Homocysteine upregulates hepcidin expression through BMP6/SMAD signaling pathway in hepatocytes
Homocysteine upregulates hepcidin expression through BMP6/SMAD signaling pathway in hepatocytes
复制标题
同型半胱氨酸通过BMP6/SMAD信号通路上调肝细胞中铁调素的表达
DOI：
10.1016/j.bbrc.2016.02.001
复制
发表时间：
2016-03-04
影响因子：
3.1
通讯作者：
Wang, Nanping
中科院分区：
文献类型：
--
作者：
Luo, Xiaoqin;Luo, Zhenyu;Wang, Nanping
患有严重高同型半胱氨酸血症的受试者具有缺铁性贫血和肝脏中的过量铁沉积。铁调素是铁稳态的中枢调节因子，在铁代谢中起关键作用。然而，同型半胱氨酸（Hcy）对hepcidin的调节在很大程度上是不清楚的。我们在HepG 2细胞中进行了实验，以确定Hcy调节hepcidin表达的机制。我们发现，治疗与同型半胱氨酸剂量依赖性增加铁调素的转录水平和蛋白水平，通过定量实时逆转录聚合酶链反应和蛋白质印迹法，分别评估。Hcy还激活了HepG 2细胞中的BMP 6信号，并增加了SMAD 1/5/8的磷酸化。我们发现，同型半胱氨酸对hepcidin表达的影响被用siRNA敲低BMP 6及其受体ALR 2/3/6所削弱。这些结果表明，同型半胱氨酸上调hepcidin的表达，通过BMP 6/SMAD途径，提出了一种新的机制，潜在的高同型半胱氨酸血症相关的扰动铁稳态。(C)2016 Elsevier Inc. All rights reserved.
Subjects with severe hyperhomocysteinemia have hypoferric anemia and excessive iron deposition in the liver. Hepcidin, the central regulator of iron homeostasis, plays a key role in iron metabolism. However, the regulation of homocysteine (Hcy) on hepcidin is largely unclear. We conducted experiments in HepG2 cells to identify the mechanisms with which Hcy modulates hepcidin expression. We found that treatment with Hcy dose-dependently increased both hepcidin transcript levels and protein levels, as assessed by quantitative real-time reverse-transcriptase polymerise chain reaction and western blotting, respectively. Hcy also activated BMP6 signaling and increased the phosphorylation of SMAD1/5/8 in HepG2 cells. We found that Hcy's effect on hepcidin expression was impaired by the knockdown of BMP6 and its receptors ALR2/3/6 with siRNAs. These results demonstrated that Hcy up-regulated hepcidin expression through the BMP6/SMAD pathway, suggesting a novel mechanism underlying the hyperhomocysteinemia-associated perturbation of iron homeostasis. (C) 2016 Elsevier Inc. All rights reserved.