【作者】 徐敏；

【导师】 孔晓妮；

【作者基本信息】 上海交通大学 ， 外科学（普外）， 2019， 硕士

【摘要】 目的:非酒精性脂肪性肝病（nonalcoholic fatty liver diseases,NAFLD）可发展为非酒精性脂肪性肝炎（non-alcoholic steatohepatitis,NASH）、肝硬化乃至肝癌,已成为危害人类健康的常见慢性肝病。但是目前临床上暂无有效的药物用于NAFLD的治疗,因此对NAFLD的发病机制、新药物的研发及新靶标的研究显得尤为迫切。肝脏脂质的合成与分解的各个环节的异常均可引起NAFLD,而氧化应激在其中发挥重要作用。我们实验室的多项研究显示,传统抗氧化应激损伤分子DJ-1可通过调节氧化应激及炎症反应,在多种肝脏疾病包括肝纤维化、肝损伤及肝癌中发挥重要作用。而其在NAFLD中的作用及机制尚不清楚,本研究旨在探讨DJ-1在其中的功能及机制。方法:给予野生型（Wild-type,WT）小鼠和DJ-1全身敲除(DJ-1^-/-)小鼠60%高脂饮食24周建立小鼠脂肪肝模型;分别采用生化试验、HE染色、油红O染色、称量体重、附睾周围白色脂肪重及肝重、葡萄糖及胰岛素耐量实验等检测两组小鼠的体重变化、胰岛素敏感性及肝脏脂质蓄积;采用Western Blot、PCR等方法检测肝脏各种代谢途径关键酶基因的变化。结果:DJ-1敲除后可显著改善高脂饮食诱导的肥胖、胰岛素抵抗及肝脏脂质蓄积,但是DJ-1缺失对小鼠的进食量、肝脏脂肪酸合成及糖酵解无明显影响,进一步研究发现DJ-1敲除后能够明显促进小鼠的能量代谢加快,并且DJ-1敲除后肝细胞的脂肪酸氧化和三羧酸循环也明显加快。结论:DJ-1的缺失可显著改善高脂饮食诱导的小鼠脂肪肝表型,其机制主要是通过促进肝脏脂肪酸氧化代谢更多还原

【Abstract】 Aims:Non-alcoholic fatty liver disease（NAFLD）can develop into non-alcoholic steatohepatitis（NASH）,liver cirrhosis and even liver cancer,which has become a common chronic disease that endangers human health.However,there is no effective drug for the treatment of NAFLD at present.The research on pathogenesis,new drugs and new targets for NAFLD are particularly urgent.Abnormalities in various aspects of the synthesis and decomposition of liver lipids can cause NAFLD,and oxidative stress damage plays an important role.Recent studies have shown that DJ-1,as a traditional anti-oxidative stress injury molecule,plays an important role in various liver diseases including liver fibrosis,liver injury and liver cancer by regulating oxidative stress and inflammatory response.The purpose of this study was to investigate the function and mechanism of DJ-1 in NAFLD.Methods:The wild-type（WT）mice and DJ-1 knockout(DJ-1^-/-)mice were fed with60%high-fat diet（HFD）for 24 weeks to establish an animal model of fatty liver.We monitored Body weight change,insulin sensitivity and liver lipid accumulation in mice by biochemical test,HE staining,oil red O staining,weighing body weight,epididymal fat weight and liver weight,glucose and insulin tolerance test.Western Blot,PCR and other methods were used to detect the changes of key enzyme genes in various metabolic pathways of the liver.Results:Ablation of DJ-1 prevents HFD-induced obesity,insulin resistance and hepatic TG accumulation.However,DJ-1 deficiency had no significant effect on the food intake,liver fatty acid synthesis and glycolysis in mice.Further research found that ablation of DJ-1 accelerate the energy metabolism significantly in mice,And then the fatty acid oxidant and tricarboxylic acid cycle（TCA）of the liver was also significantly increased.Conclusion:Deletion of DJ-1 significantly prevents HFD-induced fatty liver phenotype by promoting hepatic lipid oxidation in the liver.更多还原