PPARγ介导的miR-378c在F-53B诱导肝脂代谢紊乱中的调控机制研究

氯代聚氟烷基醚磺酸盐（F-53B）是一种新型的全氟类化合物，在环境和人体中频繁检出，对生态环境和人体健康造成了潜在的威胁。研究表明，F-53B可以干扰肝脏脂肪酸的转运和脂滴的生成，然而其对脂肪酸代谢的机制尚未完全阐明，有待于更深入的研究。miRNA是调控基因表达重要的表遗传分子，其在脂肪酸代谢通路及F-53B致肝脂代谢紊乱中的作用机制有待进一步研究。本项目从组学数据和生物信息学分析入手，筛选出受PPARγ受体活性影响的miR-378c及其靶基因Fabp4、Fabp5和Acacb。随后在分子、细胞和活体水平探究F-53B通过PPARγ-miR-378c通路致肝脂代谢紊乱的作用机制。研究结果将首次阐明受PPARγ受体调控的miR-378c在F-53B诱导的肝脏脂质累积效应中的调控作用机理，为全氟化合物的分子毒性效应提供一种新的表观遗传调控机制，也为全氟化合物毒性作用模式研究提供新的思路。

Chlorinated polyfluorinated ether sulfonate (F-53B) is a novel Perfluoroalkyl compound with widespread environmental distribution and human exposure, imposing remarkable threats to environment and human health. Previous studies indicated that F-53B exposure led to disrupted lipid droplets transportation and accumulation in liver, whereas the underlying mechanism remains unclear. MiRNAs are important epigenetic molecules that regulate gene expression, and their roles in hepatic fatty acid metabolism pathways and lipid metabolism disorders following F-53B exposure need to be further elucidated. In the present study, PPARγ-regulated miR-378c has been identified by analysis of RNA-seq and bioinformatics data, which subsequently regulate the expression of Fabp4, Fabp5 and Acacb, all of which are involved in hepatic fatty acid metabolism. The molecular mechanism of hepatic fatty acid metabolism disorder induced by F-53B exposure through the PPARγ-miR-378c pathway will be explored at molecular, in vitro and in vivo levels. This study is expected to reveal a novel epigenetic regulation mechanism of liver lipid metabolism in F-53B-induced hepatotoxicity through the PPARγ-miR-378c pathway, and provide new clues to identify the toxicity mechanism of hepatic lipid metabolism disorders following novel per/polyfluoroalkyl substances exposures.