Nontransferrin-bound iron uptake by hepatocytes is increased in theHfeknockout mouse model of hereditary hemochromatosis

• Published in: Blood Vol. 104; no. 5; pp. 1519 - 1525
• Main Authors: Chua, Anita C.G., Olynyk, John K., Leedman, Peter J., Trinder, Debbie
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2004
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-11-3872

Hereditary hemochromatosis (HH) is an iron-overload disorder caused by a C282Y mutation in theHFEgene. 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 inHfeknockout mice. Plasma NTBI levels were increased 2.5-fold inHfeknockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated fromHfeknockout mice (34.1 ± 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 ± 2.7 pmol Fe/mg protein/min;P< .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 2-fold by hepatocytes fromHfeknockout mice. We conclude that NTBI uptake by hepatocytes fromHfeknockout 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.