Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemochromatosis

• Published in: Journal of hepatology Vol. 52; no. 3; pp. 425 - 431
• Main Authors: Chua, Anita C.G, Delima, Roheeth D, Morgan, Evan H, Herbison, Carly E, Tirnitz-Parker, Janina E.E, Graham, Ross M, Fleming, Robert E, Britton, Robert S, Bacon, Bruce R, Olynyk, John K, Trinder, Debbie
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.03.2010; Elsevier
• Subjects: Animals; Antimicrobial Cationic Peptides - metabolism; Biological and medical sciences; Biological Transport - physiology; Cation Transport Proteins - metabolism; Disease Models, Animal; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Haemochromatosis; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hepcidins; Iron - metabolism; Iron overload; Iron transport; Liver; Liver - metabolism; Medical sciences; Metabolic diseases; Metals (hemochromatosis...); Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Other metabolic disorders; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; RNA, Messenger - metabolism; Spleen - metabolism; Transferrin - metabolism; Transferrin receptor 2; Iron overload; HH; TFR; hepcidin; BMP; Iron transport; FPN; Liver; hereditary haemochromatosis; IRP; transferrin receptor; ferroportin; bone morphogenetic protein; iron regulatory protein; HJV; haemojuvelin; iron regulatory element; Transferrin receptor 2; IRE; Hamp; Haemochromatosis; Transferrin; Hemochromatosis; Rodentia; Metabolic diseases; Iron; Enzymopathy; Uptake; Blood plasma; Vertebrata; Mammalia; Mouse; Animal; Gastroenterology; Models
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2009.12.010

Background & Aims Hereditary haemochromatosis type 3 is caused by mutations in transferrin receptor (TFR) 2. TFR2 has been shown to mediate iron transport in vitro and regulate iron homeostasis. The aim of this study was to determine the role of Tfr2 in iron transport in vivo using a Tfr2 mutant mouse. Methods Tfr2 mutant and wild-type mice were injected intravenously with59 Fe-transferrin and tissue59 Fe uptake was measured. Tfr1, Tfr2 and ferroportin expression was measured by real-time PCR and Western blot. Cellular localisation of ferroportin was determined by immunohistochemistry. Results Transferrin-bound iron uptake by the liver and spleen in Tfr2 mutant mice was reduced by 20% and 65%, respectively, whilst duodenal and renal uptake was unchanged compared with iron-loaded wild-type mice. In Tfr2 mutant mice, liver Tfr2 protein was absent, whilst ferroportin protein was increased in non-parenchymal cells and there was a low level of expression in hepatocytes. Tfr1 expression was unchanged compared with iron-loaded wild-type mice. Splenic Tfr2 protein expression was absent whilst Tfr1 and ferroportin protein expression was increased in Tfr2 mutant mice compared with iron-loaded wild-type mice. Conclusions A small reduction in hepatic transferrin-bound iron uptake in Tfr2 mutant mice suggests that Tfr2 plays a minor role in liver iron transport and its primary role is to regulate iron metabolism. Increased ferroportin expression due to decreased hepcidin mRNA levels is likely to be responsible for impaired splenic iron uptake in Tfr2 mutant mice.