Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis.
BACKGROUND
Iron metabolism, regulated by the iron hormone hepcidin, and oxygen homeostasis, dependent on hypoxia-inducible factors, are strongly interconnected. We previously reported that in mice in which both liver hypoxia-inducible factors-1 and -2 are stabilized (the hepatocyte von Hippel-Lindau knockout mouse model), hepcidin expression was strongly repressed and we hypothesized that hypoxia-inducible factor-2 could be the major regulatory component contributing to the hepcidin down-regulation.


METHODS
We generated and analyzed hepatocyte-specific knockout mice harboring either hypoxia-inducible factor-2α deficiency (Hif2a knockout) or constitutive hypoxia-inducible factor-2α stabilization (Vhlh/Hif1a knockout) and ex vivo systems (primary hepatocyte cultures). Hif2a knockout mice were fed an iron-deficient diet for 2 months and Vhlh/Hif1a knockout mice were treated with neutralizing erythropoietin antibody.


RESULTS
We demonstrated that hypoxia-inducible factor-2 is dispensable in hepcidin gene regulation in the context of an adaptive response to iron-deficiency anemia. However, its overexpression in the double Vhlh/Hif1a hepatocyte-specific knockout mice indirectly down-regulates hepcidin expression through increased erythropoiesis and erythropoietin production. Experiments in primary hepatocytes confirmed the non-autonomous role of hypoxia-inducible factor-2 in hepcidin regulation.


CONCLUSIONS
While our results indicate that hypoxia-inducible factor-2 is not directly involved in hepcidin repression, they highlight the contribution of hepatic hypoxia-inducible factor-2 to the repression of hepcidin through erythropoietin-mediated increased erythropoiesis, a result of potential clinical interest.
INSERM, U1016, Institut Cochin, Paris, France. carole.peyssonnaux@inserm.fr
Maria
M
Mastrogiannaki
Pavle
P
Matak
Jacques R R
JR
Mathieu
Stéphanie
S
Delga
Patrick
P
Mayeux
Sophie
S
Vaulont
Carole
C
Peyssonnaux
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005526:Food, Formulated; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D000090463:Iron Deficiencies; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D057134:Antibodies, Neutralizing; D023181:Antimicrobial Cationic Peptides; D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C579599:Hamp protein, mouse; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse