Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis
| Autor: | Stéphanie Delga, Maria Mastrogiannaki, Carole Peyssonnaux, Pavle Matak, Jacques Mathieu, Patrick Mayeux, Sophie Vaulont |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Primary Cell Culture Biology 03 medical and health sciences Mice 0302 clinical medicine Hepcidins Hepcidin hemic and lymphatic diseases Internal medicine Oxygen homeostasis medicine Basic Helix-Loop-Helix Transcription Factors Animals Erythropoiesis Erythropoietin 030304 developmental biology Regulation of gene expression Food Formulated Mice Knockout 0303 health sciences Hematology Iron Deficiencies Hypoxia-Inducible Factor 1 alpha Subunit Antibodies Neutralizing HIF1A Endocrinology Hypoxia-inducible factors Gene Expression Regulation Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis Knockout mouse biology.protein Hepatocytes Female Original Articles and Brief Reports medicine.drug Antimicrobial Cationic Peptides Signal Transduction |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 |
| Popis: | 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-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. |
| Databáze: | OpenAIRE |
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