Notch3在非酒精性脂肪性肝病SREBPs信号通路中作用机制的研究

NAFLD is a kind of common chronic liver disease, in which dysfunction of lipid metabolism plays an important role. Recent data has shown Notch family involves hepatic steatosis induced by obesity and ethanol. In our previous study, we found Notch3 mRNA was down-regulated at early stage of NAFLD, and then increased both in vivo and in vitro. In order to make it clear, we try to adopt siRNA/knockout Notch3 gene or develop recombinant adenovirus vector, and observe the association between Notch3 and insulin resistance, hepatic steatosis as well as lipid metabolism. The other aim of our project is to find out the effect of Notch3 in SREBP-1c and SREBP-2 signal pathway during NAFLD, due to indispensable of SREBPs in lipid metabolism. The purpose of our project is to provide new theoretical and experimental basis of NAFLD therapy.

非酒精性脂肪性肝病(NAFLD)是常见的慢性肝病，脂质代谢紊乱在其进程中起着重要作用，类固醇调节因子结合蛋白(SREBPs)是调节脂质代谢的主要蛋白。新近研究表明Notch家族与肥胖或酒精诱导的肝脂肪变相关。我们前期研究发现随NAFLD发生发展，鼠模及细胞实验中Notch3基因表达量均呈现先下调后上升的趋势，其机制尚无报道。本课题以此为切入点，拟从细胞和动物水平，通过siRNA基因静默/特异性基因敲除及构建腺病毒载体调控Notch3受体的表达，动态观察Notch3对胰岛素抵抗、肝脂肪变及脂质代谢的影响；采用不同时间点，进一步研究Notch3激活或失活后，SREBP-1c、SREBP-2通路相关基因和蛋白表达的动态变化，明确Notch3在脂肪酸和胆固醇代谢中的作用及确切机制，以期揭示其与SREBPs信号途径的相关性，从而为NAFLD防治提供新思路。

非酒精性脂肪性肝病(NAFLD)的发病率不断增长并已成为全球公共卫生领域的新挑战，它与脂质代谢紊乱、肥胖和代谢性危险因素密切相关，类固醇调节因子结合蛋白(SREBPs)是调节脂质代谢的主要蛋白。本课题以Notch3为切入点，从细胞和动物层面证实Notch3的增高促进肝脏炎症反应和脂质代谢失调，并随着NAFLD进展而表达上调；Notch3对脂代谢的影响以胆固醇代谢紊乱为主，沉默Notch3基因可改善脂代谢，反之亦然；在NAFLD发生过程中Notch3涉及的通路为SREBP-2信号途径，与SREBP-1c信号通路无明显相关性。SREBP-2相关基因SREBP裂解活化蛋白SCP、位点1蛋白水解酶（S1P）和位点2蛋白水解酶（S2P）等均参与整个过程，为NAFLD诊治提供新的方向。