Gadd45α调控脂代谢的分子机制研究

代谢异常与恶性肿瘤发生发展密切相关，对其机制进行深入研究并探索可行的治疗方法十分必要。本项目前期研究发现，(1)在MEFs细胞中敲除Gadd45α能够导致脂代谢重组；(2)Gadd45α敲除小鼠在自然饮食条件下自发严重的脂肪肝。这些现象提示Gadd45α是调控脂代谢的关键因子。(3)更为重要的是，Gadd45α可与脂代谢调控中枢AMPK/AXIN1复合体发生相互作用，Gadd45α功能缺失导致AMPK磷酸化水平下降。据此，我们提出新的理论假设，Gadd45α通过与AMPK/AXIN1复合体结合促进LKB1对AMPK磷酸化，激活后的AMPK磷酸化其下游底物，进而抑制性调节脂代谢信号通路。本项目将基于上述研究基础，从分子水平、细胞水平和模式动物等多个维度进行系统研究，揭示Gadd45α表达异常对机体代谢的影响，阐明Gadd45α在脂代谢调控中的分子机制，并探索干预、治疗新靶点。

Metabolism dysregulation can induce tumorigenesis and increase its progression. However, the underlying mechanisms remain unclear. In the present study, we found that the core lipid synthesis gene was markedly activated in the MEFs and livers from Gadd45αΔ/Δ mice compared with wildtype controls. Knockout of Gadd45α exacerbated adipose tissue accumulation in the liver, indicating an essential role of Gadd45α in lipid homeostasis. The AMP-activated protein kinase (AMPK) has been confirmed to be the principal sensor in charging of lipid homeostasis, switching off anabolic pathways such as fatty acid, triglyceride, cholesterol, and protein synthesis, and switching on catabolic pathways such as fatty acid oxidation and glycolysis. Using co-IP and western blot , we found that Gadd45α interact with AMPK and AXIN1. Therefore, we propose: Gadd45α inhibit lipid synthesis through AMPK pathway by binding with AMPK/AXIN1 complex and enhancing LKB1 activation. The proposed study will provide a new role for Gadd45α as lipid regulator. More importantly, it will demonstrate one underling mechanism linking metabolism dysfunction with cancer progression.