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1 Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Perth, Western Australia, Australia
2 Biomedical and Chemical Sciences, University of Western Australia, Perth, Western Australia, Australia
3 Perth, Western Australia, Australia; Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Perth, Western Australia, Australia
4 Laboratory for Cancer Medicine, Centre for Medical Research, Western Australian Institute for Medical Research, University of Western Australia, Western Australia, Australia; Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia
5 Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, United States
6 Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States
7 Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Perth, Western Australia, Australia; Western Australia Institute for Medical Research, Perth, Western Australia, Australia
* To whom correspondence should be addressed. E-mail: dtrinder{at}cyllene.uwa.edu.au.
Hereditary hemochromatosis (HH) type 3 is an iron (Fe) overload disorder caused by mutations in transferrin receptor 2 (TfR2). TfR2 is expressed highly in the liver and regulates Fe metabolism. The aim of this study was to investigate duodenal Fe absorption and hepatic Fe uptake in a TfR2 (Y245X) mutant mouse model of HH type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo using 59Fe-ascorbate in TfR2 mutant mice, wild-type mice, and Fe-loaded wild-type mice (2% dietary carbonyl Fe). Gene expression was measured by real-time RT-PCR. Liver non-heme Fe concentration increased progressively with age in TfR2 mutant mice compared with wild-type mice. Fe absorption (both duodenal Fe uptake and transfer) was increased in TfR2 mutant mice compared with wild-type mice. Likewise, expression of genes participating in duodenal Fe uptake (Dcytb, DMT1) and transfer (ferroportin) were increased in TfR2 mutant mice. Nearly all the absorbed Fe was taken up rapidly by the liver. Despite hepatic Fe loading, hepcidin expression was decreased in TfR2 mutant mice compared with wild-type mice. Even when compared with Fe-loaded wild-type mice, TfR2 mutant mice had increased Fe absorption, increased duodenal Fe transport genes expression, increased liver Fe uptake, and decreased liver hepcidin expression. In conclusion, despite systemic Fe loading, Fe absorption and liver Fe uptake were increased in TfR2 mutant mice in association with decreased expression of hepcidin. These findings support a model in which TfR2 is a sensor of Fe status and regulates duodenal Fe absorption and liver Fe uptake.
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