Pflügers Archiv - European Journal of Physiology

, Volume 455, Issue 2, pp 201–213

The relevance of the intestinal crypt and enterocyte in regulating iron absorption

Invited Review

Abstract

Rigorous regulation of iron absorption is required to meet the requirements of the body and to limit excess iron accumulation that can produce oxidative stress. Regulation of iron absorption is controlled by hepcidin and probably by the crypt program. Hepcidin is a humoral mediator of iron absorption that interacts with the basolateral transporter, ferroportin. High levels of hepcidin reduce iron absorption by targeting ferroportin to lysosomes for destruction. It is also proposed that ferroportin is expressed on the apical membrane and coordinates with ferroportin-hepcidin derived from the basal surface to modulate the uptake phase of iron absorption. The crypt program suggests that as crypt cells differentiate and migrate into the absorptive zone they absorb iron from the diet at levels inverse to the amount of iron taken up from transferrin. Under most circumstances, intestinal iron absorption is controlled at multiple levels that lead to hepcidin/ferroportin modulation of the enterocyte labile iron pool (LIP). It is likely that transcription of iron transport proteins involved in the apical and basolateral transport of iron are differentially regulated by separate LIPs. Iron-responsive protein (IRP) 1 and IRP2 do not appear to play a significant role in the expression of iron transport proteins, although IRP2 regulates L- and H-ferritin expression. Despite the importance of hepcidin, there is evidence of hepcidin-independent regulation of iron absorption possibly involving haemojuvelin (HJV) and neogenin, which may be up-regulated during ineffective erythropoiesis.

Keywords

Absorption DMT1 Regulation Uptake Release Hepcidin Ferroportin Iron responsive protein 

References

  1. 1.
    Crichton RR, Wilmet S, Legssyer R, Ward RJ (2002) Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem 91(1):9–18PubMedCrossRefGoogle Scholar
  2. 2.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13(4):399–408PubMedCrossRefGoogle Scholar
  3. 3.
    Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M, Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36(1):77–82PubMedCrossRefGoogle Scholar
  4. 4.
    Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25(1):14–15PubMedCrossRefGoogle Scholar
  5. 5.
    Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C (2003) Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33(1):21–22PubMedCrossRefGoogle Scholar
  6. 6.
    Cazzola M (2003) Genetic disorders of iron overload and the novel “ferroportin disease”. Haematologica 88(7):721–724PubMedGoogle Scholar
  7. 7.
    Millard KN, Frazer DM, Wilkins SJ, Anderson GJ (2004) Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat. Gut 53(5):655–660PubMedCrossRefGoogle Scholar
  8. 8.
    Frazer DM, Inglis HR, Wilkins SJ, Millard KN, Steele TM, McLaren GD, McKie AT, Vulpe CD, Anderson GJ (2004) Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut 53(10):1509–1515PubMedCrossRefGoogle Scholar
  9. 9.
    Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, Anderson GJ (2002) Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 123(3):835–844PubMedCrossRefGoogle Scholar
  10. 10.
    Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110(7):1037–1044PubMedCrossRefGoogle Scholar
  11. 11.
    Oates PS, Ahmed U (2007) Molecular regulation of the hepatic expression of the iron regulatory molecule hepcidin. J Gastroenterol Hepatol (in press)Google Scholar
  12. 12.
    Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S (2002) Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 99(7):4596–4601PubMedCrossRefGoogle Scholar
  13. 13.
    Pietrangelo A (2004) The ferroportin disease. Blood Cells Mol Diseases 32(1):131–138CrossRefGoogle Scholar
  14. 14.
    Oates PS (2007) The role of hepcidin and ferroportin in iron absorption. Histol Histopathol 22:791–804PubMedGoogle Scholar
  15. 15.
    Simpson RJ, Debnam ES, Laftah AH, Solanky N, Beaumont N, Bahram S, Schumann K, Srai SK (2003) Duodenal nonheme iron content correlates with iron stores in mice, but the relationship is altered by Hfe gene knock-out. Blood 101(8):3316–3318PubMedCrossRefGoogle Scholar
  16. 16.
    Frazer DM, Anderson GJ (2005) Iron imports. I. Intestinal iron absorption and its regulation. Am J Physiol Gastrointest Liver Physiol 289(4):G631–G635PubMedGoogle Scholar
  17. 17.
    Oates PS, West AR (2006) Heme in intestinal epithelial cell turnover, differentiation, detoxification, inflammation, carcinogenesis, absorption and motility. World J Gastroenterol 12(27):4281–4295PubMedGoogle Scholar
  18. 18.
    Laftah AH, Ramesh B, Simpson RJ, Solanky N, Bahram S, Schumann K, Debnam ES, Srai SK (2004) Effect of hepcidin on intestinal iron absorption in mice. Blood 103(10):3940–3944PubMedCrossRefGoogle Scholar
  19. 19.
    Yamaji S, Sharp P, Ramesh B, Srai SK (2004) Inhibition of iron transport across human intestinal epithelial cells by hepcidin. Blood 104(7):2178–2180PubMedCrossRefGoogle Scholar
  20. 20.
    Cheng H, Leblond CP (1974) Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am J Anat 141(4):461–479PubMedCrossRefGoogle Scholar
  21. 21.
    Oates PS, Thomas C (2005) Ferroportin is expressed on the mucous granule membrane of a subpopulation of goblet cells in the duodenum of the rat. Histol Histopathol 20(3):681–687PubMedGoogle Scholar
  22. 22.
    Oates PS, Thomas C, Freitas E, Callow MJ, Morgan EH (2000) Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats. Am J Physiol Gastrointest Liver Physiol 278(6):G930–G936PubMedGoogle Scholar
  23. 23.
    Fleming RE, Britton RS (2006) Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 290(4):G590–G594PubMedCrossRefGoogle Scholar
  24. 24.
    Niederkofler V, Salie R, Arber S (2005) Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 115(8):2180–2186PubMedCrossRefGoogle Scholar
  25. 25.
    Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98(15):8780–8785PubMedCrossRefGoogle Scholar
  26. 26.
    Fleming RE, Holden CC, Tomatsu S, Waheed A, Brunt EM, Britton RS, Bacon BR, Roopenian DC, Sly WS (2001) Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc Natl Acad Sci USA 98(5):2707–2711PubMedCrossRefGoogle Scholar
  27. 27.
    Weizer-Stern O, Adamsky K, Amariglio N, Rachmilewitz E, Breda L, Rivella S, Rechavi G (2006) mRNA expression of iron regulatory genes in beta-thalassemia intermedia and beta-thalassemia major mouse models. Am J Hematol 81(7):479–483PubMedCrossRefGoogle Scholar
  28. 28.
    Gardenghi S, Marongiu MF, Ramos P, Guy E, Breda L, Chadburn A, Liu Y, Amariglio N, Rechavi G, Rachmilewitz EA, Breuer W, Cabantchik ZI, Wrighting DM, Andrews NC, de Sousa M, Giardina PJ, Grady RW, Rivella S (2007) Ineffective erythropoiesis in {beta}-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood (electronic publication ahead of print; Feb 15)Google Scholar
  29. 29.
    Leong WI, Bowlus CL, Tallkvist J, Lonnerdal B (2003) DMT1 and FPN1 expression during infancy: developmental regulation of iron absorption. Am J Physiol Gastrointest Liver Physiol 285(6):G1153–G1161PubMedGoogle Scholar
  30. 30.
    Leong WI, Bowlus CL, Tallkvist J, Lonnerdal B (2003) Iron supplementation during infancy—effects on expression of iron transporters, iron absorption, and iron utilization in rat pups. Am J Clin Nutr 78(6):1203–1211PubMedGoogle Scholar
  31. 31.
    Morgan EH, Oates PS (2002) Mechanisms and regulation of intestinal iron absorption. Blood Cells Mol Diseases 29(3):384–399CrossRefGoogle Scholar
  32. 32.
    Wheby MS, Crosby WH (1963) The gastrointestinal tract and iron absorption. Blood 22:416–428PubMedGoogle Scholar
  33. 33.
    Conrad ME, Weintraub LR, Crosby WH (1964) The role of the intestine in iron kinetics. J Clin Invest 43:963–974PubMedGoogle Scholar
  34. 34.
    Waheed A, Parkkila S, Saarnio J, Fleming RE, Zhou XY, Tomatsu S, Britton RS, Bacon BR, Sly WS (1999) Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci USA 96(4):1579–1584PubMedCrossRefGoogle Scholar
  35. 35.
    Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 95(4):1472–1477PubMedCrossRefGoogle Scholar
  36. 36.
    Trinder D, Olynyk JK, Sly WS, Morgan EH (2002) Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Proc Natl Acad Sci USA 99(8):5622–5626PubMedCrossRefGoogle Scholar
  37. 37.
    Oates PS, Morgan EH (1997) Ferritin gene expression and transferrin receptor activity in intestine of rats with varying iron stores. Am J Physiol 273(3 Pt 1):G636–G646PubMedGoogle Scholar
  38. 38.
    Oates PS, Thomas C, Morgan EH (2000) Transferrin receptor activity and localisation in the rat duodenum. Pflugers Arch 440(1):116–124PubMedGoogle Scholar
  39. 39.
    West AR, Thomas C, Sadlier J, Oates PS (2006) Haemochromatosis protein is expressed on the terminal web of enterocytes in proximal small intestine of the rat. Histochem Cell Biol 125(3):283–292PubMedCrossRefGoogle Scholar
  40. 40.
    Fergelot P, Ropert-Bouchet M, Abgueguen E, Orhant M, Radosavljevic M, Grimber G, Jouan H, Le Gall JY, Mosser J, Gilfillan S, Bahram S (2002) Iron overload in mice expressing HFE exclusively in the intestinal villi provides evidence that HFE regulates a functional cross-talk between crypt and villi enterocytes. Blood Cells Mol Diseases 28(3):348–360CrossRefGoogle Scholar
  41. 41.
    Vujic Spasic M, Kiss J, Herrmann T, Kessler R, Stolte J, Galy B, Rathkolb B, Wolf E, Stremmel W, Hentze MW, Muckenthaler MU (2007) Physiological systemic iron metabolism in mice deficient for duodenal Hfe. Blood (electronic publication ahead of print; Jan 30)Google Scholar
  42. 42.
    Rodriguez A, Pan P, Parkkila S (2007) Expression studies of neogenin and its ligand hemojuvelin in mouse tissues. J Histochem Cytochem 55(1):85–96PubMedCrossRefGoogle Scholar
  43. 43.
    Rajagopalan S, Deitinghoff L, Davis D, Conrad S, Skutella T, Chedotal A, Mueller BK, Strittmatter SM (2004) Neogenin mediates the action of repulsive guidance molecule. Nat Cell Biol 6(8):756–762PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA (2007) Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem (electronic publication ahead of print; Mar 1)Google Scholar
  45. 45.
    Rouault TA (2002) Post-transcriptional regulation of human iron metabolism by iron regulatory proteins. Blood Cells Mol Diseases 29(3):309–314CrossRefGoogle Scholar
  46. 46.
    Recalcati S, Alberghini A, Campanella A, Gianelli U, De Camilli E, Conte D, Cairo G (2006) Iron regulatory proteins 1 and 2 in human monocytes, macrophages and duodenum: expression and regulation in hereditary hemochromatosis and iron deficiency. Haematologica 91(3):303–310PubMedGoogle Scholar
  47. 47.
    Guo B, Phillips JD, Yu Y, Leibold EA (1995) Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem 270(37):21645–21651PubMedCrossRefGoogle Scholar
  48. 48.
    Meyron-Holtz EG, Ghosh MC, Iwai K, LaVaute T, Brazzolotto X, Berger UV, Land W, Ollivierre-Wilson H, Grinberg A, Love P, Rouault TA (2004) Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J 23(2):386–395PubMedCrossRefGoogle Scholar
  49. 49.
    Galy B, Ferring D, Minana B, Bell O, Janser HG, Muckenthaler M, Schumann K, Hentze MW (2005) Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood 106(7):2580–2589PubMedCrossRefGoogle Scholar
  50. 50.
    Latunde-Dada GO, Vulpe CD, Anderson GJ, Simpson RJ, McKie AT (2004) Tissue-specific changes in iron metabolism genes in mice following phenylhydrazine-induced haemolysis. Biochim Biophys Acta 1690(2):169–176PubMedGoogle Scholar
  51. 51.
    Schumann K, Moret R, Kunzle H, Kuhn LC (1999) Iron regulatory protein as an endogenous sensor of iron in rat intestinal mucosa. Possible implications for the regulation of iron absorption. Eur J Biochem 260(2):362–372PubMedCrossRefGoogle Scholar
  52. 52.
    Yeh KY, Yeh M, Watkins JA, Rodriguez-Paris J, Glass J (2000) Dietary iron induces rapid changes in rat intestinal divalent metal transporter expression. Am J Physiol Gastrointest Liver Physiol 279(5):G1070–G1079PubMedGoogle Scholar
  53. 53.
    Frazer DM, Wilkins SJ, Becker EM, Murphy TL, Vulpe CD, McKie AT, Anderson GJ (2003) A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut 52(3):340–346PubMedCrossRefGoogle Scholar
  54. 54.
    Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile DJ, Pietrangelo A (2003) The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. J Hepatol 39(5):710–715PubMedCrossRefGoogle Scholar
  55. 55.
    Barisani D, Parafioriti A, Bardella MT, Zoller H, Conte D, Armiraglio E, Trovato C, Koch RO, Weiss G (2004) Adaptive changes of duodenal iron transport proteins in celiac disease. Physiol Genomics 17(3):316–325PubMedCrossRefGoogle Scholar
  56. 56.
    Ludwiczek S, Theurl I, Bahram S, Schumann K, Weiss G (2005) Regulatory networks for the control of body iron homeostasis and their dysregulation in HFE mediated hemochromatosis. J Cell Physiol 204(2):489–499PubMedCrossRefGoogle Scholar
  57. 57.
    Starzynski RR, Lipinski P, Drapier JC, Diet A, Smuda E, Bartlomiejczyk T, Gralak MA, Kruszewski M (2005) Down-regulation of iron regulatory protein 1 activities and expression in superoxide dismutase 1 knock-out mice is not associated with alterations in iron metabolism. J Biol Chem 280(6):4207–4212PubMedCrossRefGoogle Scholar
  58. 58.
    Rabie A, Simpson RJ, Bomford A, Cunninghame-Graham D, Peters TJ (1995) Relationship between duodenal cytosolic aconitase activity and iron status in the mouse. Biochim Biophys Acta 1245(3):414–420PubMedGoogle Scholar
  59. 59.
    Tong WH, Rouault TA (2007) Metabolic regulation of citrate and iron by aconitases: role of iron-sulfur cluster biogenesis. Biometals (electronic publication ahead of print; Jan 5)Google Scholar
  60. 60.
    LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, Drake SK, Miller G, Abu-Asab M, Tsokos M, Switzer R 3rd, Grinberg A, Love P, Tresser N, Rouault TA (2001) Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 27(2):209–214PubMedCrossRefGoogle Scholar
  61. 61.
    Oates PS, Trinder D, Morgan EH (2000) Gastrointestinal function, divalent metal transporter-1 expression and intestinal iron absorption. Pflugers Arch 440(3):496–502PubMedGoogle Scholar
  62. 62.
    Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, Hentze MW, Rouault TA, Andrews NC, Hediger MA (2001) Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 509(2):309–316PubMedCrossRefGoogle Scholar
  63. 63.
    Zoller H, Theurl I, Koch R, Kaser A, Weiss G (2002) Mechanisms of iron mediated regulation of the duodenal iron transporters divalent metal transporter 1 and ferroportin 1. Blood Cells Mol Diseases 29(3):488–497CrossRefGoogle Scholar
  64. 64.
    Tchernitchko D, Bourgeois M, Martin ME, Beaumont C (2002) Expression of the two mRNA isoforms of the iron transporter Nramp2/DMTI in mice and function of the iron responsive element. Biochem J 363(Pt 3):449–455PubMedCrossRefGoogle Scholar
  65. 65.
    Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275(26):19906–19912PubMedCrossRefGoogle Scholar
  66. 66.
    Chen H, Su T, Attieh ZK, Fox TC, McKie AT, Anderson GJ, Vulpe CD (2003) Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. Blood 102(5):1893–1899PubMedCrossRefGoogle Scholar
  67. 67.
    Chen H, Huang G, Su T, Gao H, Attieh ZK, McKie AT, Anderson GJ, Vulpe CD (2006) Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency. J Nutr 136(5):1236–1241PubMedGoogle Scholar
  68. 68.
    Levy JE, Montross LK, Andrews NC (2000) Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 105(9):1209–1216PubMedCrossRefGoogle Scholar
  69. 69.
    Brown MS, Ye J, Rawson RB, Goldstein JL (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100(4):391–398PubMedCrossRefGoogle Scholar
  70. 70.
    Touret N, Martin-Orozco N, Paroutis P, Furuya W, Lam-Yuk-Tseung S, Forbes J, Gros P, Grinstein S (2004) Molecular and cellular mechanisms underlying iron transport deficiency in microcytic anemia. Blood 104(5):1526–1533PubMedCrossRefGoogle Scholar
  71. 71.
    Thomas C, Oates PS (2002) IEC-6 cells are an appropriate model of intestinal iron absorption in rats. J Nutr 132(4):680–687PubMedGoogle Scholar
  72. 72.
    Canonne-Hergaux F, Levy JE, Fleming MD, Montross LK, Andrews NC, Gros P (2001) Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders. Blood 97(4):1138–1140PubMedCrossRefGoogle Scholar
  73. 73.
    Trinder D, Oates PS, Thomas C, Sadleir J, Morgan EH (2000) Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload. Gut 46(2):270–276PubMedCrossRefGoogle Scholar
  74. 74.
    Townsend A, Drakesmith H (2002) Role of HFE in iron metabolism, hereditary haemochromatosis, anaemia of chronic disease, and secondary iron overload. Lancet 359(9308):786–790PubMedCrossRefGoogle Scholar
  75. 75.
    Moura E, Noordermeer MA, Verhoeven N, Verheul AF, Marx JJ (1998) Iron release from human monocytes after erythrophagocytosis in vitro: an investigation in normal subjects and hereditary hemochromatosis patients. Blood 92(7):2511–2519PubMedGoogle Scholar
  76. 76.
    Montosi G, Paglia P, Garuti C, Guzman CA, Bastin JM, Colombo MP, Pietrangelo A (2000) Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. Blood 96(3):1125–1129PubMedGoogle Scholar
  77. 77.
    Drakesmith H, Sweetland E, Schimanski L, Edwards J, Cowley D, Ashraf M, Bastin J, Townsend AR (2002) The hemochromatosis protein HFE inhibits iron export from macrophages. Proc Natl Acad Sci USA 99(24):15602–15607PubMedCrossRefGoogle Scholar
  78. 78.
    Kohgo Y, Niitsu Y, Kondo H, Kato J, Tsushima N, Sasaki K, Hirayama M, Numata T, Nishisato T, Urushizaki I (1987) Serum transferrin receptor as a new index of erythropoiesis. Blood 70(6):1955–1958PubMedGoogle Scholar
  79. 79.
    Shih YJ, Baynes RD, Hudson BG, Flowers CH, Skikne BS, Cook JD (1990) Serum transferrin receptor is a truncated form of tissue receptor. J Biol Chem 265(31):19077–19081PubMedGoogle Scholar
  80. 80.
    Finch CA, Huebers H, Eng M, Miller L (1982) Effect of transfused reticulocytes on iron exchange. Blood 59(2):364–369PubMedGoogle Scholar
  81. 81.
    Cook JD, Dassenko S, Skikne BS (1990) Serum transferrin receptor as an index of iron absorption. Br J Haematol 75(4):603–609PubMedGoogle Scholar
  82. 82.
    Brandao M, Oliveira JC, Bravo F, Reis J, Garrido I, Porto G (2005) The soluble transferrin receptor as a marker of iron homeostasis in normal subjects and in HFE-related hemochromatosis. Haematologica 90(1):31–37PubMedGoogle Scholar
  83. 83.
    Flanagan JM, Peng H, Wang L, Gelbart T, Lee P, Johnson Sasu B, Beutler E (2006) Soluble transferrin receptor-1 levels in mice do not affect iron absorption. Acta Haematol 116(4):249–254PubMedCrossRefGoogle Scholar
  84. 84.
    Zoller H, Pietrangelo A, Vogel W, Weiss G (1999) Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet 353(9170):2120–2123PubMedCrossRefGoogle Scholar
  85. 85.
    Zoller H, Koch RO, Theurl I, Obrist P, Pietrangelo A, Montosi G, Haile DJ, Vogel W, Weiss G (2001) Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 120(6):1412–1419PubMedCrossRefGoogle Scholar
  86. 86.
    Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA (2002) Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol 282(4):G598–G607PubMedGoogle Scholar
  87. 87.
    Stuart KA, Anderson GJ, Frazer DM, Powell LW, McCullen M, Fletcher LM, Crawford DH (2003) Duodenal expression of iron transport molecules in untreated haemochromatosis subjects. Gut 52(7):953–959PubMedCrossRefGoogle Scholar
  88. 88.
    Zoller H, Theurl I, Koch RO, McKie AT, Vogel W, Weiss G (2003) Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Gastroenterology 125(3):746–754PubMedCrossRefGoogle Scholar
  89. 89.
    Kelleher T, Ryan E, Barrett S, Sweeney M, Byrnes V, O’Keane C, Crowe J (2004) Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis. Gut 53(8):1174–1179PubMedCrossRefGoogle Scholar
  90. 90.
    Gleeson F, Ryan E, Barrett S, Russell J, Kelleher B, Crowe J (2005) Duodenal Dcytb and hephaestin mRNA expression are not significantly modulated by variations in body iron homeostasis. Blood Cells Mol Diseases 35(3):303–308CrossRefGoogle Scholar
  91. 91.
    Fleming RE, Migas MC, Zhou X, Jiang J, Britton RS, Brunt EM, Tomatsu S, Waheed A, Bacon BR, Sly WS (1999) Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci USA 96(6):3143–3148PubMedCrossRefGoogle Scholar
  92. 92.
    Dupic F, Fruchon S, Bensaid M, Borot N, Radosavljevic M, Loreal O, Brissot P, Gilfillan S, Bahram S, Coppin H, Roth MP (2002) Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains. Gastroenterology 122(3):745–751PubMedCrossRefGoogle Scholar
  93. 93.
    Muckenthaler M, Roy CN, Custodio AO, Minana B, deGraaf J, Montross LK, Andrews NC, Hentze MW (2003) Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 34(1):102–107PubMedCrossRefGoogle Scholar
  94. 94.
    Herrmann T, Muckenthaler M, van der Hoeven F, Brennan K, Gehrke SG, Hubert N, Sergi C, Grone HJ, Kaiser I, Gosch I, Volkmann M, Riedel HD, Hentze MW, Stewart AF, Stremmel W (2004) Iron overload in adult Hfe-deficient mice independent of changes in the steady-state expression of the duodenal iron transporters DMT1 and Ireg1/ferroportin. J Mol Med 82(1):39–48PubMedCrossRefGoogle Scholar
  95. 95.
    Muckenthaler MU, Rodrigues P, Macedo MG, Minana B, Brennan K, Cardoso EM, Hentze MW, de Sousa M (2004) Molecular analysis of iron overload in beta2-microglobulin-deficient mice. Blood Cells Mol Diseases 33(2):125–131CrossRefGoogle Scholar
  96. 96.
    Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC (2005) A mouse model of juvenile hemochromatosis. J Clin Invest 115(8):2187–2191PubMedCrossRefGoogle Scholar
  97. 97.
    McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291(5509):1755–1759PubMedCrossRefGoogle Scholar
  98. 98.
    Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2(6):399–409PubMedCrossRefGoogle Scholar
  99. 99.
    Viatte L, Lesbordes-Brion JC, Lou DQ, Bennoun M, Nicolas G, Kahn A, Canonne-Hergaux F, Vaulont S (2005) Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood 105(12):4861–4864PubMedCrossRefGoogle Scholar
  100. 100.
    Kawabata H, Fleming RE, Gui D, Moon SY, Saitoh T, O’Kelly J, Umehara Y, Wano Y, Said JW, Koeffler HP (2005) Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105(1):376–381PubMedCrossRefGoogle Scholar
  101. 101.
    Drake SF, Morgan EH, Herbison CE, Delima RD, Graham RM, Chua AC, Leedman PJ, Fleming R, Bacon BR, Olynyk JK, Trinder D (2006) Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3. Am J Physiol Gastrointest Liver Physiol 292(1):G323–G328PubMedCrossRefGoogle Scholar
  102. 102.
    Wallace DF, Summerville L, Lusby PE, Subramaniam VN (2005) First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin. Gut 54(7):980–986PubMedCrossRefGoogle Scholar
  103. 103.
    Theurl I, Ludwiczek S, Eller P, Seifert M, Artner E, Brunner P, Weiss G (2005) Pathways for the regulation of body iron homeostasis in response to experimental iron overload. J Hepatol 43(4):711–719PubMedCrossRefGoogle Scholar
  104. 104.
    Ludwiczek S, Theurl I, Artner-Dworzak E, Chorney M, Weiss G (2004) Duodenal HFE expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability. J Mol Med 82(6):373–382PubMedCrossRefGoogle Scholar
  105. 105.
    Anderson GJ, Frazer DM, Wilkins SJ, Becker EM, Millard KN, Murphy TL, McKie AT, Vulpe CD (2002) Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochem Soc Trans 30(4):724–726PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.School of Biomedical, Biomolecular and Chemical SciencesUniversity of Western AustraliaNedlandsAustralia

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