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Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1
Open accessAbstract
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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“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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Metadata
- 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
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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