The role of Hfe in transferrin-bound iron uptake by hepatocytes

Authors

  • Anita C.G. Chua,

    1. School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, Western Australia, Australia
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  • Carly E. Herbison,

    1. School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, Western Australia, Australia
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  • Sarah F. Drake,

    1. School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, Western Australia, Australia
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  • Ross M. Graham,

    1. School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, Western Australia, Australia
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  • John K. Olynyk,

    1. School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, Western Australia, Australia
    2. Western Australian Institute for Medical Research, Western Australia, Australia
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  • Debbie Trinder

    Corresponding author
    1. School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, Western Australia, Australia
    2. Western Australian Institute for Medical Research, Western Australia, Australia
    • School of Medicine and Pharmacology, The University of Western Australia, Fremantle Hospital, PO Box 480, Fremantle 6959, Western Australia, Australia
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    • fax: (618)-94312977.


  • Potential conflict of interest: Nothing to report.

Abstract

HFE-related hereditary hemochromatosis results in hepatic iron overload. Hepatocytes acquire transferrin-bound iron via transferrin receptor (Tfr) 1 and Tfr1-independent pathways (possibly Tfr2-mediated). In this study, the role of Hfe in the regulation of hepatic transferrin-bound iron uptake by these pathways was investigated using Hfe knockout mice. Iron and transferrin uptake by hepatocytes from Hfe knockout, non–iron-loaded and iron-loaded wild-type mice were measured after incubation with 50 nM 125I-Tf-59Fe (Tfr1 pathway) and 5 μM 125I-Tf-59Fe (Tfr1-independent or putative Tfr2 pathway). Tfr1 and Tfr2 messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and western blotting, respectively. Tfr1-mediated iron and transferrin uptake by Hfe knockout hepatocytes were increased by 40% to 70% compared with iron-loaded wild-type hepatocytes with similar iron levels and Tfr1 expression. Iron and transferrin uptake by the Tfr1-independent pathway was approximately 100-fold greater than by the Tfr1 pathway and was not affected by the absence of Hfe. Diferric transferrin increased hepatocyte Tfr2 protein expression, resulting in a small increase in transferrin but not iron uptake by the Tfr1-independent pathway. Conclusion: Tfr1-mediated iron uptake is regulated by Hfe in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by Hfe. Diferric transferrin up-regulated hepatocyte Tfr2 protein expression but not iron uptake, suggesting that Tfr2 may have a limited role in the Tfr1-independent pathway. (HEPATOLOGY 2008.)

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