Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemochromatosis.
OBJECTIVE
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 with (59)Fe-transferrin and tissue (59)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.
School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle 6959, Western Australia, Australia.
Anita C G
AC
Chua
Roheeth D
RD
Delima
Evan H
EH
Morgan
Carly E
CE
Herbison
Janina E E
JE
Tirnitz-Parker
Ross M
RM
Graham
Robert E
RE
Fleming
Robert S
RS
Britton
Bruce R
BR
Bacon
John K
JK
Olynyk
Debbie
D
Trinder
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D027682:Cation Transport Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism*; D064451:Hepcidins; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism*; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; C480029:Tfrc protein, mouse; D014168:Transferrin; D000098742:Ferroportin; D007501:Iron