Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA.
Departments of Pathology and Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Biomolecules. 2022 Aug 22;12(8):1162. doi: 10.3390/biom12081162.
Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs' role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetylcysteine (NAC) prevented the palmitic acid-mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in utero environment.
胎盘绒毛外滋养细胞（EVTs）的正常功能对于向发育中的胎儿充分输送氧气和营养物质以及正常的胎儿编程至关重要。EVTs 对螺旋动脉的增殖和浸润依赖于叶酸的充足水平。多药耐药相关蛋白 1（MRP1）是一种外排转运蛋白，已知其能从这些细胞中去除叶酸。我们假设棕榈酸增加了 MRP1 介导的 EVTs 中叶酸的去除，从而干扰了 EVTs 在早期胎盘血管重塑中的作用。在不存在或存在 0.5 mM 和 0.7 mM 棕榈酸的情况下，将妊娠早期人类 EVTs 的 HTR-8/SVneo 和 Swan-71 细胞分别培养 72 小时。棕榈酸增加了两种细胞系中的 基因表达和 MRP1 蛋白表达。叶酸从细胞向培养基中的外排率随着培养细胞中迁移和侵袭功能的降低而增加。用 N-乙酰半胱氨酸（NAC）处理可防止棕榈酸介导的 MRP1 上调，并恢复 EVTs 的侵袭和迁移能力。最后，在 Swan-71 细胞的 基因敲除亚系中，侵袭和迁移功能显著增加。本研究的新发现表明，棕榈酸增加了 MRP1 介导的叶酸外排，提供了一个缺失的环节，有助于解释母体摄入饱和脂肪酸如何损害宫内环境。
