Hypoxia Inducible Factor-2a Is Translationally Repressed in Response to Dietary Iron Deficiency in Sprague-Dawley Rats

Abstract

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-α contains an IRE and undergoes iron-dependent regulation in vitro, though the translational regulation of HIF-2α in vivo remains unknown. To examine HIF-2α translational regulation in vivo, we evaluated the effects of iron deficiency on the regulation of hepatic IRP activity and HIF-2α 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-2α repression (P < 0.05). In agreement with a decrease in translation, the levels of HIF-2α proteins were also decreased. The relative abundance of HIF-2α mRNA did not differ between treatment groups. Taken together, these results suggest that the translation of HIF-2α 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.

Differential contribution of key metabolic substrates and cellular oxygen in HIF signalling

“…Transcription is regulated by NF-κB [5] and numerous epigenetic factors [6], including microRNAs miR-155 [7], miR-199a [8], miR-30c-2-3p and miR30a-3p [9]. Translation is up-regulated through the Akt and Erk pathways [10], and inhibited by iron regulatory proteins IRP1/2 [11,12] and small regulatory molecules [13], interacting with the iron regulatory element in 5'-UTR of HIF-2α mRNA. AMPK decreases HIF-α production [14], and also orchestrates cellular response to energy stress in a HIF-independent manner [15,16].…”

Hypoxia-Inducible Factors Link Iron Homeostasis and Erythropoiesis

“…An in vivo study reported that iron deficiency in liver significantly increased activity of IRP1 and IRP2, and thereby decreased translation of HIF2a mRNA 108 . Two recent studies demonstrated the importance of IRPs in Hif2a regulation using knockout mice.…”

IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation

“…Iron deficiency may further increase this fraction, as suggested by dietary experiments in rats 34 and by the recently reported translational repression of HIF2a mRNA in rat livers. 35 This response would further reduce Epo expression and erythropoietic activity under iron-limiting conditions. Hypoxia or increased iron supply favor conversion of apo-to [4Fe-4S]-IRP1, which acts as cytosolic aconitase and fails to bind to HIF2a mRNA, allowing HIF2a synthesis.…”