The role of hepcidin in iron metabolism
Authors:
J. Houda 1; D. Pospíšilová 1; M. Horváthová 2
Authors‘ workplace:
Dětská klinika při LF UP a FN, Olomoucpřednosta prof. MUDr. V. Mihál, CSc.
1; Ústav biologie při LF UP, Olomoucpřednosta doc. RNDr. V. Divoký, Ph. D.
2
Published in:
Čes-slov Pediat 2014; 69 (5): 301-312.
Category:
Review
Overview
Iron is essential for proper function of the cells in human body. Iron is involved in tissue oxygenation, antioxidant defence, cell proliferation and in other important metabolic processes as a part of haemoproteins (haemoglobin, myoglobin) and different iron-containing enzymes. It is crucial to keep iron homeostasis balanced, because of the potential iron toxicity. Hepcidin plays a key role in this process by controlling iron absorption from the diet, iron recycling from senescent erythrocytes and iron release from stores. Many diseases are accompanied by abnormal hepcidin level. Inappropriately low hepcidin leads to iron overload and is typical for hereditary haemochromatosis. Increased hepcidin level contributes to the development of anaemia caused by insufficient iron supply for erythropoiesis.
Molecular mechanisms affecting hepcidin production are still subject of intensive research. More detailed knowledge about these mechanisms may contribute to the identification of new molecules involved in the regulation of iron metabolism and to the development of new drugs potentially useful in the treatment of disorders associated with disrupted iron homeostasis.
Key words:
iron metabolism, hepcidin, ferroportin, hereditary haemochromatosis, anaemia of chronic diseases
Sources
1. Shayeghi M, Latunde-Dada G, Oakhill J, et al. Identification of an intestinal heme transporter. Cell 2005; 122 (5): 789–801.
2. 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 (5): 917–928.
3. Gunshin H, Mackenzie B, Berger U, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388 (6641): 482–488.
4. Donovan A, Lima C, Pinkus J, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1 (3): 191–200.
5. Vulpe C, Kuo Y, Murphy T, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999; 21 (2): 195–199.
6. Gunshin H, Fujiwara Y, Custodio A, et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005; 115 (5): 1258–1266.
7. Krause A, Neitz S, Mägert H, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480 (2–3): 147–150.
8. Park C, Valore E, Waring A, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276 (11): 7806–7810.
9. Bekri S, Gual P, Anty R, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology 2006; 131 (3): 788–796.
10. Kulaksiz H, Fein E, Redecker P, et al. Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide. J Endocrinol 2008; 197 (2): 241–249.
11. Hunter H, Fulton D, 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 (40): 37597–37603.
12. Wallace D, Jones M, Pedersen P, et al. Purification and partial characterisation of recombinant human hepcidin. Biochimie 2006; 88 (1): 31–37.
13. Kemna E, Tjalsma H, Podust V, et al. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem 2007; 53 (4): 620–628.
14. Nagy J, Lakner L, Poór V, et al. Serum prohepcidin levels in chronic inflammatory bowel diseases. J Crohns Colitis 2010; 4 (6): 649–653.
15. Hilton K, Lambert L. Molecular evolution and characterization of hepcidin gene products in vertebrates. Gene 2008; 415 (1–2): 40–48.
16. 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 (11): 7811–7819.
17. 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 USA 2001; 98 (15): 8780–8785.
18. Zhang A-S, Enns C. Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J Biol Chem 2009; 284 (2): 711–715.
19. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113 (9): 1271–1276.
20. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med 2011; 62: 347–360.
21. Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis 2004; 32 (1): 131–138.
22. Babitt J, Huang F, Wrighting D, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006; 38 (5): 531–539.
23. Xia Y, Babitt J, Sidis Y, et al. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 2008; 111 (10): 5195–5204.
24. Steinbicker A, Sachidanandan C, Vonner A, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 2011; 117 (18): 4915–4923.
25. Andriopoulos B, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009; 41 (4): 482–487.
26. Roy C, Enns C. Iron homeostasis: new tales from the crypt. Blood 2000; 96 (13): 4020–4027.
27. Gao J, Chen J, Kramer M, et al. 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.
28. Schmidt P, Toran P, Giannetti A, et al. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 2008; 7 (3): 205–214.
29. Goswami T, Andrews N. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006; 281 (39): 28494––28498.
30. Ramey G, Deschemin J-C, Vaulont S. Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica 2009; 94 (6): 765–772.
31. Silvestri L, Pagani A, Nai A, et al. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 2008; 8 (6): 502–511.
32. Lee D-H, Zhou L-J, Zhou Z, et al. Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis. Blood 2010; 115 (15): 3136–3145.
33. Cau M, Melis M, Congiu R, et al. Iron-deficiency anemia secondary to mutations in genes controlling hepcidin. Expert Rev Hematol 2010; 3 (2): 205–216.
34. Nai A, Pagani A, Silvestri L, et al. Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood 2010; 116 (5): 851–852.
35. Yilmaz-Keskin E, Sal E, De Falco L, et al. Is the acronym IRIDA acceptable for slow responders to iron in the presence of TMPRSS6 mutations? Turk J Pediatr 2013; 55 (5): 479–484.
36. Zhang S-P, Wang Z, Wang L-X, et al. AG490: an inhibitor of hepcidin expression in vivo. World J Gastroenterol WJG 2011; 17 (45): 5032–5034.
37. Lakhal S, Schödel J, Townsend A, et al. Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis. The Journal of biological chemistry 2011; 286 (6): 4090–4097.
38. Maurer E, Gütschow M, Stirnberg M. Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: identification of a hypoxia-responsive element in the TMPRSS6 promoter region. Biol Chem 2012; 393 (6): 535–540.
39. Meynard D, Vaja V, Sun C, et al. Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 2011; 118 (3): 747–756.
40. Bartnikas T, Andrews N, Fleming M. Transferrin is a major determinant of hepcidin expression in hypo-transferrinemic mice. Blood 2011; 117 (2): 630–637.
41. Pak M, Lopez M, Gabayan V, et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 2006; 108 (12): 3730–3735.
42. Adamsky K, Weizer O, Amariglio N, et al. Decreased hepcidin mRNA expression in thalassemic mice. Br J Haematol 2004; 124 (1): 123–124.
43. Papanikolaou G, Tzilianos M, Christakis J, et al. Hepcidin in iron overload disorders. Blood 2005; 105 (10): 4103–4105.
44. Pospisilova D, Holub D, Zidova Z, et al. Hepcidin levels in Diamond-Blackfan anemia reflect erythropoietic activity and transfusion dependence. Haematologica 2014.
45. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13 (9): 1096–1101.
46. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 2009; 114 (1): 181–186.
47. Tanno T, Rabel A, Lee Y, et al. Expression of growth differentiation factor 15 is not elevated in individuals with iron deficiency secondary to volunteer blood donation. Transfusion (Paris) 2010; 50 (7): 1532–1535.
48. Talbot N, Lakhal S, Smith T, et al. Regulation of hepcidin expression at high altitude. Blood 2012; 119 (3): 857–860.
49. Smith T, Robbins P, Ratcliffe P. The human side of hypoxia-inducible factor. Br J Haematol 2008; 141 (3): 325–334.
50. Gordeuk V, Miasnikova G, Sergueeva A, et al. Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression. Blood 2011; 118 (19): 5278–5282.
51. Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 2007; 132 (1): 294–300.
52. Inamura J, Ikuta K, Jimbo J, et al. Upregulation of hepcidin by interleukin-1beta in human hepatoma cell lines. Hepatology research: Official Journal of the Japan Society of Hepatology 2005; 33 (3): 198–205.
53. Lee P, Peng H, Gelbart T, et al. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 2005; 102 (6): 1906–1910.
54. Salahudeen A, Bruick R. Maintaining Mammalian iron and oxygen homeostasis: sensors, regulation, and cross-talk. Ann NY Acad Sci 2009; 1177: 30–38.
55. Goodnough L, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010; 116 (23): 4754–4761.
56. Oustamanolakis P, Koutroubakis I, Messaritakis I, et al. Serum hepcidin and prohepcidin concentrations in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2011; 23 (3): 262–268.
57. Kroot J, Kemna E, Bansal S, et al. Results of the first international round robin for the quantification of urinary and plasma hepcidin assays: need for standardization. Haematologica 2009; 94 (12): 1748–1752.
58. Šuláková A, Pozler O, Nováčková L. Prevalence a typ anémie v době stanovení diagnózy nespecifického střevního zánětu u dětí. Čes-slov Pediat 2012; 67 (1): 3–10.
59. Preza G, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 2011; 121 (12): 4880–4888.
60. Corradini E, Schmidt P, Meynard D, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 2010; 139 (5): 1721–1729.
61. Sasu B, Cooke K, Arvedson T, et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 2010; 115 (17): 3616–3624.
62. Hashizume M, Uchiyama Y, Horai N, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production. Rheumatol Int 2010; 30 (7): 917–923.
63. Yu P, Hong C, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 2008; 4 (1): 33–41.
64. Poli M, Girelli D, Campostrini N, et al. Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood 2011; 117 (3): 997–1004.
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Neonatology Paediatrics General practitioner for children and adolescentsArticle was published in
Czech-Slovak Pediatrics
2014 Issue 5
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