Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis

被引:136
作者
Mastrogiannaki, Maria [2 ,3 ]
Matak, Pavle [2 ,3 ]
Mathieu, Jacques R. R. [2 ,3 ]
Delga, Stephanie [2 ,3 ]
Mayeux, Patrick [2 ,3 ]
Vaulont, Sophie [2 ,3 ]
Peyssonnaux, Carole [1 ,2 ,3 ]
机构
[1] INSERM, Inst Cochin, Fac Med Cochin Port Royal, U1016, F-75014 Paris, France
[2] CNRS, UMR8104, Paris, France
[3] Univ Paris 05, Paris, France
来源
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL | 2012年 / 97卷 / 06期
基金
欧洲研究理事会;
关键词
hepatic HIF-2; hepcidin expression; erythropoiesis; IRON-HOMEOSTASIS; SOLUBLE HEMOJUVELIN; PEPTIDE HEPCIDIN; GENE-EXPRESSION; C/EBP-ALPHA; MOUSE-LIVER; HUMAN-CELLS; TMPRSS6; PATHWAYS; ANEMIA;
D O I
10.3324/haematol.2011.056119
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:827 / 834
页数:8
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