PP2A介导Insulin-Akt-Foxo1和 AMPK通路动态调控的分子机理及对肝脏糖脂合成代谢的影响

Foxo1是叉头蛋白转录因子家族重要一员，调控一些重要糖异生基因转录，受胰岛素信号通路抑制性调节，因而传统观念认为抑制Foxo1活化可作为2型糖尿病治疗策略。课题组前期在Foxo1肝敲小鼠中发现血脂升高；进一步在Foxo1-S253A小鼠中发现其血脂降低，AMPK活化，且该活化可能与PP2A有关，高度提示在Insulin-Akt和AMPK信号通路之间，存在一种全新的Foxo1-PP2A介导机制，动态调控糖脂代谢。本研究拟采用Foxo1-S253A小鼠肝组织、原代肝细胞及转染Foxo1-S253A或Foxo1 siRNA质粒的HepG2细胞，经AMPK及PP2A阻断剂分别处理后，检测一系列蛋白磷酸化、相互作用及其它生化指标，逐一验证这一调控机制的各个环节，并考察其对肝脏糖脂代谢的影响。研究结果将为全面认识Foxo1功能及2型糖尿病防治策略提供全新资料。

Foxo1, an important member of the fork head protein transcription factor family, is involved in regulating some important gluconeogenic gene transcriptions and is modulated negatively by insulin signaling pathway. It is therefore thought that the inhibition of Foxo1 activation can be used as a strategy for the treatment of type 2 diabetes mellitus. Our group found that blood lipid was enhanced in hepatic Foxo1 knockout mice while lipid lowering was observed in Foxo1-S253A mice, accompanied by AMPK activated in relation to the function of PP2A, indicating that there might be a novel insulin-Akt-Foxo1-PP2A-AMPK signal pathway involved in glucose and lipid metabolism regulation. In our study, the existence of this signaling pathway as well as its influence on liver glucose and lipid metabolism will be confirmed via the examination of the protein phosphorylation, the interaction and other biochemical indices for liver tissues, Foxo1-S253A mouse primary hepatocytes and HepG2 cells transfected with Foxo1-S253A or Foxo1 siRNA plasmids after treatment with AMPK and PP2A antagonists, respectively. This study will provide key insights into the function of Foxo1 and type 2 diabetes prevention strategies.