Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling.
Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling.
复制标题
DOI：
10.1096/fba.2023-00113
复制
发表时间：
2024-01
影响因子：
2.7
通讯作者：
中科院分区：
文献类型：
--
作者：
正常的胎儿发育严重依赖于胎盘的最佳营养供应，胎盘氨基酸转运已被证明与胎儿生长呈正相关。雷帕霉素机制靶点（mTOR）是胎盘氨基酸转运蛋白（如系统A）的正调节因子。油酸（OA）先前已显示对原代人滋养层（PHT）细胞中的胎盘mTOR信号传导和系统A氨基酸摄取具有刺激作用。我们研究了PHT中OA和系统A活性之间的机制联系。我们发现，使用小干扰RNA敲低raptor或rictor抑制mTOR复合物1或2，阻止OA刺激的系统A氨基酸转运，表明OA与mTOR相互作用。磷脂酸（PA）是磷脂生物合成的关键中间体，也是mTOR通路的已知调节因子;然而，磷脂生物合成通路尚未在胎盘中进行广泛研究。我们确定了胎盘的酰基转移酶亚型参与从头磷脂合成。1-酰基甘油-3-磷酸-O-酰基转移酶-4（该途径中的一种酶）的沉默阻止了OA介导的mTOR和系统A氨基酸转运的刺激。这些数据表明，OA刺激mTOR和氨基酸转运PHT细胞介导的从头合成PA。我们推测母体循环中的脂肪酸，如OA，通过与mTOR相互作用调节对胎儿生长至关重要的胎盘功能，并且妊娠晚期高脂血症可能对增加营养转移到胎儿至关重要。调节氨基酸摄取的雷帕霉素（mTOR）脂质感应机制的胎盘机制靶点。含有油酸（18：1）酰基的磷脂酸的从头合成刺激胎盘mTOR。mTOR的激活导致系统A介导的氨基酸摄取增加。
Normal fetal development is critically dependent on optimal nutrient supply by the placenta, and placental amino acid transport has been demonstrated to be positively associated with fetal growth. Mechanistic target of rapamycin (mTOR) is a positive regulator of placental amino acid transporters, such as System A. Oleic acid (OA) has been previously shown to have a stimulatory role on placental mTOR signaling and System A amino acid uptake in primary human trophoblast (PHT) cells. We investigated the mechanistic link between OA and System A activity in PHT. We found that inhibition of mTOR complex 1 or 2, using small interfering RNA to knock down raptor or rictor, prevented OA‐stimulated System A amino acid transport indicating the interaction of OA with mTOR. Phosphatidic acid (PA) is a key intermediary for phospholipid biosynthesis and a known regulator of the mTOR pathway; however, phospholipid biosynthetic pathways have not been extensively studied in placenta. We identified placental isoforms of acyl transferase enzymes involved in de novo phospholipid synthesis. Silencing of 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase‐4, an enzyme in this pathway, prevented OA mediated stimulation of mTOR and System A amino acid transport. These data indicate that OA stimulates mTOR and amino acid transport in PHT cells mediated through de novo synthesis of PA. We speculate that fatty acids in the maternal circulation, such as OA, regulate placental functions critical for fetal growth by interaction with mTOR and that late pregnancy hyperlipidemia may be critical for increasing nutrient transfer to the fetus. Placental mechanistic target of rapamycin (mTOR) lipid sensing mechanism which modulates amino acid uptake. De novo synthesis of phosphatidic acid containing an oleic acid (18:1) acyl group stimulates placental mTOR. Activation of mTOR leads to increased System A mediated amino acid uptake.