Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.
Department of Pharmacy, Hokkaido University Hospital, Kita-14-jo, Nishi-5-chome, Kita-ku, Sapporo, 060-8648, Japan.
Placenta. 2019 Jan;75:34-41. doi: 10.1016/j.placenta.2018.11.010. Epub 2018 Nov 27.
Polyunsaturated fatty acids (PUFAs), including arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are essential for adequate fetal growth. The aim of the present study was to elucidate the effects of PUFAs on the expression and function of placental transporters, which play important roles in placental functions including the supply of nutrients to the fetus, excretion of metabolites, and protection of the fetus from xenobiotics.
Human placental choriocarcinoma BeWo cells were used as a trophoblast model. PUFA-induced alteration in the gene expression of 84 transporters was investigated by a commercially available PCR array. Protein levels and the activity of transporters were assessed by western blotting and uptake experiments, respectively. The placental expression of the transporters was analyzed using pregnant Wistar rats.
PUFAs (AA, EPA, and DHA) increased cystine/glutamate transporter xCT/SLC7A11, which mediates the cellular uptake of cystine coupled with the efflux of glutamate in human placental choriocarcinoma BeWo cells. These PUFAs also increased [C]-cystine uptake in BeWo cells. PUFA-induced xCT/SLC7A11 mRNA expression was not blocked by nuclear factor-erythroid 2-related factor-2 (NRF2) knockdown. Reverse transcription (RT)-PCR analysis indicated that xCT/Slc7a11 mRNA was detected in rat placenta and the expression level at gestational day (GD) 12 was higher than that at GD 20.
These results indicate that PUFAs promoted cystine uptake in placental cells by inducing xCT/SLC7A11 expression and NRF2 did not contribute to upregulation of xCT/SLC7A11 by PUFAs. Furthermore, xCT expression in rat placenta may change during pregnancy.
多不饱和脂肪酸（PUFAs），包括花生四烯酸（AA）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），是胎儿生长所必需的。本研究旨在阐明 PUFAs 对胎盘转运体表达和功能的影响，这些转运体在胎盘功能中发挥重要作用，包括向胎儿供应营养物质、排泄代谢物以及保护胎儿免受外源性物质的侵害。
使用人胎盘绒毛癌细胞系 BeWo 作为滋养层模型。通过商业可用的 PCR 阵列研究了 PUFAs 对 84 种转运体基因表达的影响。通过 Western 印迹和摄取实验分别评估了蛋白水平和转运体的活性。使用怀孕的 Wistar 大鼠分析了转运体在胎盘的表达。
PUFAs（AA、EPA 和 DHA）增加了胱氨酸/谷氨酸转运体 xCT/SLC7A11，该转运体介导胱氨酸的细胞摄取，同时将谷氨酸排出细胞。这些 PUFAs 还增加了 BeWo 细胞中的 [C]-胱氨酸摄取。PUFA 诱导的 xCT/SLC7A11 mRNA 表达不受核因子-红细胞 2 相关因子 2（NRF2）敲低的阻断。逆转录（RT）-PCR 分析表明，xCT/Slc7a11 mRNA 在大鼠胎盘组织中被检测到，且在妊娠第 12 天的表达水平高于第 20 天。
这些结果表明，PUFAs 通过诱导 xCT/SLC7A11 表达促进胎盘细胞摄取胱氨酸，而 NRF2 不参与 PUFAs 对 xCT/SLC7A11 的上调。此外，大鼠胎盘 xCT 的表达可能在妊娠期间发生变化。
