Anemic copper-deficient rats, but not mice, display low hepcidin expression and high ferroportin levels.
The transmembrane protein ferroportin (Fpn) is essential for iron efflux from the liver, spleen, and duodenum. Fpn is regulated predominantly by the circulating iron regulatory hormone hepcidin, which binds to cell surface Fpn, initiating its degradation. Accordingly, when hepcidin concentrations decrease, Fpn levels increase. A previous study found that Fpn levels were not elevated in copper-deficient (CuD) mice that had anemia, a condition normally associated with dramatic reductions in hepcidin. Lack of change in Fpn levels may be because CuD mice do not display reduced concentrations of plasma iron (holotransferrin), a modulator of hepcidin expression. Here, we examined Fpn protein levels and hepcidin expression in CuD rats, which exhibit reduced plasma iron concentrations along with anemia. We also examined hepcidin expression in anemic CuD mice with normal plasma iron levels. We found that CuD rats had higher liver and spleen Fpn levels and markedly lower hepatic hepcidin mRNA expression than did copper-adequate (CuA) rats. In contrast, hepcidin levels did not differ between CuD and CuA mice. To examine potential mediators of the reduced hepcidin expression in CuD rats, we measured levels of hepatic transferrin receptor 2 (TfR2), a putative iron sensor that links holotransferrin to hepcidin production, and transcript abundance of bone morphogenic protein 6 (BMP6), a key endogenous positive regulator of hepcidin production. Diminished hepcidin expression in CuD rats was associated with lower levels of TfR2, but not BMP6. Our data suggest that holotransferrin and TfR2, rather than anemia or BMP6, are signals for hepcidin synthesis during copper deficiency.
Jenkitkasemwong
Supak
S
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA.
Broderius
Margaret
M
Nam
Hyeyoung
H
Prohaska
Joseph R
JR
Knutson
Mitchell D
MD
D000740:Anemia / Q000150:complications*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D064451:Hepcidins; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; C578703:Hamp protein, rat; D064451:Hepcidins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C548977:Tfr2 protein, rat; D000098742:Ferroportin; D003300:Copper; D007501:Iron; D002570:Ceruloplasmin