INSERM, U1016, Institut Cochin, Paris, France.
Haematologica. 2012 Jun;97(6):827-34. doi: 10.3324/haematol.2011.056119. Epub 2011 Dec 29.
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.
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.
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.
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.
铁代谢受铁激素hepcidin 调节，氧平衡依赖于缺氧诱导因子，两者紧密相连。我们之前报道过，在肝脏缺氧诱导因子-1 和 -2 都稳定的小鼠中（肝细胞 von Hippel-Lindau 敲除小鼠模型），hepcidin 的表达受到强烈抑制，我们假设缺氧诱导因子-2 可能是导致 hepcidin 下调的主要调节成分。
我们生成并分析了具有缺氧诱导因子-2α 缺乏（Hif2a 敲除）或组成型缺氧诱导因子-2α 稳定（Vhlh/Hif1a 敲除）的肝细胞特异性敲除小鼠，并进行了体外系统（原代肝细胞培养）分析。Hif2a 敲除小鼠喂食缺铁饮食 2 个月，Vhlh/Hif1a 敲除小鼠用中和性促红细胞生成素抗体处理。
我们证明，在缺铁性贫血适应性反应的背景下，缺氧诱导因子-2 在 hepcidin 基因调节中不是必需的。然而，在双 Vhlh/Hif1a 肝细胞特异性敲除小鼠中，其过表达通过增加红细胞生成和促红细胞生成素产生间接下调 hepcidin 表达。原代肝细胞实验证实了缺氧诱导因子-2 在 hepcidin 调节中的非自主作用。
虽然我们的结果表明缺氧诱导因子-2 不直接参与 hepcidin 的抑制，但它们突出了肝缺氧诱导因子-2 通过促红细胞生成素介导的增加红细胞生成对 hepcidin 抑制的作用，这是一个具有潜在临床意义的结果。
