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Duodenal HFE expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability

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Abstract

HFE affects the interaction of transferrin bound iron with transferrin receptors (TfR) thereby modulating iron uptake. To study genetically determined differences in HFE expression we examined individual HFE levels in C57BL/Sv129 mice and assessed their relationship to the regulation of iron homeostasis in the duodenum and the liver, and their regulation by diet. We found an up to 14-fold variation in inter-individual expression of HFE mRNA in the duodenum. Mice with high duodenal HFE mRNA expression presented with significantly higher levels of TfR and DMT-1 mRNAs and an increased IRP-1 binding affinity as compared to mice with low HFE levels. Duodenal HFE expression was positively associated with serum iron and liver HFE levels. Dietary iron supplementation decreased HFE in the duodenum but not in the liver. This was paralleled by reduced amounts of DMT-1 and FP-1 in the duodenum while the expression of DMT-1, FP-1, and hepcidin in the liver were increased with dietary iron overload. Duodenal and liver HFE levels are regulated by divergent penetration of as yet unelucidated modifier genes and to a much lesser extent by dietary iron. These measures control duodenal iron transport and liver iron homeostasis by modulating HFE expression either directly or via stimulation of iron sensitive regulatory molecules, such as hepcidin, which then exert their effects on body iron homeostasis.

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Acknowledgements

The authors are grateful to Yukinori Yoshida for providing the monoclonal murine ant-HFE antibody, Klaus Schümann for giving advice on iron feeding of mice, and Markus Seifert for excellent technical assistance. This work was supported by grants from the Austrian National Bank, Project 8764 and by the Austrian Research Funds, FWF-14215 and 15943.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Innsbruck, Anichstrasse 35, 6020 , Innsbruck, Austria

    Susanne Ludwiczek, Igor Theurl & Guenter Weiss

  2. Department of Medical Biochemistry, University of Innsbruck, Fritz-Preglstrasse 3, 6020 , Innsbruck, Austria

    Erika Artner-Dworzak

  3. Departments of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA

    Michael Chorney

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  1. Susanne Ludwiczek
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  2. Igor Theurl
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Correspondence to Guenter Weiss.

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Susanne Ludwiczek and Igor Theurl contributed equally to the work

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Ludwiczek, S., Theurl, I., Artner-Dworzak, E. et al. Duodenal HFE expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability. J Mol Med 82, 373–382 (2004). https://doi.org/10.1007/s00109-004-0542-3

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