StAR在非酒精性脂肪性肝病发生发展中的作用机制研究

Nonalcoholic fatty liver disease (NAFLD) has been the main hepatic disease in china, which induces to heavy burden on people's health, thus the studies on NAFLD has been one of the hot topics in medicine. Insulin resistance, lipid medabolism disorder and inflammation are the major mechanism for NAFLD. Steroidogenic acute regulatory protein (StAR) is one of the transporters of cholesterol. Our group studied it's role in non-steroid genesis tissue for the first time. The results indicated that StAR could maintain homeostasis of lipid metabolism and inhibit inflammation by activating nuclear receptor PPARγ and LXRα, furthermore, ameliorate insulin resistance in peripheral tissue. The previous work of this study shows that StAR mRNA level reduced obviously in mouse liver of steatosis induced by high fat diet. Based on our previous study, we proposed that StAR could retard the evolvement and development of NAFLD by maintaining homeostasis of lipid metabolism, inhibiting inflammation via activating PPARγ? and LXRα and ??ameliorating insulin resistance. In the present study, we plan to study the role of StAR and to expound the underlying mechanism in the genesis and development of NAFLD in animal and cultured hepatocytes by overexpressing or inhibiting StAR. It will provide the new drug target for the prevention and treatment for NAFLD in the clinic.

非酒精性脂肪性肝病（NAFLD）已成为我国常见肝病之一，给人类健康带来沉重负担，对NAFLD的研究已成为当前的热点和难点，其中胰岛素抵抗、脂代谢紊乱以及炎症是其主要发病机制。类固醇合成急性调节蛋白（StAR）是一类胆固醇转运蛋白，本课题组首次在非类固醇合成组织中研究了其作用，发现其可通过增加氧化固醇激活核受体PPARγ和LXRα，维持脂质代谢平衡和抑制炎症反应，并可改善外周器官的胰岛素抵抗状态。在此基础上，本课题提出StAR可能通过促进胆固醇生成氧化固醇，激活核受体PPARγ/LXRα，进而改善胰岛素抵抗状态，调节脂质代谢以及炎症反应，从而减缓NAFLD的发生发展。因此，本课题拟利用StAR过表达及干扰表达的慢病毒载体，在LDLR-/-小鼠NAFLD模型体内及体外培养的肝细胞中，研究StAR在NAFLD发生发展中的作用机制。本研究将为NAFLD的防治提供理论基础和实验依据以及新的靶点。

非酒精性脂肪性肝病（NAFLD）是我国常见肝病之一，其病理类型包括单纯性脂肪肝、非酒精性脂肪性肝炎（NASH），后者可发展为相关肝硬化甚至肝癌。肝细胞内脂质蓄积是NAFLD进展过程的第一步。类固醇合成急性调节蛋白（StAR）是一类胆固醇转运蛋白，在胆汁酸、脂质合成及胆固醇代谢中起重要作用。本课题拟利用StAR 过表达的腺病毒载体，在游离脂肪酸处理的体外培养肝细胞中及高脂喂养的小鼠NAFLD模型体内，研究StAR在NAFLD 发生发展中的作用及其可能机制。我们发现StAR在脂肪肝病人、NAFLD细胞及小鼠模型中表达明显降低，且肝脏过表达StAR可通过激活法尼醇X受体（FXR）通路，减少肝脏中的脂质蓄积、维持肝糖代谢稳态。过表达StAR降低肝细胞内二酰基甘油的水平，抑制PKCε磷酸化，从而改善细胞的胰岛素信号转导。另外，FXR失活可逆转StAR的保护性作用。因而，本课题提出StAR 可通过促进胆汁酸合成，激活法尼醇X受体（FXR），进而改善胰岛素抵抗状态，调节糖脂代谢以及炎症反应，从而减缓NAFLD的发生发展。本研究将为NAFLD的防治提供理论基础和实验依据以及新的靶点。