Autophagic flux inhibition, apoptosis, and mitochondrial dysfunction in bile acids‐induced impairment of human placental trophoblast
Autophagic flux inhibition, apoptosis, and mitochondrial dysfunction in bile acids‐induced impairment of human placental trophoblast
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DOI：
10.1002/jcp.30774
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发表时间：
2022-05
影响因子：
5.6
通讯作者：
Xi Yang;Yulai Zhou;Huan Li;Fuzhen Song;Juan Li;Yong Zhang;Yi Lin;Huijuan Zhang;Jianxia Fan
中科院分区：
文献类型：
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作者：
Xi Yang;Yulai Zhou;Huan Li;Fuzhen Song;Juan Li;Yong Zhang;Yi Lin;Huijuan Zhang;Jianxia Fan
妊娠期肝内胆汁淤积症（ICP）是一种常见的妊娠特异性疾病，其特征是胆汁酸水平升高和不良胎儿结局。我们以前报道过多的胆汁酸导致ICP胎盘滋养细胞功能障碍。但具体机制尚不清楚。自噬是保护细胞在不利条件下存活的基本过程。在这里，我们评估了胆汁酸浓度增加对滋养层细胞自噬的影响，在体外和体内。首先，我们证明了自噬底物p62/隔离体-1在ICP患者的胎盘组织和用疏水性胆汁酸（包括鹅去氧胆酸和脱氧胆酸）处理的人滋养层中积累。此外，我们发现疏水性胆汁酸处理通过抑制AMP活化蛋白激酶/unc-51样激酶1自噬信号通路，以时间和浓度依赖性方式损害自噬通量。值得注意的是，体外或体内ICP小鼠模型中，滋养层细胞在饥饿沿着胆汁酸处理时易于发生凋亡性细胞死亡。此外，我们揭示了线粒体功能障碍是主要的生物学过程中过量胆汁酸诱导的滋养细胞损伤饥饿下的蛋白质组学分析。总的来说，我们的研究提出了一个复杂的相互作用，过量的胆汁酸诱导的自噬流量，线粒体功能障碍，细胞凋亡的胎盘滋养层细胞可能在ICP的发病机制中发挥关键作用。
Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy‐specific disease, characterized by increased bile acid levels and adverse fetal outcomes. We previously reported excessive bile acids led to dysfunction of placental trophoblasts in ICP. However, the detailed mechanism is still unclear. Autophagy is fundamental process for protecting cell survival against adverse conditions. Here, we evaluated the effect of increased concentration of bile acids on autophagy in trophoblasts in vitro and in vivo. First, we demonstrated that the autophagy substrate p62/sequestosome‐1 was accumulated in placental tissues from patients with ICP and in human trophoblasts treated with hydrophobic bile acids, including chenodeoxycholic acid and deoxycholic acid. Furthermore, we found that treatment with hydrophobic bile acids impaired autophagic flux in both time‐ and concentration‐dependent manners, by suppressing the AMP‐activated protein kinase/unc‐51‐like kinase 1 autophagic signaling pathway. Notably, trophoblasts were prone to apoptotic cell death upon starvation along with bile‐acids treatment in vitro or in an ICP mouse model in vivo. Additionally, we revealed mitochondrial dysfunction was the predominant biological process in excessive bile acids induced trophoblast impairment under starvation by proteomic assay. Collectively, our study proposed a complex interaction of excessive bile acids induced autophagic flux, mitochondrial dysfunction, and cellular apoptosis in placental trophoblasts may play a critical role in the pathogenesis of ICP.