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

• Published in: The Journal of clinical investigation Vol. 117; no. 7; pp. 1926 - 1932
• Main Authors: Peyssonnaux, Carole, Zinkernagel, Annelies S, Schuepbach, Reto A, Rankin, Erinn, Vaulont, Sophie, Haase, Volker H, Nizet, Victor, Johnson, Randall S
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2007
• Subjects: Albumins - genetics; Albumins - metabolism; Anemia; Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Base Sequence; Biomedical research; Cation Transport Proteins - metabolism; Cloning; Diet; DNA binding proteins; Down-Regulation; Gene Deletion; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepcidins; Homeostasis; Homeostasis - drug effects; Humans; Hydrocarbons; Hypoxia; Hypoxia-Inducible Factor 1 - deficiency; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Integrases - genetics; Integrases - metabolism; Iron; Iron - pharmacology; Iron in the body; Liver; Liver - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Peptides; Physiological aspects; Polycythemia - genetics; Polycythemia - metabolism; Polycythemia - pathology; Promoter Regions, Genetic - genetics; Protein Binding; Transcription factors; Transgenic animals; Up-Regulation; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; France; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci31370

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.