Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress
Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress
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叶酸通过囊性纤维化跨膜电导调节器 (CFTR) 激活的内质网应激保护高同型半胱氨酸血症小鼠的肝细胞免于凋亡
DOI：
10.1002/jcb.25946
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发表时间：
2017-09-01
影响因子：
4
通讯作者：
Huang, Ying
中科院分区：
文献类型：
--
作者：
Yang, Anning;Sun, Yue;Huang, Ying
叶酸缺乏是肝损伤的已知危险因素;然而，其潜在机制仍不清楚。在这项研究中，我们采用高同型半胱氨酸诱导的载脂蛋白E缺陷（ApoE（-/-））小鼠喂养高蛋氨酸饮食的肝损伤模型，发现高同型半胱氨酸通过下调囊性纤维化跨膜传导调节因子（CFTR）表达诱导内质网（ER）应激和肝细胞凋亡;观察结果与补充膳食叶酸减弱。CFTR表达的调节是由CFTR启动子甲基化和组蛋白H3（H3 K27 me 3）上赖氨酸27的三甲基化介导的。从机制上讲，叶酸抑制同型半胱氨酸诱导的CFTR启动子甲基化和H3 K27 me 3，这导致CFTR表达上调，并减少ER应激和肝细胞凋亡。进一步的研究表明，叶酸抑制DNA甲基转移酶1和zeste增强子同源物2的表达，下调细胞内S-腺苷甲硫氨酸（SAM）和S-腺苷高半胱氨酸（SAH）的浓度，上调SAM/SAH比率，从而抑制Hcy诱导的DNA超甲基化和CFTR启动子中的H3 K27 me 3。总之，我们的研究结果提供了深入了解叶酸通过调节CFTR表达在同型半胱氨酸诱导的ER应激和肝细胞凋亡中的保护作用。(C)2017 Wiley Periodicals，Inc.
Folate deficiency is a known risk factor for liver injury; however, the underlying mechanism remains unclear. In this study, we employed a high homocysteine-induced liver injury model of Apolipoprotein E-deficient (ApoE(-/-)) mice fed high-methionine diet and found that high homocysteine induced endoplasmic reticulum (ER) stress and liver cell apoptosis by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression; observations that were attenuated with supplementation of dietary folate. The regulation on CFTR expression was mediated by CFTR promoter methylation and trimethylation of lysine 27 on histone H3 (H3K27me3). Mechanistically, folate inhibited homocysteine-induced CFTR promoter methylation and H3K27me3, which resulted in upregulation of CFTR expression, and reduced ER stress and liver cell apoptosis. Further study showed that folate inhibited the expression of DNA methyltransferase 1 and enhancer of zeste homolog 2, downregulated the cellular concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) and upregulated the SAM/SAH ratio, leading to the inhibition of Hcy-induced DNA hypermethylation and H3K27me3 in CFTR promoter. In conclusion, our results provide insight into the protective role of folate in homocysteine-induced ER stress and liver cell apoptosis through the regulation of CFTR expression. (C) 2017 Wiley Periodicals, Inc.