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 2

Albumin-Cre/VHLflox/flox mice develop erythrocytosis and iron deficiency.

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Albumin-Cre/VHLflox/flox mice develop erythrocytosis and iron deficienc...
(A) WT and Albumin-Cre/VHLflox/flox (VHL–/–) mice (4 weeks old). Right: Spleen and liver weights of 3- to 4-week-old WT and Albumin-Cre/VHLflox/flox mice (n = 8 in each group). (B) H&E stainings of liver sections from WT and Albumin-Cre/VHLflox/flox mice. Solid arrow indicates steatosis, dashed arrow inflammatory cell infiltrate. (C) EPO mRNA expression in kidney and liver of WT (black bars) and Albumin-Cre/VHLflox/flox (gray bars) mice by real-time RT-PCR (n = 8). EPO, rbc, hematocrit, and hemoglobin levels in blood or serum from 5-week-old mice. n = 8 in each group. (D) Peripheral blood smears from WT and Albumin-Cre/VHLflox/flox mice. Solid arrow indicates hypochromasia, dashed arrow anisocytosis. Right: mean corpuscular hemoglobin (MCH) of WT and Albumin-Cre/VHLflox/flox mice. Original magnification, ×200. (E) Quantification of liver iron level in WT and Albumin-Cre/VHLflox/flox mice using the method of Torrance et al. (33) (n = 5 in each group). (F) Western blot analysis of ferritin in liver extracts from WT and Albumin-Cre/VHLflox/flox mice. (G) Iron staining of splenic sections by Perls Prussian blue. Original magnification, ×200.