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MUCOSAL BIOLOGY

Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3

¹School of Medicine and Pharmacology and ²Western Australian Institute for Medical Research, Fremantle Hospital; ³School of Biomedical and Chemical Sciences; ⁴Laboratory for Cancer Medicine, Centre for Medical Research, Western Australian Institute for Medical Research and ⁵School of Medicine and Pharmacology, Royal Perth Hospital, The University of Western Australia, Perth, Western Australia, Australia; and Departments of ⁶Pediatrics and ⁷Internal Medicine, St. Louis University School of Medicine, St. Louis, Missouri

Submitted 22 June 2006 ; accepted in final form 21 August 2006

Hereditary hemochromatosis 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 hereditary hemochromatosis type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo by ⁵⁹Fe-labeled 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 nonheme 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 of 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 gene 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.

hereditary hemochromatosis; iron metabolism; liver iron overload and transferrin receptor 2; hepcidin

This article has been cited by other articles:

				D. F. Wallace, L. Summerville, E. M. Crampton, and V. N. Subramaniam Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis Am J Physiol Cell Physiol, February 1, 2008; 294(2): C383 - C390. [Abstract] [Full Text] [PDF]

				L. Lin, E. V. Valore, E. Nemeth, J. B. Goodnough, V. Gabayan, and T. Ganz Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4 Blood, September 15, 2007; 110(6): 2182 - 2189. [Abstract] [Full Text] [PDF]