DOI: 10.1073/pnas.96.6.3143. Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1

Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1

10.1073/pnas.96.6.3143

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE −/− mice have increased duodenal expression of the divalent metal transporter (DMT1). By 4 weeks of age, the HFE −/− mice demonstrated iron loading when compared with HFE +/+ littermates, with elevated transferrin saturations (68.4% vs. 49.8%) and elevated liver iron concentrations (985 μg/g vs. 381 μg/g). By using Northern blot analyses, we quantitated duodenal expression of both classes of DMT1 transcripts: one containing an iron responsive element (IRE), called DMT1(IRE), and one containing no IRE, called DMT1(non-IRE). The positive control for DMT1 up-regulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMT1(IRE) mRNA. HFE −/− mice also demonstrated an increase in duodenal DMT1(IRE) mRNA (average 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data support the model for HH in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1(IRE) mRNA, up-regulation of DMT1, and increased absorption of dietary iron.

Bibliography

Fleming, R. E., Migas, M. C., Zhou, X., Jiang, J., Britton, R. S., Brunt, E. M., Tomatsu, S., Waheed, A., Bacon, B. R., & Sly, W. S. (1999). Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1. Proceedings of the National Academy of Sciences, 96(6), 3143â3148.

Authors 10

Robert E. Fleming (first)
Mary C. Migas (additional)
XiaoYan Zhou (additional)
Jinxing Jiang (additional)
Robert S. Britton (additional)
Elizabeth M. Brunt (additional)
Shunji Tomatsu (additional)
Abdul Waheed (additional)
Bruce R. Bacon (additional)
William S. Sly (additional)

References 46 Referenced 215

10.1073/pnas.96.4.1579
10.1182/blood.V74.6.2187.bloodjournal7462187
P M Smith, B E Godfrey, R Williams Clin Sci 37, 519–531 (1969). / Clin Sci by Smith P M (1969)
G D McLaren, M H Nathanson, A Jacobs, D Trevett, W Thomson J Lab Clin Med 117, 390–401 (1991). / J Lab Clin Med by McLaren G D (1991)
10.1136/gut.11.9.727
10.1056/NEJM197907263010402
10.1111/j.1600-0609.1989.tb01200.x
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10.1093/nar/13.5.1431
J D Torrance, T H Bothwell Methods Haematol 1, 90–115 (1980). / Methods Haematol by Torrance J D (1980)
J Fielding Methods Haematol 1, 15–43 (1980). / Methods Haematol by Fielding J (1980)
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McLaren G. D. (1989) J. Lab. Clin. Med. 137–138.

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:39 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:58 p.m.)
Indexed	1 month, 3 weeks ago (July 7, 2025, 2:27 a.m.)
Issued	26 years, 5 months ago (March 16, 1999)
Published	26 years, 5 months ago (March 16, 1999)
Published Online	26 years, 5 months ago (March 16, 1999)
Published Print	26 years, 5 months ago (March 16, 1999)

Funders 0

None

BibTeX

@article{Fleming_1999, title={Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1}, volume={96}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.96.6.3143}, DOI={10.1073/pnas.96.6.3143}, number={6}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Fleming, Robert E. and Migas, Mary C. and Zhou, XiaoYan and Jiang, Jinxing and Britton, Robert S. and Brunt, Elizabeth M. and Tomatsu, Shunji and Waheed, Abdul and Bacon, Bruce R. and Sly, William S.}, year={1999}, month=mar, pages={3143–3148} }

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        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
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      "order": 2,
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      "group": {
        "name": "publication_history",
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    }
  ]
}