大气细颗粒物诱导肝脏脂肪变性的关键组分识别及作用机制研究

PM2.5暴露会导致出现非酒精性脂肪肝（NAFLD）样症状，脂肪变性不仅是NAFLD等肝脏疾病的最初表型，还会增加心血管疾病和糖尿病的风险。然而目前对PM2.5中诱导肝脏脂肪变性的关键组分不清，作用机制不明。本项目拟首先基于GC−ToF-MS非靶向技术以甘油三酯为检测终点体外初筛PM2.5中可能导致脂肪变性的组分，并通过环境浓度下诱导细胞脂肪变性的剂量效应关系甄别主控效应组分。在此基础上，采用核受体结合反应考察主控效应组分与可能调控脂肪变性的核受体的结合，利用核受体激动剂或抑制剂进一步确认可与核受体结合造成脂肪变性的关键组分。最后，采用正常和瘦素缺陷型NAFLD小鼠在体验证关键组分的作用，并采用转录组测序技术阐明关键组分通过核受体调控脂肪酸代谢、脂滴蛋白合成、极低密度脂蛋白合成及分泌导致脂肪变性的作用机制。旨在为不同区域特征污染物控制、安全性评估、健康防护和临床治疗提供理论依据和技术支持。

Exposure to PM2.5 can lead to a non-alcoholic fatty liver disease (NAFLD)- like phenotype. Steatosis is not only the first phenotype of liver diseases such as NAFLD, but also increases risk of cardiovascular and type 2 diabetes mellitus. However, so far the key components of PM2.5-induced hepatic steatosis are unknown, the underlying mechanism is still unclear as well. In this project, the components of PM2.5 that may cause hepatic steatosis will be initially screened by gas chromatography coupled to a time-of-flight mass spectrometry (GC-ToF-MS) non-target technology, combined with triglyceride as the test endpoints in vitro. The main effect components will be further identified by steatosis tests after dose-dependent treatments of cells at the environmental concentrations. On this basis, the binding ability of the main effect components to the nuclear receptors that may be involved in steatosis will be investigated by using the nuclear receptor binding reaction, and the key effect components that can be combined with the nuclear receptors to cause steatosis will be further confirmed by using the activators or inhibitors of the nuclear receptors. Finally, the normal and NAFLD mice will be used to verified the role of key components in vivo. The transcriptome sequencing technology will be used to clarify the mechanism of key components induce steatosis through nuclear receptors regulating fatty acids metabolism, lipid droplet proteins synthesis, synthesis and secretion of very low density lipoprotein. The purpose of this study is to provide theoretical basis and technical support for characteristic pollutants control, safety assessment, health protection and clinical treatment in different regions.