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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1519-1525. Prepublished online as a Blood First Edition Paper on May 20, 2004; DOI 10.1182/blood-2003-11-3872. This Article Full Text (PDF) All Versions of this Article: 2003-11-3872v1 104/5/1519    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chua, A. C Articles by Trinder, D. Search for Related Content PubMed PubMed Citation Articles by Chua, A. C Articles by Trinder, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 13, 2003 Accepted May 4, 2004 Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis Anita C Chua, John K Olynyk, Peter L Leedman, and Debbie Trinder* Department of Medicine, School of Medicine and Pharmacology, Fremantle Hospital, The University of Western Australia, Fremantle, Western Australia, Australia Department of Medicine, School of Medicine and Pharmacology, Fremantle Hospital, The University of Western Australia, Fremantle, Western Australia, Australia; Western Australian Institute for Medical Research, Nedlands, Western Australia, Australia Laboratory of Cancer Medicine, School of Medicine and Pharmacology, Western Australian Institute for Medical Research, Royal Perth Hospital,, The University of Western Australia, Perth, Western Australia, Australia * Corresponding author; email: dtrinder{at}cyllene.uwa.edu.au. Hereditary hemochromatosis (HH) is an iron overload disorder caused by a C282Y mutation in the HFE gene. In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate. The aim of this study was to examine the importance of NTBI in the pathogenesis of hepatic iron loading in Hfe knockout mice. Plasma NTBI levels were increased 2.5-fold in Hfe knockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1±2.8 pmol Fe/mg protein/min) increased by two-fold compared with control mice (17.8±2.7 pmol Fe/mg protein/min;p<0.001; mean±SEM; n=7). Ferrous ion chelators, bathophenanthroline disulfonate and 2',2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types. Divalent metal ions inhibited ferric citrate uptake by hepatocytes, as did diferric transferrin. Divalent metal transporter 1 (DMT1) mRNA and protein expression was increased approximately two-fold by hepatocytes from Hfe knockout mice. We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading. Ferric ion was reduced to ferrous ion and taken up by hepatocytes by a pathway shared with diferric transferrin. Inhibition of uptake by divalent metals and up-regulation of DMT1 expression suggested that NTBI uptake was mediated by DMT1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. E. Herbison, K. Thorstensen, A. C. G. Chua, R. M. Graham, P. Leedman, J. K. Olynyk, and D. Trinder The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells Am J Physiol Cell Physiol, December 1, 2009; 297(6): C1567 - C1575. [Abstract] [Full Text] [PDF] J. Gao, N. Zhao, M. D. Knutson, and C. A. Enns The Hereditary Hemochromatosis Protein, HFE, Inhibits Iron Uptake via Down-regulation of Zip14 in HepG2 Cells J. Biol. Chem., August 1, 2008; 283(31): 21462 - 21468. [Abstract] [Full Text] [PDF] S. F. Drake, E. H. Morgan, C. E. Herbison, R. Delima, R. M. Graham, A. C. G. Chua, P. J. Leedman, R. E. Fleming, B. R. Bacon, J. K. Olynyk, et al. Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3 Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G323 - G328. [Abstract] [Full Text] [PDF] C. Chaudhury, J. Kim, S. Mehnaz, M. A. Wani, T. M. Oberyszyn, C. L. Bronson, S. Mohanty, W. L. Hayton, J. M. Robinson, and C. L. Anderson Accelerated Transferrin Degradation in HFE-Deficient Mice Is Associated with Increased Transferrin Saturation J. Nutr., December 1, 2006; 136(12): 2993 - 2998. [Abstract] [Full Text] [PDF] J. P. Liuzzi, F. Aydemir, H. Nam, M. D. Knutson, and R. J. Cousins Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells PNAS, September 12, 2006; 103(37): 13612 - 13617. [Abstract] [Full Text] [PDF] R. S. Ohgami, D. R. Campagna, A. McDonald, and M. D. Fleming The Steap proteins are metalloreductases Blood, August 15, 2006; 108(4): 1388 - 1394. [Abstract] [Full Text] [PDF] I. T. Mak, J. J. Chmielinska, L. Nedelec, A. Torres, and W. B. Weglicki D-Propranolol Attenuates Lysosomal Iron Accumulation and Oxidative Injury in Endothelial Cells J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 522 - 528. [Abstract] [Full Text] [PDF]

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