Iron regulatory proteins (IRP) regulate cellular iron metabolism by binding to iron-responsive elements (IRE) located in untranslated regions of mRNA-encoding proteins of iron metabolism. Recently, IRE have been identified in mRNA-encoding proteins with previously uncharacterized roles in iron metabolism, thus expanding the role of IRP beyond the regulation of cellular iron homeostasis. The mRNA for HIF 2-alpha contains an IRE and undergoes iron-dependent regulation in vitro, though the translational regulation of HIF-2alpha in vivo remains unknown. To examine HIF-2alpha translational regulation in vivo, we evaluated the effects of iron deficiency on the regulation of hepatic IRP activity and HIF-2alpha translation. Rats were fed either a control (C; 50 mg Fe/kg diet) or iron-deficient (ID; <5 mg Fe/kg diet) diet or were pair-fed (PF) the C diet for 21 d. In ID rats, there was a 2-fold increase in IRP activity compared to the PF group (P < 0.05), which was reflected by a 30-40% increase in HIF-2alpha repression (P < 0.05). In agreement with a decrease in translation, the levels of HIF-2alpha proteins were also decreased. The relative abundance of HIF-2alpha mRNA did not differ between treatment groups. Taken together, these results suggest that the translation of HIF-2alpha in the liver is regulated in part by the action of IRP in response to dietary iron deficiency and provide evidence that IRP may assist in coordinating the cellular response to alterations in iron and oxygen status associated with iron deficiency anemia.
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