Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)

TLDR

Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated, with the liver‑derived peptide hepcidin acting as a key regulator of iron absorption and homeostasis that is increased by iron overload and decreased by anemia and hypoxia, though the underlying mechanisms remain unknown. The study aims to establish the von Hippel–Lindau/hypoxia‑inducible transcription factor (VHL/HIF) pathway as a critical link between iron homeostasis and hepcidin regulation in vivo. The VHL‑HIF pathway mobilizes iron by simultaneously downregulating hepcidin and upregulating erythropoietin and ferroportin to support erythrocyte production. The authors demonstrate that the VHL‑HIF pathway is essential for linking iron homeostasis to hepcidin regulation in vivo.

Abstract

Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel–Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.