A role of SMAD4 in iron metabolism through the positive regulation of hepicidin expression
A role of SMAD4 in iron metabolism through the positive regulation of hepicidin expression
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DOI：
10.1016/j.cmet.2005.10.010
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发表时间：
2005-12-01
期刊：
影响因子：
29
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Wang, RH;Li, CL;Deng, CX
遗传性血色病是高加索人最常见的遗传性疾病之一，其特征是多个器官的铁超载。铁调素在肝脏中合成，在铁超载综合征中起重要作用。在这里，我们表明，Cre-IoxP介导的SMAD 4的肝脏特异性破坏导致铁调素的表达和铁在许多器官中的积累显着降低，这在肝脏，肾脏和胰腺中最明显。参与肠铁吸收的基因的转录水平，包括Dcytb，DMT 1和ferroportin，在铁调素的情况下显着升高。我们证明SMAD 4的异位过表达激活铁调素启动子，并与组蛋白H3的转录活性形式的表观遗传修饰有关。此外，铁调素的转录激活在SMAD 4缺陷型肝细胞中响应于铁过载、TGF-β、BMP或IL-6而被废除。我们的研究揭示了TGF-β/SMAD 4在调节hepcidin表达，从而调节肠道铁转运和铁稳态中的新作用。
Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-IoxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis.