载质蛋白A-I的表达对肝细胞内质网应激和细胞凋亡影响的研究

One important factor which promotes non-alcoholic steatohepatitis (NASH) may be the damage and pathological changes in hepatocytes caused by endoplasmic reticulum stress (ERS), which later results in apoptosis. ATP-binding cassette transporter A1 (ABCA1) is a transmembrane protein that transports cholesterol and phospholipids into apolipoprotein A-I (apoA-I). Results from our previous studies reveal apoA-I expression can significantly suppress hepatic lipid accumulation and ERS. Therefore, we hypothesize that apoA-I expression can reduce ERS, which results in the suppression of both intrinsic and ERS-induced pathways for apoptosis. We will overexpress apoA-I in hepatic cell lines to promote lipid transport. We will also evaluate the lipid accumulation in hepatocytes in apoA-I transgenic and knockout mice. In these cells and animals, we will evaluate the effects of apoA-I on ERS-related proteins and effects of these proteins on apoptotic pathways such as caspase-9 and caspase-4/12. This project will investigate the effects of apoA-I on ERS and apoptosis as well as their signaling pathways. The results will provide theoretical basis for the prevention and treatment of NASH.

造成非酒精性脂肪性肝炎（NASH）的重要因素之一是由内质网应激（ERS）导致的肝细胞损害和病变，并进一步引起细胞凋亡。跨膜转运蛋白ATP结合盒转运蛋白A1（ABCA1）负责将细胞内的胆固醇和磷脂转运给载脂蛋白A-I（apoA-I）。前期我们研究发现ABCA1和apoA-I的过量表达可显著降低肝细胞内的脂质堆积和ERS。我们进而提出假设：apoA-I的表达可降低ERS，从而抑制内源性凋亡途径和ERS介导的凋亡途径。本课题拟利用过表达apoA-I促进肝细胞内脂质的运输，评估apoA-I转基因和基因敲除小鼠NASH模型中肝细胞内的脂质堆积；检测上述细胞和动物中apoA-I表达对ERS相关蛋白的影响及这些蛋白对caspase-9、caspase-4/12等细胞凋亡信号通路的影响。本课题将探索通过apoA-I增强脂质转运而减缓肝细胞ERS和凋亡的信号通路，对防治NASH提供一定的理论依据。

造成非酒精性脂肪性肝炎（NASH）的重要因素之一是由内质网应激（ERS）导致的肝细胞损伤和病变，并进一步引起细胞凋亡。跨膜转运蛋白ATP结合盒转运蛋白A1负责将细胞内的胆固醇和磷脂转运给载脂蛋白A-I（apoA-I）。我们研究发现，apoA-I可以在HepG2显著降低棕榈酸引起的ERS以及ERS和线粒体引起的细胞凋亡。在注射了ERS诱导剂衣霉素后，apoA-I转基因小鼠相比野生型小鼠在ERS水平、脂质堆积和脂质合成均有显著缓解。本课题探索了通过apoA-I增强脂质转运而减缓肝细胞ERS和凋亡的机制，对防治NASH提供了一定的理论依据。