Endoplasmic reticulum oxidoreductin 1α mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis
Endoplasmic reticulum oxidoreductin 1α mediates hepatic endoplasmic reticulum stress in homocysteine-induced atherosclerosis
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内质网氧化还原素1α在同型半胱氨酸诱导的动脉粥样硬化中介导肝内质网应激
DOI：
10.1093/abbs/gmu081
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发表时间：
2014-10-01
影响因子：
3.7
通讯作者：
Jiang, Yideng
中科院分区：
文献类型：
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作者：
Yang, Xiaoling;Xu, Hua;Jiang, Yideng
内质网应激是不同病理过程的重要调节因子，也是同型半胱氨酸（Hcy）诱导肝损伤的机制之一。然而，在动脉粥样硬化背景下hcy诱导肝内质网应激的分子事件目前尚不清楚。内质网氧化还原蛋白1 α (ERO1 α)在维持内质网应激功能中起重要作用。在本研究中，我们检测了高同型半胱氨酸血症患者肝脏中ERO1 α的表达，以及在Hcy存在的情况下，ERO1 α在肝细胞ER应激中的作用。采用蛋氨酸饲粮喂养载脂蛋白e缺乏（ApoE-/-）小鼠，建立HHcy模型，用叶酸和不同浓度的Hcy孵育肝细胞。我们的研究结果表明，Hcy触发内质网应激的特征是葡萄糖调节蛋白78 （GRP78）、蛋白激酶rna样内质网激酶（PERK）、激活转录因子（ATF） 6和X-box结合蛋白1 （XBP-1）的含量增加。与ApoE-/-组和对照肝细胞相比，HHcy小鼠和hcy处理肝细胞中ERO1 α的表达均降低（P < 0.05）。用小干扰RNA敲低ERO1 α的表达可显著增强hcy诱导的内质网应激。同时，er1 α基因在肝细胞中过表达时，内质网应激相关因子GRP78、PERK、ATF6、XBP-1的表达均显著降低。我们的研究结果表明，ERO1 α可能参与了hcy诱导的肝内质网应激，抑制ERO1 α的表达可以加速这一过程。
Endoplasmic reticulum (ER) stress is emerging as an important modulator of different pathological process and as a mechanism contributing to homocysteine (Hcy)-induced hepar injury. However, the molecular event that Hcy-induced ER stress in the hepar under the atherosclerosis background is currently unknown. Endoplasmic reticulum oxidoreductin 1 alpha (ERO1 alpha) plays a crucial role in maintaining ER stress function. In this study, we determined the expression of ERO1 alpha in the hepar in hyperhomocysteinemia and the effect of ERO1 alpha in hepacytes ER stress in the presence of Hcy. HHcy model was established by feeding the methionine diet in apolipoprotein-E-deficient (ApoE-/-) mice, and the hepatocytes were incubated with folate and different concentrations of Hcy. Our results showed that Hcy triggered ER stress characterized by an increased contents of glucose-regulated protein 78 (GRP78), protein kinase RNA-like ER kinase (PERK), activating transcription factor (ATF) 6 and X-box binding protein-1 (XBP-1). The ERO1 alpha expressions in HHcy mice and Hcy-treated hepatocytes were decreased compared with those in ApoE-/- group and control hepacytes (P < 0.05), respectively. Knocking-down the expression of ERO1 alpha with small-interfering RNA significantly augmented Hcy-induced ER stress. Meanwhile, the expressions of ER stress-related factor including GRP78, PERK, ATF6 and XBP-1, were significantly decreased when the ERO1 alpha gene was over-expressed in hepacytes. Our results suggested that ERO1 alpha may be involved in Hcy-induced hepar ER stress, and the inhibition of ERO1 alpha expression can accelerate this process.