Yang Anning, Zhang Huiping, Sun Yue, Wang Yanhua, Yang Xiaoming, Yang Xiaoling, Zhang Hui, Guo Wei, Zhu Guangrong, Tian Jue, Jia Yuexia, Jiang Yideng
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China; West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
Prenatal Diagnosis Center of Ningxia Medical University General Hospital, Yinchuan, China; Ningxia Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Yinchuan, China.
Placenta. 2016 Oct;46:49-62. doi: 10.1016/j.placenta.2016.08.086. Epub 2016 Aug 24.
Inflammation and dysregulated lipid metabolism are involved in the pathogenesis of preeclampsia, and fatty acid binding protein 4 (FABP4) is known to regulate both inflammation and lipid metabolism. In the present study, we elucidated the role of FABP4 using in vitro and in vivo models of preclampsia. We found increased expression of FABP4 in the placenta of preeclamptic rats, which was further confirmed in HTR-8 cells, an extravillous trophoblast cell line, treated with L-NAME. Overexpression of FABP4 in HTR-8 cells resulted in upregulated expression of pro-inflammatory cytokines IL-6 and TNF-α, and increased lipid accumulation, suggesting that FABP4 plays a role in preeclampsia. Furthermore, downregulation of methylation in the promotor resulted in increased FABP4 expression, which was mediated by downregulated DNA methyltransferase 1 (DNMT1). Bioinformatics analysis showed that miR-148a/152 regulated the expression of DNMT1, and additional in vitro studies revealed that miR-148a/152 inhibited DNMT1 expression by directly binding to its 3'-UTR. Interestingly, DNMT1 enhanced the expression of miR-148a/152 by downregulation of methylation in its promotor. Taken together, our results showed that FABP4 may be involved in the pathogenesis of preeclampsia, and the expression of FABP4 is enhanced by miR-148a/152 mediated inhibition of DNMT1 expression.
炎症和脂质代谢失调参与了先兆子痫的发病机制，已知脂肪酸结合蛋白4（FABP4）可调节炎症和脂质代谢。在本研究中，我们使用先兆子痫的体外和体内模型阐明了FABP4的作用。我们发现先兆子痫大鼠胎盘中FABP4的表达增加，在用L-NAME处理的绒毛外滋养层细胞系HTR-8细胞中进一步得到证实。FABP4在HTR-8细胞中的过表达导致促炎细胞因子IL-6和TNF-α的表达上调，以及脂质积累增加，这表明FABP4在先兆子痫中起作用。此外，启动子甲基化的下调导致FABP4表达增加，这是由DNA甲基转移酶1（DNMT1）下调介导的。生物信息学分析表明，miR-148a/152调节DNMT1的表达，另外的体外研究表明，miR-148a/152通过直接结合其3'-UTR抑制DNMT1的表达。有趣的是，DNMT1通过下调其启动子中的甲基化来增强miR-148a/152的表达。综上所述，我们的结果表明FABP4可能参与先兆子痫的发病机制，并且miR-148a/152介导的DNMT1表达抑制增强了FABP4的表达。
