Mishra Jay S, Zhao Hanjie, Hattis Sari, Kumar Sathish
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.
Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA.
Nutrients. 2020 Apr 30;12(5):1271. doi: 10.3390/nu12051271.
Gestational diabetes mellitus (GDM) results in reduced docosahexaenoic acid (DHA) transfer to the fetus, likely due to placental dysfunction. Sirtuin-1 (SIRT1) is a nutrient sensor and regulator of lipid metabolism. This study investigated whether the high glucose and insulin condition of GDM regulates DHA transfer and expression of fatty acid transporters and if this effect is related to SIRT1 expression and function. Syncytialized primary human trophoblasts were treated with and without glucose (25 mmol/L) and insulin (10 mol/L) for 72 h to mimic the insulin-resistance conditions of GDM pregnancies. In control conditions, DHA transfer across trophoblasts increased in a time- and dose-dependent manner. Exposure to GDM conditions significantly decreased DHA transfer, but increased triglyceride accumulation and fatty acid transporter expression (CD36, FABP3, and FABP4). GDM conditions significantly suppressed SIRT1 mRNA and protein expression. The SIRT1 inhibitor decreased DHA transfer across control trophoblasts, and recombinant SIRT1 and SIRT1 activators restored the decreased DHA transport induced by GDM conditions. The results demonstrate a novel role of SIRT1 in the regulation of DHA transfer across trophoblasts. The suppressed SIRT1 expression and the resultant decrease in placental DHA transfer caused by high glucose and insulin levels suggest new insights of molecular mechanisms linking GDM to fetal DHA deficiency.
妊娠期糖尿病（GDM）会导致二十二碳六烯酸（DHA）向胎儿的转运减少，这可能是由于胎盘功能障碍所致。沉默调节蛋白1（SIRT1）是一种营养传感器和脂质代谢调节因子。本研究调查了GDM的高血糖和胰岛素状态是否会调节DHA转运以及脂肪酸转运蛋白的表达，以及这种作用是否与SIRT1的表达和功能有关。将人原代滋养层细胞进行同步化处理，分别在添加和不添加葡萄糖（25 mmol/L）及胰岛素（10 μmol/L）的条件下培养72小时，以模拟GDM妊娠的胰岛素抵抗状态。在对照条件下，DHA跨滋养层细胞的转运呈时间和剂量依赖性增加。暴露于GDM条件下会显著降低DHA转运，但会增加甘油三酯积累和脂肪酸转运蛋白表达（CD36、FABP3和FABP4）。GDM条件会显著抑制SIRT1 mRNA和蛋白表达。SIRT1抑制剂会降低DHA跨对照滋养层细胞的转运，而重组SIRT1和SIRT1激活剂可恢复由GDM条件诱导的DHA转运减少。结果表明SIRT1在调节DHA跨滋养层细胞转运中具有新作用。高血糖和胰岛素水平导致的SIRT1表达受抑制以及胎盘DHA转运减少，为将GDM与胎儿DHA缺乏联系起来的分子机制提供了新见解。
