Oleate attenuates palmitate-induced endoplasmic reticulum stress and apoptosis in placental trophoblasts
Oleate attenuates palmitate-induced endoplasmic reticulum stress and apoptosis in placental trophoblasts
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DOI：
10.1530/rep-16-0576
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发表时间：
2017-04-01
期刊：
影响因子：
3.8
通讯作者：
Nelson, D. Michael
中科院分区：
文献类型：
--
作者：
Colvin, Bryanne N.;Longtine, Mark S.;Nelson, D. Michael
孕前肥胖症越来越普遍，使孕妇和后代容易患妊娠期糖尿病、先兆子痫、胎儿生长异常和死胎。肥胖妇女表现出两种最常见的膳食脂肪酸，棕榈酸和油酸的水平升高，含有这些营养物质的母体血液沐浴在体内胎盘绒毛的滋养层表面。我们测试的假设，即组成和浓度的游离脂肪酸调节活力和功能的原代人绒毛滋养层细胞培养。我们发现，棕榈酸增加合体滋养层细胞死亡，特别是通过半胱天冬酶介导的细胞凋亡，而油酸不会导致增强的细胞死亡。重要的是，暴露于等摩尔量的两种脂肪酸不会增加死亡或凋亡，这表明油酸可以保护合胞体滋养层免受棕榈酸诱导的死亡。我们进一步发现，棕榈酸酯，而不是油酸酯或油酸与棕榈酸酯，增加内质网（ER）的压力，通过未折叠的蛋白质反应的信号，并产生CHOP介导的诱导凋亡。最后，我们表明，油酸或油酸加棕榈酸都导致增加脂滴合胞体滋养层，而棕榈酸不。数据显示棕榈酸酯通过诱导ER应激和CHOP介导的细胞凋亡对人合胞体滋养层细胞有毒，而油酸酯无毒，消除棕榈酸酯毒性并诱导脂肪积累。我们推测，我们的体外研究结果提供了途径，代谢环境的肥胖孕妇可以产生绒毛滋养层功能障碍和次优胎盘功能。
Pre-pregnancy obesity is increasingly common and predisposes pregnant women and offspring to gestational diabetes, pre-eclampsia, fetal growth abnormalities and stillbirth. Obese women exhibit elevated levels of the two most common dietary fatty acids, palmitate and oleate, and the maternal blood containing these nutrients bathes the surface of trophoblasts of placental villi in vivo. We test the hypothesis that the composition and concentration of free fatty acids modulate viability and function of primary human villous trophoblasts in culture. We found that palmitate increases syncytiotrophoblast death, specifically by caspase-mediated apoptosis, whereas oleate does not cause enhanced cell death. Importantly, exposure to both fatty acids in equimolar amounts yielded no increase in death or apoptosis, suggesting that oleate can protect syncytiotrophoblasts from palmitate-induced death. We further found that palmitate, but not oleate or oleate with palmitate, increases endoplasmic reticulum (ER) stress, signaling through the unfolded protein response, and yielding CHOP-mediated induction of apoptosis. Finally, we show that oleate or oleate plus palmitate both lead to increased lipid droplets in syncytiotrophoblasts, whereas palmitate does not. The data show palmitate is toxic to human syncytiotrophoblasts, through the induction of ER stress and apoptosis mediated by CHOP, whereas oleate is not toxic, abrogates palmitate toxicity and induces fat accumulation. We speculate that our in vitro results offer pathways by which the metabolic milieu of the obese pregnant woman can yield villous trophoblast dysfunction and sub-optimal placental function.