Lithocholic acid activates mTOR signaling inducing endoplasmic reticulum stress in placenta during intrahepatic cholestasis of pregnancy
Lithocholic acid activates mTOR signaling inducing endoplasmic reticulum stress in placenta during intrahepatic cholestasis of pregnancy
复制标题
石胆酸激活 mTOR 信号诱导妊娠肝内胆汁淤积期间胎盘内质网应激
DOI：
10.1016/j.lfs.2018.12.050
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发表时间：
2019-02-01
期刊：
影响因子：
6.1
通讯作者：
Gao Yunfei
中科院分区：
文献类型：
--
作者：
Sheng Chao;Lin Xiaojun;Gao Yunfei
目的：妊娠期肝内胆汁淤积症（ICP）是一种妊娠特异性疾病，可增加不良胎儿结局的风险。然而，其病理生理机制尚未完全了解。在这里，我们探讨了mTOR信号和ER应激在ICP胎盘中的作用。材料和方法：胎盘组织收集正常和ICP妊娠。免疫组化检测胎盘中mTOR信号和内质网应激。体外实验采用人胎盘滋养层细胞系HTR-8/SVneo。与正常胎盘相比，Bip的表达及pS 6（S235/236）和pAkt（S473）的磷酸化水平均明显增高。在体外研究中，特异性针对石胆酸而非牛磺胆酸或熊去氧胆酸的胆汁酸显著增加了pS 6 K1（T389）、pS 6（S235/236）或pAkt（S473）的磷酸化，而mTOR抑制剂可以抑制上调。同样，IRE 1 α和BiP的表达在石胆酸（20 μ M）给药下急剧增加，而相同的抑制剂也可以降低表达。此外，透射电子显微镜显示扩大的内质网腔下的石胆酸治疗。不同剂量的石胆酸处理后，细胞活力明显下降。意义：胆汁酸可激活mTOR信号通路，导致内质网应激，导致滋养细胞活力下降。mTOR通路激活可能与ICP的病理生理学相关。
Aims: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which increases risks of adverse fetal outcomes. However, the pathophysiology is not fully understood. Here, we explored the roles of mTOR signaling and ER stress in placenta during ICP.Materials and methods: Placental tissues were collected from normal and ICP pregnancies. mTOR signaling and endoplasmic reticulum stress were detected by immunohistochemistry in the placenta. The human placenta trophoblast cell line HTR-8/SVneo was used in vitro experiment.Key findings: ICP placenta displayed histological abnormalities with fewer trophoblasts. Moreover, the expression of Bip and the phosphorylation of pS6(S235/236) or pAkt(S473) were higher comparing with normal placenta. In in vitro studies, the bile acids specifically to lithocholic acid rather than taurocholic acid or ursodeoxycholic acid, drastically increased the phosphorylation of pS6K1(T389), pS6(S235/236), or pAkt(S473), whereas the mTOR inhibitor can prohibit the upregulation. Similarly, the expressions of IRE1 alpha and BiP increased sharply under lithocholic acid (20 mu M) administration, while the same inhibitor can also decrease the expression. Additionally, transmission electron microscopy showed enlarged endoplasmic reticulum lumen under the lithocholic acid treatment. Furthermore, the cell viability reduced sharply under treatment with different dose of lithocholic acid. The mTOR inhibitor can reverse the decrease of cell viability to some extent.Significance: Bile acid can activate mTOR signaling which resulted in endoplasmic reticulum stress, leading to trophocyte viability decrease. mTOR pathway activation may be associated with the pathophysiology of ICP.