CIS通过调节生长激素信号通路参与肝脏脂肪变性发病机制的研究

Non-alcoholic fatty liver disease(NAFLD) is a clinicopathologic syndrome, the earliest and the most important histologic feature is hepatocyte steatosis. Our previous and other studies suggest that growth hormone is associated with NAFLD, but the precise mechanism remains poorly understood. Cytokine inducible src homology 2 domain containing protein(CIS) has a prominent function as a negative regulator of growth hormone signaling pathway. Our research plan: Initially, establish vitro and vivo models of hepatic steatosis. Secondly, enhance or inhibit the expression of CIS in the model .Then, detect the the steatotis change of the models in vitro and vivo after CIS enhanced or suppressed ;Detect the other factor such as JAK2, STAT5, IGF-1 by quantitative RT-PCR, western-blot methods etc ,which are the key factors of growth hormone signaling pathways . In addition ,the expression of the genes related to lipid uptake、lypolysis、lipogenesis will also be tested. The purpose of our study is to test our working hypothesis that CIS is involved in the development of hepatocyte steatosis by regulating growth hormone signaling pathway, and explore the new mechanisms and therapeutic targets of NAFLD.

非酒精性脂肪性肝病（NAFLD）以肝细胞脂肪变性为主要特征。我们前期及其他研究均提示生长激素与NAFLD密切相关,但具体机制仍有诸多不明；细胞因子诱导的含SH2区域的蛋白（CIS）被认为是生长激素信号通路的重要负性调控因子，我们在脂肪肝动物模型中发现CIS基因表达上调。本研究拟在建立肝脏脂肪变性的离体和动物模型的基础上，通过采用腺病毒载入及RNA干扰的方法，在体外和体内两个水平上对CIS进行表达增强或抑制，观察其对于肝细胞脂肪变性的影响，并进一步观测生长激素信号通路的关键因子的变化以及肝细胞脂肪代谢相关基因的变化，检测CIS是否通过调节生长激素信号通路参与肝脏脂肪变性的发病机制，以期探寻NAFLD发病的新机制及提供防治的新靶点。

非酒精性脂肪肝（NAFLD）是指以肝细胞脂肪变性为主要特征的临床病理综合征，其患病率日益升高，但其发病机制目前尚未明确。前期研究证实生长激素与NAFLD密切相关，本研究旨在探索生长激素负性调节蛋白细胞因子诱导的含SH2区域的蛋白（CIS）参与肝脏脂肪变性的分子机制。课题组成功构建了NAFLD的动物及细胞模型，并发现在NAFLD细胞及动物模型中CIS的mRNA和蛋白表达水平均显著上调。而利用siRNA抑制CIS表达后NAFLD细胞的脂化程度显著降低，相反的，感染CIS慢病毒的NAFLD细胞中脂化程度进一步加深。进一步研究发现抑制CIS表达能够上调STAT5与JAK2的表达，并且提高了生长激素相关基因IGF-1的表达。同时，课题组还发现抑制CIS表达能够降低脂肪酸摄取基因CD36与生脂基因SCD-1的表达并提高脂解基因PPAR-α的表达。本课题表明CIS是NAFLD抑制基因中的重要一员，其能够通过负性调控STAT-JAK信号通路来调节肝细胞的脂肪变性，研究也为治疗NAFLD提供了新的思路和新的靶点。