期刊
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
卷 97, 期 6, 页码 827-834出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2011.056119
关键词
hepatic HIF-2; hepcidin expression; erythropoiesis
类别
资金
- Agence Nationale pour la Recherche [ANR-08-JCJC-0123, ANR-08-GENO]
- European Research Council under the European Community [261296]
- Association pour la Recherche sur le Cancer (ARC)
- European Research Council (ERC) [261296] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-08-JCJC-0123] Funding Source: Agence Nationale de la Recherche (ANR)
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. Design and Methods We generated and analyzed hepatocyte-specific knockout mice harboring either hypoxia-inducible factor-2 alpha deficiency (Hif2a knockout) or constitutive hypoxia-inducible factor-2 alpha 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.
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