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Cited by 269Iron Metabolism and DisordersNeurological diseases and metabolismTrace Elements in Health

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

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Fleming, Robert E., Migas, Mary C., Zhou, XiaoYan, Jiang, Jinxing, Britton, Robert S., Brunt, Elizabeth M., Tomatsu, Shunji, Waheed, Abdul +2 more·1999·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.96.6.3143PMC PMC15909
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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.

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  • Disruption of yeast frataxin homologue YFH1 in yeast strain Δyfh1 induced accumulation of iron in mitochondria and enhanced sensitivity to oxidative stress by H2O2 and iron overload.

    “For instance, the disruption of the yeast frataxin homologue (YFH1) in yeast strain (Δyfh1) induced an accumulation of iron in mitochondria and enhanced their sensitivity to oxidative stress (by H2O2 and iron overload) (13, 93).”

    From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [93]

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  1. [1]Waheed, A., Parkkila, S., Saarnio, J., Fleming, R. E., Zhou, X.-Y., Tomatsu, S., Britton, R. S., Bacon, B. R. & Sly, W. S. (1999) Proc. Natl. Acad. Sci. USA , 96, 1579-1584.
  2. [12]Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J. & Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. USA 95, 1475-1477.
  3. [11]Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X.-Y., Tomatsu, S., Fleming, R. E. & Sly, W. S. (1997) Proc. Natl. Acad. Sci. USA 94, 13198-13202.
  4. [21]Zhou, X.-Y., Tomatsu, S., Fleming, R. E., Parkkila, S., Waheed, A., Jiang, J., Fei, Y., Brunt, E. M., Ruddy, D. A., Prass, C. E., et al . (1998) Proc. Natl. Acad. Sci. USA 95, 2492-2497.
  5. [30]Fleming, M. D., Romano, M. A., Ma, S., Garrick, L. M., Garrick, M. D. & Andrews N. C. (1998) Proc. Natl. Acad. Sci. USA 95, 1148-1153.
  6. [39]Altstatt, L. B., Pollack, S., Feldman, M. H., Reba, R. C. & Crosby, W. H. (1967) Proc. Soc. Exp. Biol. Med. 124, 353-355.
  7. [44]Saarnio, J., Parkkila, S., Parkkila, A.-K., Waheed, A., Karttunen, T. & Sly, W. S. (1999) J. Histochem. Cytochem ., in press.
  8. [43]Parkkila, S., Waheed, A., Britton, R. S., Feder, J. N., Tsuchihashi, Z., Schatzman, R. C., Bacon, B. R. & Sly, W. S. (1997) Proc. Natl. Acad. Sci. USA 94, 2534-2539.

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Authors
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.
Affiliations
  • Saint Louis University (US)
  • Department of Pediatrics, Edward A. Doisy Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, and Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO 63104
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1999-03-16
Volume
96
Issue
6
Pages
3143-3148
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.96.6.3143
PMC
PMC15909
OpenAlex
W2089161230
Cited by
269
References
46
Citations by year
2026: 1 · 2025: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 7 · 2014: 7 · 2013: 5 · 2012: 5
FWCI
21.44
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (GM34182)
  • National Institute of General Medical Sciences (GM35182, R01GM034182)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 53405, R01DK041816, DK 41816, R01DK053405)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
Keywords
hereditary hemochromatosis, HFE gene, DMT1, iron absorption, iron-responsive element, transferrin receptor, dietary iron deficiency, iron overload, liver iron concentration, transferrin saturation, Hfe knockout mice
MeSH terms
Solute Carrier Family 11, Member 2, Animals, Carrier Proteins, Duodenum, Hemochromatosis, Iron, Mutation, Cation Transport Proteins, Iron-Binding Proteins, Mice

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