Delayed Hepcidin Response Explains the Lag Period in Iron Absorption Following a Stimulus to Increase Erythropoiesis

Overview

Journal Gut

Specialty Gastroenterology

Date 2004 Sep 14

PMID 15361505

Citations 33

Authors

D M Frazer

H R Inglis

S J Wilkins

K N Millard

T M Steele

G D McLaren

A T McKie

C D Vulpe

G J Anderson

Affiliations

Soon will be listed here.

Abstract

Introduction: The delay of several days between an erythropoietic stimulus and the subsequent increase in intestinal iron absorption is commonly believed to represent the time required for body signals to programme the immature crypt enterocytes and for these cells to migrate to the villus. Recent data however suggest that signals from the body to alter absorption are mediated by circulating hepcidin and that this peptide exerts its effect on mature villus enterocytes.

Methods: We have examined the delay in the absorptive response following stimulated erythropoiesis using phenylhydrazine induced haemolysis and correlated this with expression of hepcidin in the liver and iron transporters in the duodenum.

Results: There was a delay of four days following haemolysis before a significant increase in iron absorption was observed. Hepatic hepcidin expression did not decrease until day 3, reaching almost undetectable levels by days 4 and 5. This coincided with the increase in duodenal expression of divalent metal transporter 1, duodenal cytochrome b, and Ireg1.

Conclusion: These results suggest that the delayed increase in iron absorption following stimulated erythropoiesis is attributable to a lag in the hepcidin response rather than crypt programming, and are consistent with a direct effect of the hepcidin pathway on mature villus enterocytes.

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References

McKie A, Barrow D, Latunde-Dada G, Rolfs A, Sager G, Mudaly E . An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001; 291(5509):1755-9. DOI: 10.1126/science.1057206. View

Nicolas G, Chauvet C, Viatte L, Danan J, Bigard X, Devaux I . The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002; 110(7):1037-44. PMC: 151151. DOI: 10.1172/JCI15686. View

Wang X, Ong W, Connor J . Increase in ferric and ferrous iron in the rat hippocampus with time after kainate-induced excitotoxic injury. Exp Brain Res. 2002; 143(2):137-48. DOI: 10.1007/s00221-001-0971-y. View

Anderson G, Frazer D, Wilkins S, Becker E, Millard K, MURPHY T . Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochem Soc Trans. 2002; 30(4):724-6. DOI: 10.1042/bst0300724. View

Enns C, Shindelman J, Tonik S, SUSSMAN H . Radioimmunochemical measurement of the transferrin receptor in human trophoblast and reticulocyte membranes with a specific anti-receptor antibody. Proc Natl Acad Sci U S A. 1981; 78(7):4222-5. PMC: 319761. DOI: 10.1073/pnas.78.7.4222. View

WIDDOWSON E, McCance R . The absorption and excretion of iron before, during and after a period of very high intake. Biochem J. 1937; 31(11):2029-34. PMC: 1267176. DOI: 10.1042/bj0312029. View

Anderson G, Powell L, Halliday J . The endocytosis of transferrin by rat intestinal epithelial cells. Gastroenterology. 1994; 106(2):414-22. DOI: 10.1016/0016-5085(94)90600-9. View

ORiordan D, Sharp P, Sykes R, Srai S, Epstein O, Debnam E . Cellular mechanisms underlying the increased duodenal iron absorption in rats in response to phenylhydrazine-induced haemolytic anaemia. Eur J Clin Invest. 1995; 25(10):722-7. DOI: 10.1111/j.1365-2362.1995.tb01950.x. View

Cortell S, CONRAD M . Effect of endotoxin on iron absorption. Am J Physiol. 1967; 213(1):43-7. DOI: 10.1152/ajplegacy.1967.213.1.43. View

10.

Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt S, Moynihan J . Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000; 403(6771):776-81. DOI: 10.1038/35001596. View

11.

Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J . Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2002; 33(1):21-2. DOI: 10.1038/ng1053. View

12.

Fleming M, Trenor 3rd C, Su M, Foernzler D, Beier D, Dietrich W . Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997; 16(4):383-6. DOI: 10.1038/ng0897-383. View

13.

Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B . Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002; 99(7):4596-601. PMC: 123693. DOI: 10.1073/pnas.072632499. View

14.

Park C, Valore E, Waring A, Ganz T . Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2000; 276(11):7806-10. DOI: 10.1074/jbc.M008922200. View

15.

Huebers H, Csiba E, Huebers E, Finch C . Molecular advantage of diferric transferrin in delivering iron to reticulocytes: a comparative study. Proc Soc Exp Biol Med. 1985; 179(2):222-6. DOI: 10.3181/00379727-179-42090. View

16.

Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P . A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2000; 276(11):7811-9. DOI: 10.1074/jbc.M008923200. View

17.

Ahmad K, Ahmann J, Migas M, Waheed A, Britton R, Bacon B . Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis. 2003; 29(3):361-6. DOI: 10.1006/bcmd.2002.0575. View

18.

Camaschella C, Roetto A, De Gobbi M . Juvenile hemochromatosis. Semin Hematol. 2002; 39(4):242-8. DOI: 10.1053/shem.2002.35635. View

19.

Pootrakul P, Wattanasaree J, Anuwatanakulchai M, Wasi P . Increased red blood cell protoporphyrin in thalassemia: a result of relative iron deficiency. Am J Clin Pathol. 1984; 82(3):289-93. DOI: 10.1093/ajcp/82.3.289. View

20.

Abboud S, Haile D . A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000; 275(26):19906-12. DOI: 10.1074/jbc.M000713200. View