Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency
Hepcidin suppression and defective iron recycling account for dysregulation of iron homeostasis in heme oxygenase-1 deficiency
复制标题
DOI：
10.1111/j.1582-4934.2008.00494.x
复制
发表时间：
2009-09-01
影响因子：
5.3
通讯作者：
Winkels, Dorine W.
中科院分区：
文献类型：
--
作者：
Kartikasari, Apriliana E. R.;Wagener, Frank A. D. T. G.;Winkels, Dorine W.
血红素加氧酶-1（HO-1）对铁稳态的贡献已经被假定，因为它通过主要从血红素催化剂中释放铁来促进铁的再循环。这种酶似乎也负责炎症状况的解决。在患有HO-1缺乏症的患者中，炎症和体内铁稳态的失调，包括贫血和肝脏和肾脏含铁血黄素沉着症，是明显的。在这里，我们假设HO-1是关键的铁转运蛋白，主要的细胞铁出口商，铁调素，铁稳态的关键调节剂在炎症性贫血的发病机制中的中心调节。我们目前在人THP-1单核细胞中的实验表明HO-1诱导的铁介导的表面铁转运蛋白表达，与HO-1在铁循环中的作用一致。令人惊讶的是，我们在HO-1缺陷患者中观察到低铁调素水平，尽管存在炎症和含铁血黄素沉着症，这两种铁调素诱导剂。相反，我们观察到高度增加的可溶性转铁蛋白受体水平。这表明HO-1缺乏症中铁调素水平的降低反映了由于贫血而导致的骨髓中对铁的需求增加。使用人肝癌细胞，我们证明HO-活性没有直接调节HAMP的表达的影响，编码铁调素的基因。因此，我们认为铁循环减少可能部分导致铁调素水平低。这些研究结果表明，铁稳态失调HO-1缺乏是铁再循环缺陷和红细胞活性相关的铁调素表达抑制的结果。因此，这项研究表明HO-1在维持体内铁平衡方面起着至关重要的作用。
Heme oxygenase-1 (HO-1) contribution to iron homeostasis has been postulated, because it facilitates iron recycling by liberating iron mostly from heme catabolism. This enzyme also appears to be responsible for the resolution of inflammatory conditions. In a patient with HO-1 deficiency, inflammation and dysregulation of body iron homeostasis, including anemia and liver and kidney hemosiderosis, are evidenced. Here we postulated that HO-1 is critical in the regulation of ferroportin, the major cellular iron exporter, and hepcidin, the key regulator of iron homeostasis central in the pathogenesis of anemia of inflammation. Our current experiments in human THP-1 monocytic cells indicate a HO-1-induced iron-mediated surface-ferroportin expression, consistent with the role of HO-1 in iron recycling. Surprisingly, we observed low hepcidin levels in the HO-1-deficient patient, despite the presence of inflammation and hemosiderosis, both inducers of hepcidin. Instead, we observed highly increased soluble transferrin receptor levels. This suggests that the decreased hepcidin levels in HO-1 deficiency reflect the increased need for iron in the bone marrow due to the anaemia. Using human hepatoma cells, we demonstrate that HO-activity did not have a direct modulating effect on expression of HAMP, the gene that encodes for hepcidin. Therefore, we argue that the decreased iron recycling may, in part, have contributed to the low hepcidin levels. These findings indicate that dysregulation of iron homeostasis in HO-1 deficiency is the result of both defective iron recycling and erythroid activity-associated inhibition of hepcidin expression. This study therefore shows a crucial role for HO-1 in maintaining body iron balance.