RNA编译酶ADAR1在非酒精性脂肪性肝炎发病中的作用及分子机制研究

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease, which may develop into end-stage hepatocirrhosis and hepatocellular carcinoma, resulting in very poor prognosis and posing a serious threat to the health of the people. During the pathological process of non-alcoholic steatohepatitis (NASH), inflammation plays a critical role in the transition from simple steatosis to steatohepatitis, causing a deterioration of the disease. However, the mechanism by which inflammation occurs in the fatty liver tissue is unclear, which blocks the development of an effective therapeutic drug. Our recent investigation indicated that alteration of RNA signaling pathway caused by hepatocytic metabolism abnormality is closely related to inflammation. Excessive intracellular accumulation of fats not only may inhibit the expression of RNA editing enzyme ADAR1 (adenosine deaminase acting on RNA 1), but also can cause the pathological changes similar to steatohepatitis in the mouse hepatocytes whose ADAR1 genes are specifically knocked down. In this study, we will, based on our previous work and through analyzing different mice that ADAR1 genes are specifically knocked out in the hepatocytes, ① investigate the role of the nonspecific immune system RNA sensing pathways regulated by ADAR1in the development of NASH; ② elucidate the molecular mechanism of inflammatory reaction in the liver tissues; and ③ explore the ways to block the RNA sensing pathway to prevent inflammation in the fatty liver tissues. In this project, we will possibly reveal a novel molecular mechanism in the development of NASH, and provide a new drug target for setting up clinical therapeutic approaches to the disease.

非酒精性脂肪肝是一种常见的慢性肝病，可发展为终末期肝硬化及肝癌，导致严重不良预后，对人民健康造成严重威胁。在其病理进程中炎症的发生起有关键性作用，促使单纯性脂肪肝转化为脂肪性肝炎，导致疾病的恶化。然而脂肪肝中炎症的发生机制尚未阐明，阻碍了有效治疗药物的研发。我们最近的研究提示肝细胞代谢异常引起的RAN信号通路的改变与炎症发生密切相关。细胞内过量的脂肪积累不仅可抑制RNA编译酶ADAR1表达，而且在小鼠肝细胞中特异敲除ADAR1基因可引起肝脏类似于脂肪性肝炎的病理改变。 本研究拟在我们先期工作基础上通过对不同肝细胞特异基因敲除小鼠的分析①研究ADAR1 调控的非特异免疫系统RNA感知信号通路在脂肪性肝炎进展中的作用；②阐述肝组织中炎症发生的分子机制；③探讨阻断RNA感知信号通路防止脂肪肝组织中炎症发生的方式。本研究将有可能发现脂肪性肝炎发病中新的相关分子机制，为建立临床治疗方案提供药物靶点。

非酒精性脂肪肝病（NAFLD）是最常见的慢性肝病之一，可伴有肝细胞内脂质异常蓄积和炎症反应。常与超重/肥胖、2型糖尿病和代谢功能障碍等并存。NAFLD发病机制复杂，部分患者可向肝纤维化、肝硬化甚至肝细胞癌进展，持续的炎症反应可加速这一进程。然而脂肪肝中炎症的发生机制尚未阐明，本课题组基于前期研究发现肝细胞代谢异常引起的RAN信号通路的改变与炎症发生密切相关。肝细胞内大量的脂肪积累抑制RNA编译酶ADAR1表达。小鼠肝细胞中特异敲除ADAR1基因可引起肝脏产生脂肪性肝炎的病理改变。本课题组首先构建NAFLD体外细胞模型，结合高通量RNA测序技术，深入研究突变ADAR1在NAFLD发生及进展中的分子机制。此外，本课题组通过构建NAFLD小鼠模型，结合代谢组学，对NAFLD发病过程中ADAR1表达水平、及其所调控的炎症信号通路进行研究。同时构建肝脏特异性敲除ADAR1基因小鼠和细胞内 RNA 受体 MDA-5 的基因敲除小鼠， 明确阻断ADAR1调控的RNA感知信号通路防止脂肪肝组织中炎症发生的方式，为NAFLD的治疗靶点奠定基础理论。