JAZF1基因表达缺陷对脂糖代谢及炎症信号通路的影响

Type 2 diabetes mellitus (T2DM) or insulin resistance (IR) is known as a disease related chronic, low-grade tissue inflammation. To investigate the mechanism of insulin resistance, it is necessary to set up a excellent model with the better feature of IR. In this study, we combine tissue specificity RNA interference (RNAi) with and Cre／LoxP recombinase system to establish two recombinase adenovirus vectors, JAZF1-shRNA-loxP and aP2-Cre for targeting adipose tissues. Then, to set up an insulin resistance animal model with both high fat feeding and JAZF1 deficiency, JAZF1-shRNA-loxp and aP2-Cre were transferred into mice to preferably imitate insulin resistance in humans. whereafter, hyperinsulinaemic - euglycaemic clamps were performed to investigate the changes of glucose and lipid metabolism, insulin sensitivity,proinflammatory cytokines and PI3K/Akt,mTOR/S6K1 pathway in mice with JAZF1-shRNA-loxP and aP2-Cre.The biological effects are furthefr observed via blocking mTOR pathway by rapamycin.It is possible to understand the role mechanism of these changes from both JAZF1 deficiency and environmental factors in this model. Therefore, this study will identify JAZF1 as a potentially important target for the beneficial effects of JAZF1 in the treatment of diabetes and obesity.

T2DM或胰岛素抵抗（IR）目前也被认为是遗传有关的慢性低度炎症性疾病，构建能较好展现IR临床特征的动物模型是研究其发病机制的重要手段。本研究采用RNAi技术与基于Cre／LoxP重组酶系统组织特异性时空基因打靶技术相结合，构建JAZF1-shRNA-loxP腺病毒表达载体和组织特异性启动子-Cre重组酶腺病毒载体，分别转入高脂喂养的小鼠体内，塑造一个JAZF1基因表达缺陷和高脂喂养共同诱导的IR动物模型，尽可能展现类似IR的病理生理特征。利用扩展胰岛素钳夹术评价模型小鼠糖、脂代谢、胰岛素敏感性、炎症因子及PI3K/Akt和mTOR/S6K1信号系统的变化。并采用雷帕霉素阻断mTOR信号，进一步观察其外周生物学效应。初步勾勒出JAZF1基因缺陷和环境因素共同作用的特定条件下，糖、脂代谢紊乱及炎性信号调控变化及可能作用机制。为寻找IR发生的病理生理机制提供极有价值的数据和资料。

（juxtaposed with another zinc finger gene 1，与另一个锌指并列的基因1）又名Tip27（TAK1-interacting protein 27，与TAK1相作用的蛋白27）。JAZF1包含三个推定的C2H2锌指基序及在Glu131 和Glu146之间一个富含Glu/Asp区。本课题组构建了JAZF1过表达腺病毒载体Ad-JAZF1及JAZF1转基因小鼠JAZF1-Tg鼠，利用高脂喂养JAZF1过表达转基因小鼠，初步探讨JAZF1基因表达上调对高脂喂养小鼠肝脏促炎因子TNF-a, MCP-1 and IL-8的影响的调节及其可能的机制JAZF1基因表达上调可能通过抑制饱和脂肪酸-棕榈酸所诱导的肝细胞促炎因子TNF-α、MCP-1及IL-8的表达及分泌，在体内高脂诱导的JAZF1转基因鼠，通过抑制JNK/SAPK信号通路, 减缓了机体慢性低度炎症的发生发展，从而缓解2型糖尿病及相关代谢性疾病的进展。此研究结果，无疑为代谢性疾病发病机制的研究提供新的思路，并且为JAZF1的功能研究带来新的突破。在脂质代谢中，发现JAZF1激活AMPK信号，减少肝细胞内脂肪的从头合成，改善脂肪酸诱导的肝细胞内甘油三酯的累积。同时，在胰岛素的刺激下，JAZF1过表达可抑制胰岛素诱导的SREBP-1c启动子活性。相关文章正在拟稿中，并准备投稿，发表。