Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis.
Transferrin receptor 2 (TfR2) is a membrane glycoprotein that mediates cellular iron uptake from holotransferrin. Homozygous mutations of this gene cause one form of hereditary hemochromatosis in humans. We recently reported that homozygous TfR2(Y245X) mutant mice, which correspond to the TfR2(Y250X) mutation in humans, showed a phenotype similar to hereditary hemochromatosis. In this study, we further analyzed the phenotype as well as iron-related gene expression in these mice by comparing the TfR2-mutant and wild-type siblings. Northern blot analyses showed that the levels of expression of hepcidin mRNA in the liver were generally lower, whereas those of duodenal DMT1, the main transporter for uptake of dietary iron, were higher in the TfR2-mutant mice as compared to the wild-type siblings. Expression of hepcidin mRNA in the TfR2 mutant mice remained low even after intraperitoneal iron loading. In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA. These results suggest that up-regulation of hepcidin expression by inflammatory stimuli is independent of TfR2 and that TfR2 is upstream of hepcidin in the regulatory pathway of body iron homeostasis.
Kawabata
Hiroshi
H
Division of Hematology/Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. hkawabat@kanazawa-med.ac.jp
Fleming
Robert E
RE
Gui
Dorina
D
Moon
Seo Y
SY
Saitoh
Takayuki
T
O'Kelly
James
J
Umehara
Yutaka
Y
Wano
Yuji
Y
Said
Jonathan W
JW
Koeffler
H Phillip
HP
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004386:Duodenum / Q000378:metabolism; D005260:Female; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D064451:Hepcidins; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D007501:Iron; D033862:Iron-Binding Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D014443:Tyrosine; D000099236:Solute Carrier Family 11, Member 2; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C503640:TFR2 protein, human; C503641:TFR2 protein, mouse