Alimentary TractIntestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis☆,☆☆
Section snippets
HFE-knockout mice
Mice deficient in HFE were generated by targeted disruption of the murine HFE gene in the region of the C282Y mutation in embryonic stem cells.20 The mutant allele, following embryo transfer, was bred to homozygosity on an svj-129 wild-type background from which the offspring were maintained on regular pelleted chow after weaning. Congenic strain wild-type mice (Central Biomedical Services, University of Cambridge, England) were housed and maintained under identical conditions. Animals were
Results
Uptake of 18 μmol/L ferrous and ferric iron by intestinal mucosa was linear over the first 20 minutes of incubation. Uptake was significantly inhibited by preexposure to 10 mmol/L sodium fluoride and 0.1 mmol/L 2,4-dinitrophenol (which inhibit glycolysis and the respiratory chain, respectively), confirming the energy dependence of the iron uptake process. Acidification of the incubation medium to pH 5.5 with acetate enhanced uptake of 18 μmol/L ferrous iron (12.5 ± 1.6 vs. 4.7 ± 0.4 pmol · mg−1
Discussion
Living organisms have acquired mechanisms to take up, transport, and store iron that also function to protect them from its toxic effects.27 Transport of iron in the circulation, its entry into cells, and intracellular storage have long been described in humans.28 However, the molecular physiology of the capture of dietary iron within the lumen of the proximal small intestine, its principal site of absorption, has not been subject to detailed experimental investigation. DMT1 is a strong
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Address requests for reprints to: Timothy M. Cox, M. D., Department of Medicine, Level 5, Addenbrooke's Hospital, Cambridge, CB2 2QQ, England. e-mail: [email protected]; fax: (44) 1223 336846.
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Supported by a training fellowship award from the Wellcome Trust (W.J.H.G.), a Sackler Award (W.J.H.G.), and in part from the European Union (EU BIOMED, BMH 4 -CT 96-0994), the Grocer's Charity, and the Peel Medical Research Trust.