMC2211381 DOI:

Gagliardo B, Kubat N, Faye A, et al. Pro-hepcidin is unable to degrade iron exporter ferroportin unless maturated by furin-dependent process. J Hepatol. 2009;50:394-401. DOI:

Peyssonnaux C, Zinkernagel AS, Datta V, Lauth X, Johnson RS, Nizet V. TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood. 2006;107:3727-32. PMid:16391018 PMCid:PMC1895778 DOI:

Bekri S, Gual P, Anty R, Luciani N, Dahman M, Ramesh B, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology. 2006;131:788 -96. PMid:16952548 DOI:

Nguyen NB, Callaghan KD, Ghio AJ, Haile DJ, Yang F. Hepcidin expression and iron transport in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2006;291:L417-25. PMid:16648237 DOI:

Merle U, Fein E, Gehrke SG, Stremmel W, Kulaksiz H. The iron regulatory peptide hepcidin is expressed in the heart and regulated by hypoxia and inflammation. Endocrinology. 2007;148: 2663-8. PMid:17363462 DOI:

Kulaksiz H, Fein E, Redecker P, Stremmel W, Adler G, Cetin Y. Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide. J Endocrinol. 2008;197:241-9. PMid:18434354 DOI:

Gnana-Prakasam JP, Martin PM, Mysona BA, Roon P, Smith SB, Ganapathy V. Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe. Biochem J. 2008;411:79 - 88. PMCid:PMC3731152 DOI:

Isoda M, Hanawa H, Watanabe R, Yoshida T, Toba K, Yoshida K, et al. Expression of the peptide hormone hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction. J Nutr Biochem. 2010;21:749 -56 DOI:

De Domenico I, Zhang TY, Koening CL, Branch RW, London N, Lo E, et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest. 2010;120:2395-405. PMid:20530874 PMCid:PMC2898601 DOI:

Theurl I, Theurl M, Seifert M, Mair S, Nairz M, Rumpold H, et al. Autocrine formation of hepcidin induces iron retention in human monocytes. Blood. 2008;111:2392-9. PMid:18073346 DOI:

Keel SB, Abkowitz JL. The microcytic red cell and the anemia of inflammation. N Engl J Med. 2009;361:1904 -6 PMid:19890136 PMCid:PMC3741048 DOI:

Hunter HN, Fulton DB, Ganz T, et al. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002; 277:37597-603. PMid:12138110 DOI:

Lou DQ, Nicolas G, Lesbordes JC, Viatte L, Grimber G, Szajnert MF, Kahn A, and Vaulont S. Functional differences between íµí¥í¯í¶èäèí­ 1 and 2 in transgenic mice. Blood. 2004;103: 2816-2821. PMid:14604961 DOI:

Ganz T, Nemeth E. Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol. 2006;290(2):G199-203. PMid:16407589 DOI:

Schibli DJ, Hunter HN, Aseyev V, Starner TD, Wiencek JM, McCray PB, Jr, Tack BF, Vogel HJ. The Solution Structures of the Human ?-Defensins Lead to a Better Understanding of the Potent Bactericidal Activity of HBD3 against Staphylococcus aureus. J Biol Chem. 2002;277:8279-8289. PMid:11741980 DOI:

Matsuzaki K,Nakayama M, Fukui M,Otaka A, Funakoshi S, Fujii N, Bessho K, Miyajima K. Role of disulfide linkages in tachyplesin-lipid interactions. Biochemistry. 1993; 32:11704-11710. PMid:8218239 DOI:

Aumelas A, Mangoni M, Roumestand C, Chiche L, Despaux E, Grassy G, Calas B, Chavanieu A. Synthesis and solution structure of the antimicrobial peptide protegrin-1. Eur J Biochem. 1996;237(3):575-83. PMid:8647100 DOI:

Berrocal-Lobo M, Segura A, Moreno M, Lopez G, Garcia-Olmedo F, Molina A. Snakin-2, an Antimicrobial Peptide from Potato Whose Gene Is Locally Induced by Wounding and Responds to Pathogen Infection. Plant Physiol. 2002; 128:951-961. PMid:11891250 PMCid:PMC152207 DOI:

Park CH, Valore EV, Waring AJ, Ganz T. Adjacent cysteine residues as a redox switch. J Biol Chem. 2001; 276:7806-7810. PMid:11113131 DOI:

Sow FB, Florence WC, Satoskar AR, Schlesinger LS, Zwilling BS, Lafuse WP. Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis. J Leukoc Biol. 2007;82:934 -45. PMid:17609338 DOI:

Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730-3735. PMCid:PMC1895477

Domenico I, Ward DM, Kaplan J. Hepcidin regulation: ironing out the details. J Clin Invest. 2007;117:1755-8. PMCid:PMC1904333 DOI:

Justyna P, Ewa Z. The role of hepcidin, ferroportin, HCP1, and DMT1 protein in iron absorption in the human digestive tract. Prz Gastroenterol. 2014; 9(4): 208-213. DOI:

Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659-693. DOI:

Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest. 2013;123(6):2337-43. PMCid:PMC3668831 DOI:

Zhang AS, Enns CA. Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program. 2009:207-14. PMid:20008200 DOI:

Kemna EH, Kartikasari AE, van Tits LJ, í¥t al. Regulation of hepcidin: insights from biochemical analyses on human serum samples. Blood Cells Mol Dis. 2008;40:339-46. PMid:18023212 DOI:

Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037-1044. PMid:12370282 PMCid:PMC151151 DOI:

Nemeth E, Ganz T. Hepcidin and iron-loading anemias. Haematologica. 2006;91(6):727-732.

Ganz T, Nemeth E. Regulation of iron acquisition and iron distribution in mammals. Biochim Biophys Acta. 2006;1763(7):690-699. PMid:16790283 DOI:

Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730-3735. PMid:16882706 PMCid:PMC1895477 DOI:

Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142:24 -38. PMid:20603012 DOI:

Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology. 2011;53:1333-41. PMid:21480335 PMCid:PMC3074982 DOI:

Corradini E, Meynard D, Wu Q, Chen S, Ventura P, Pietrangelo A, Babitt JL. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology. 2011;54:273-84. PMid:21488083 PMCid:PMC3277401 DOI:

Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531-9. PMid:16604073 DOI:

Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood. 2010;115: 3817-26. PMCid:PMC2865872 DOI:

Silvestri L, Pagani A, Nai A, De D, I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8:502-11. PMid:18976966 PMCid:PMC2648389 DOI:

Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood. 2007; 110: 2182-2189. PMid:17540841 PMCid:PMC1976373 DOI:

Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117: 1933-1939. PMid:17607365 PMCid:PMC1904317 DOI:

Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7: 205-214. PMCid:PMC2292811 DOI:

Goswami T, Andrews NC. Hereditary hemochromatosis protein HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006; 281: 28494-28498. DOI:

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(3):217-227. PMid:19254567 PMCid:PMC2673483 DOI:

Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S. Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis. 2002; 29: 327-35. PMid:12547223 DOI:

Pinto JP, Ribeiro S, Pontes H, Thowfeequ S, Tosh D, Carvalho F, Porto G. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood. 2008;111:5727-33. PMid:18326822 PMCid:PMC2597200 DOI:

Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica. 2010;95:505-8. PMCid:PMC2833083 DOI:

Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res. 2006;55:667- 74. PMid:16497104 DOI:

Kearney SL, Nemeth E, Neufeld EJ, Thapa D, Ganz T, Weinstein DA,Cunningham MJ: Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer. 2007; 48: 57-63. PMid:16220548 DOI:

Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, High levels of GDF15 in thalassemia supress expression of the iron regulatory protein hepcidin. Nat Med. 2007; 13: 1096-1101. PMid:17721544 DOI:

Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-6. PMCid:PMC398432 DOI:

Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxiainducible transcription factors (HIFs). J Clin Invest. 2007;117:1926 -32. PMid:17557118 PMCid:PMC1884690 DOI:

Silvestri L, Pagani A, Camaschella C. Furinmediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2008;111:924 -31. PMid:17938254 DOI:

Lakhal S, Schoedel J, Townsend AR, Pugh CW, Ratcliffe PJ, Mole DR. Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signalling and iron homeostasis. J Biol Chem. 2011;286:4090 -7. PMid:20966077 PMCid:PMC3039360 DOI:

Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle. 2008;7(1):28-32. PMid:18212530 DOI:

Choi SO, Cho YS, Kim HL, Park JW. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3. Biochem Biophys Res Commun. 2007;356(1):312-317. PMid:17349976 DOI:

Braliou GG, Verga Falzacappa MV, Chachami G, Casanovas G, Muckenthaler MU, Simos G. 2-Oxoglutarate-dependent oxygenases control hepcidin gene expression. J Hepatol. 2008;48(5):801-810. PMid:18313788 DOI:

Lok CN, Ponka P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem. 1999;274(34):24147-24152. DOI:

Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem. 1999; 274(34):24142-24146. PMid:10446187 DOI:

Mole DR. Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal. 2010;12(4):445-58. PMid:19650690 DOI:

Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time-course analysis of hepcidin,serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 2005;106(5):1864-1866. PMid:15886319 DOI:

Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu Rev Nutr. 2010;30:105-122. PMid:20420524 PMCid:PMC3108097 DOI:

Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101(7):2461-2463. PMid:12433676 DOI:

Tessel E, Galesloot SV, Anneke JGM, Siem MK. Serum hepcidin: reference ranges and biochemical correlates in the general population. Blood. 2011. 23;117(25):e218-25. DOI:

Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011-1023. PMid:15758012 DOI:

Papanikolaou G, Tzilianos M, Christakis JI, Bogdanos D, Tsimirika K,MacFarlane J, Goldberg YP, Sakellaropoulos N, Ganz T, Nemeth E: Hepcidin in iron overload disorders. Blood. 2005; 105: 4103-4105. PMid:15671438 PMCid:PMC1895089 DOI:

Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204-3209. PMid:16835372 PMCid:PMC1895528 DOI:

Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109(1):353-358. DOI:

Pietrangelo A, Dierssen U, Valli L, Garuti C, Rump A, Corradini E, Ernst M, Klein C, Trautwein C. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132(1):294-300. PMid:17241879 DOI:

Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA. 2005;102(6):1906-1910. PMid:15684062 PMCid:PMC548537 DOI:

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(6):399-409. PMid:16330325 DOI:

Yu PB, Hong CC, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2008;4(1):33-41. PMid:18026094 PMCid:PMC2727650 DOI:

Zhang K, Shen X, Wu J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 2006;124(3):587-599. PMid:16469704 DOI:

Oliveira SJ, Pinto JP, Picarote G, et al. ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity. PLoS One. 2009;4(8):e6618. PMid:19672300 PMCid:PMC2719873 DOI:

Peslova G, Petrak J, Kuzelova K, Hrdy I, Halada P, Kuchel P, et al. Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood. Blood. 2009; 113: 6225-36. PMid:19380872 DOI:

Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008; 112: 4292-7. PMid:18689548 DOI:

132. Swinkels DW, Girelli D, Laarakkers C, Kroot J, Campostrini N,Kemna EH,Tjalsma H. Advances in quantitative hepcidin measurements by time-of-flight mass spectrometry. PLoS ONE. 2008; 3: e2706. PMCid:PMC2442656 DOI:

Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW.Hepcidin in human iron disorders: diagnostic implications. Clin Chem. 2011;57(12):1650-69. DOI:

Tomosugi N, Kawabata H, Wakatabe R, Higuchi M, Yamaya, Umehara H, Ishikawa I. Detection of serum hepcidin in renal failure and inflammation by using Protein Chip System. Blood. 2006; 108: 1381-7. DOI:

Peters HP, Laarakkers CM, Swinkels DW, Wetzels JF. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant. 2010; 25: 848-53. DOI:

Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009; 75: 976-81. PMid:19212416 DOI:

Costa E, Swinkels DW, Laarakkers CM, Rocha-Pereira P, Rocha S, Reis F. et al. Hepcidin serum levels and resistance to recombinant human erythropoietin therapy in haemodialysis patients. Acta Haematol. 2009; 122: 226-9. DOI: