Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).
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.
Peyssonnaux
Carole
C
Molecular Biology Section, Division of Biological Sciences, UCSD School of Medicine, La Jolla, CA 92093-0377, USA.
Zinkernagel
Annelies S
AS
Schuepbach
Reto A
RA
Rankin
Erinn
E
Vaulont
Sophie
S
Haase
Volker H
VH
Nizet
Victor
V
Johnson
Randall S
RS
D000418:Albumins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000378:metabolism; D015536:Down-Regulation; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D064451:Hepcidins; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
D000418:Albumins; D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D051793:Hypoxia-Inducible Factor 1; D000098742:Ferroportin; D007501:Iron; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C045073:Cre recombinase; D019426:Integrases