Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
Carole Peyssonnaux, Annelies S. Zinkernagel, Reto A. Schuepbach, Erinn Rankin, Sophie Vaulont, Volker H. Haase, Victor Nizet, Randall S. Johnson
Carole Peyssonnaux, Annelies S. Zinkernagel, Reto A. Schuepbach, Erinn Rankin, Sophie Vaulont, Volker H. Haase, Victor Nizet, Randall S. Johnson
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Research Article

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

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.

Authors

Carole Peyssonnaux, Annelies S. Zinkernagel, Reto A. Schuepbach, Erinn Rankin, Sophie Vaulont, Volker H. Haase, Victor Nizet, Randall S. Johnson

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Figure 1

Iron deficiency downregulates hepcidin in an HIF-1–dependent fashion.

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Iron deficiency downregulates hepcidin in an HIF-1–dependent fashion. ...
(A) Hepcidin mRNA level in livers of WT mice under regular or low-iron diet (3 weeks), determined by real-time RT-PCR. Results, normalized to 18S ribosomal RNA expression, are expressed as mean ± SD (n = 5 in each group). (B) HIF-1 expression in liver extracts of iron-starved WT mice by Western blotting. (C) Hepcidin mRNA expression in livers of WT and Albumin-Cre/HIF-1αflox/flox (HIF-1–/–) iron-starved mice by real-time RT-PCR (n = 8).