Iron Overload in Adult Hfe-deficient Mice Independent of Changes in the Steady-state Expression of the Duodenal Iron Transporters DMT1 and Ireg1/ferroportin

Overview

Journal J Mol Med (Berl)

Specialty General Medicine

Date 2003 Nov 18

PMID 14618243

Citations 24

Authors

Thomas Herrmann

Martina Muckenthaler

Frank van der Hoeven

Karen Brennan

Sven G Gehrke

Nadia Hubert

Consolato Sergi

Hermann-Josef Grone

Iris Kaiser

Isabella Gosch

Martin Volkmann

Hans-Dieter Riedel

Matthias W Hentze

A Francis Stewart

Wolfgang Stremmel

Affiliations

Soon will be listed here.

Abstract

Patients suffering from hereditary hemochromatosis (HH) show progressive iron overload as a consequence of increased duodenal iron absorption. It has been hypothesized that mutations in the HH gene HFE cause misprogramming of the duodenal enterocytes towards a paradoxical iron-deficient state, resulting in increased iron transporter expression. Previous reports concerning gene expression levels of the duodenal iron transporters DMT1 and IREG1 in HH patients and animal models are controversial, however, and in many cases only mRNA expression levels were investigated. To analyze the duodenal expression of DMT1, Ireg1, Dcytb, and hephaestin and the association with iron overload in adult Hfe(-/-) mice, an Hfe(-/-) mouse line was generated. Duodenal DMT1 and Ireg1 protein levels, duodenal DMT1, Ireg1, Dcytb, hephaestin, and TfR1 mRNA levels, and hepatic hepcidin mRNA levels were quantified and the correlation to liver iron contents was calculated. We report that duodenal DMT1 and Ireg1 mRNA levels and DMT1 and Ireg1 protein levels remained unaffected by the Hfe deletion. Furthermore, duodenal hephaestin and TfR1 mRNA expression and hepatic hepcidin mRNA expression remained unaltered, while the duodenal mRNA expression of the brush border ferric reductase Dcytb was significantly increased in Hfe(-/-) mice. We found no correlation between the expression level of any of the analyzed transcripts and the liver iron content. In conclusion, the lack of correlation between DMT1 and Ireg1 protein expression and the liver iron content suggests that elevated duodenal iron transporter expression is not required for high liver iron overload. Hfe(-/-) mice do not necessarily display features of iron deficiency in the duodenum, indicated by an increase in mRNA and protein levels of DMT1 and Ireg1. Rather, the duodenal ferric reductase Dcytb may act as a possible mediator of iron overload in Hfe deficiency.

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References

Lebeau A, Frank J, Biesalski H, Weiss G, Srai S, Simpson R . Long-term sequelae of HFE deletion in C57BL/6 x 129/O1a mice, an animal model for hereditary haemochromatosis. Eur J Clin Invest. 2002; 32(8):603-12. DOI: 10.1046/j.1365-2362.2002.01026.x. View

Hubert N, Hentze M . Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A. 2002; 99(19):12345-50. PMC: 129447. DOI: 10.1073/pnas.192423399. View

Lebron J, West Jr A, Bjorkman P . The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol. 1999; 294(1):239-45. DOI: 10.1006/jmbi.1999.3252. View

Fleming R, Migas M, Zhou X, Jiang J, Britton R, Brunt E . Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci U S A. 1999; 96(6):3143-8. PMC: 15909. DOI: 10.1073/pnas.96.6.3143. View

Cardoso C, de Sousa M . HFE, the MHC and hemochromatosis: paradigm for an extended function for MHC class I. Tissue Antigens. 2003; 61(4):263-75. DOI: 10.1034/j.1399-0039.2003.00065.x. View

Muckenthaler M, Roy C, Custodio A, Minana B, deGraaf J, Montross L . Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 2003; 34(1):102-7. DOI: 10.1038/ng1152. View

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

Vulpe C, Kuo Y, MURPHY T, Cowley L, Askwith C, Libina N . Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999; 21(2):195-9. DOI: 10.1038/5979. View

Riegert P, Gilfillan S, Nanda I, Schmid M, Bahram S . The mouse HFE gene. Immunogenetics. 1998; 47(2):174-7. DOI: 10.1007/s002510050344. View

10.

Rolfs A, Bonkovsky H, Kohlroser J, McNeal K, Sharma A, Berger U . Intestinal expression of genes involved in iron absorption in humans. Am J Physiol Gastrointest Liver Physiol. 2002; 282(4):G598-607. DOI: 10.1152/ajpgi.00371.2001. View

11.

Ajioka R, Levy J, Andrews N, Kushner J . Regulation of iron absorption in Hfe mutant mice. Blood. 2002; 100(4):1465-9. DOI: 10.1182/blood-2001-11-0037. View

12.

Zhang Y, Buchholz F, Muyrers J, Stewart A . A new logic for DNA engineering using recombination in Escherichia coli. Nat Genet. 1998; 20(2):123-8. DOI: 10.1038/2417. View

13.

Canonne-Hergaux F, Levy J, Fleming M, Montross L, Andrews N, Gros P . Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders. Blood. 2001; 97(4):1138-40. DOI: 10.1182/blood.v97.4.1138. View

14.

Zoller H, Pietrangelo A, Vogel W, Weiss G . Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet. 1999; 353(9170):2120-3. DOI: 10.1016/S0140-6736(98)11179-0. View

15.

Zoller H, Koch R, Theurl I, Obrist P, Pietrangelo A, Montosi G . Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology. 2001; 120(6):1412-9. DOI: 10.1053/gast.2001.24033. View

16.

Ganz T . Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003; 102(3):783-8. DOI: 10.1182/blood-2003-03-0672. View

17.

Bridle K, Frazer D, Wilkins S, Dixon J, Purdie D, Crawford D . Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003; 361(9358):669-73. DOI: 10.1016/S0140-6736(03)12602-5. View

18.

Raja K, Pountney D, Bomford A, Przemioslo R, Sherman D, Simpson R . A duodenal mucosal abnormality in the reduction of Fe(III) in patients with genetic haemochromatosis. Gut. 1996; 38(5):765-9. PMC: 1383162. DOI: 10.1136/gut.38.5.765. View

19.

Levy J, Montross L, Cohen D, Fleming M, Andrews N . The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood. 1999; 94(1):9-11. View

20.

Feder J, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy D, Basava A . A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996; 13(4):399-408. DOI: 10.1038/ng0896-399. View