The Role of Hfe in Transferrin-Bound Iron Uptake by Hepatocytes

A.C.G. Chua, C.E. Herbison, S.F. Drake, Ross Graham, John Olynyk, Debbie Trinder

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    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 We 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 I-125-Tf-Fe-59 (Tfr1 pathway) and 5 mu M I-125-Tf-Fe-59 (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 We in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by We. 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.
    Original languageEnglish
    Pages (from-to)1737-1744
    JournalHepatology
    Volume47
    Issue number5
    DOIs
    Publication statusPublished - 2008

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    Transferrin
    Hepatocytes
    Iron
    Proteins
    Transferrin Receptors
    Iron Overload
    Hemochromatosis
    Liver
    Knockout Mice
    Real-Time Polymerase Chain Reaction
    Western Blotting

    Cite this

    Chua, A.C.G. ; Herbison, C.E. ; Drake, S.F. ; Graham, Ross ; Olynyk, John ; Trinder, Debbie. / The Role of Hfe in Transferrin-Bound Iron Uptake by Hepatocytes. In: Hepatology. 2008 ; Vol. 47, No. 5. pp. 1737-1744.
    @article{37bdddc3b6ea43c7a5ec90595d8159e7,
    title = "The Role of Hfe in Transferrin-Bound Iron Uptake by Hepatocytes",
    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 We 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 I-125-Tf-Fe-59 (Tfr1 pathway) and 5 mu M I-125-Tf-Fe-59 (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 We in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by We. 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.",
    author = "A.C.G. Chua and C.E. Herbison and S.F. Drake and Ross Graham and John Olynyk and Debbie Trinder",
    year = "2008",
    doi = "10.1002/hep.22180",
    language = "English",
    volume = "47",
    pages = "1737--1744",
    journal = "Hepatology",
    issn = "0270-9139",
    publisher = "John Wiley & Sons",
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    Chua, ACG, Herbison, CE, Drake, SF, Graham, R, Olynyk, J & Trinder, D 2008, 'The Role of Hfe in Transferrin-Bound Iron Uptake by Hepatocytes' Hepatology, vol. 47, no. 5, pp. 1737-1744. https://doi.org/10.1002/hep.22180

    The Role of Hfe in Transferrin-Bound Iron Uptake by Hepatocytes. / Chua, A.C.G.; Herbison, C.E.; Drake, S.F.; Graham, Ross; Olynyk, John; Trinder, Debbie.

    In: Hepatology, Vol. 47, No. 5, 2008, p. 1737-1744.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The Role of Hfe in Transferrin-Bound Iron Uptake by Hepatocytes

    AU - Chua, A.C.G.

    AU - Herbison, C.E.

    AU - Drake, S.F.

    AU - Graham, Ross

    AU - Olynyk, John

    AU - Trinder, Debbie

    PY - 2008

    Y1 - 2008

    N2 - 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 We 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 I-125-Tf-Fe-59 (Tfr1 pathway) and 5 mu M I-125-Tf-Fe-59 (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 We in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by We. 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.

    AB - 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 We 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 I-125-Tf-Fe-59 (Tfr1 pathway) and 5 mu M I-125-Tf-Fe-59 (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 We in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by We. 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.

    U2 - 10.1002/hep.22180

    DO - 10.1002/hep.22180

    M3 - Article

    VL - 47

    SP - 1737

    EP - 1744

    JO - Hepatology

    JF - Hepatology

    SN - 0270-9139

    IS - 5

    ER -