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The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells
Journal article   Peer reviewed

The role of transferrin receptor 1 and 2 in transferrin-bound iron uptake in human hepatoma cells

C.E. Herbison, K. Thorstensen, A.C.G. Chua, R.M. Graham, P. Leedman, J.K. Olynyk and D. Trinder
American Journal of Physiology: Cell Physiology, Vol.297(6), pp.C1567-C1575
2009
DOI: https://doi.org/10.1152/ajpcell.00649.2008
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Abstract

Transferrin receptor (TFR) 1 and 2 are expressed in the liver; TFR1 levels are regulated by cellular iron levels while TFR2 levels are regulated by transferrin saturation. The aims of this study were to 1) determine the relative importance of TFR1 and TFR2 in transferrin-bound iron (TBI) uptake by HuH7 human hepatoma cells and 2) characterize the role of metal-transferrin complexes in the regulation of these receptors. TFR expression was altered by 1) incubation with metal-transferrin (Tf) complexes, 2) TFR1 and TFR2 small interfering RNA knockdown, and 3) transfection with a human TFR2 plasmid. TBI uptake was measured using (59)Fe-(125)I-labeled Tf and mRNA and protein expression by real-time PCR and Western blot analysis, respectively. Fe(2)Tf, Co(2)Tf, and Mn(2)Tf increased TFR2 protein expression, indicating that the upregulation was not specifically regulated by iron-transferrin but also other metal-transferrins. In addition, Co(2)Tf and Mn(2)Tf upregulated TFR1, reduced ferritin, and increased hypoxia-inducible factor-1alpha protein expression, suggesting that TFR1 upregulation was due to a combination of iron deficiency and chemical hypoxia. TBI uptake correlated with changes in TFR1 but not TFR2 expression. TFR1 knockdown reduced iron uptake by 80% while TFR2 knockdown did not affect uptake. At 5 microM transferrin, iron uptake was not affected by combined TFR1 and TFR2 knockdown. Transfection with a hTFR2 plasmid increased TFR2 protein expression, causing a 15-20% increase in iron uptake and ferritin levels. This shows for the first time that TFR-mediated TBI uptake is mediated primarily via TFR1 but not TFR2 and that a high-capacity TFR-independent pathway exists in hepatoma cells.

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Collaboration types
Domestic collaboration
International collaboration
Citation topics
1 Clinical & Life Sciences
1.184 Physiology & Metals
1.184.573 Iron Metabolism
Web Of Science research areas
Cell Biology
Physiology
ESI research areas
Molecular Biology & Genetics
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