经典死亡蛋白FADD对脂代谢的调控及其分子机制研究

Our research team has been long-timely investigating the non-apoptotic biological functions of classic apoptotic protein FADD. Recently we have revealed several new biological functions and the underlying mechanisms of FADD protein. These studies have better interpreted the diversity of FADD biological function. Our previous proteomic studies show that FADD, as a classic death protein, is most likely involved in cellular metabolic processes, including fatty acid metabolism, glucose metabolism. FADD deficiency has a distinct impact on fatty acids β-oxidation in MEF cell and adipocytes or adipose tissue in animal. All these results suggest important biological regulation of FADD on adipocytes and this novel function of FADD is probably not due to its apoptotic or death function. This phenotype and detailed mechanism has not been reported up to now. This proposal will use genetically modified cell and animal models of FADD to systematically investigate the role of FADD in lipid metabolism and the related mechanisms. This proposal aims to broaden our understanding and knowledge on the biological functions of FADD and lipid metabolism. We will also explore the possibility of FADD and its regulation as therapeutic or intervention target for obesity, and thus provide novel theory and approach for prevention or treatment of obesity.

本课题组长期从事经典细胞凋亡蛋白FADD非凋亡生物学功能研究，近年来相继发现了FADD的多种新生物学功能及其机制，较好诠释了FADD生物学功能的多样性。本课题组前期的蛋白质组学研究显示：作为经典死亡蛋白的FADD很可能参与细胞的代谢过程，包括脂肪酸代谢、糖代谢。FADD缺失对细胞的脂肪酸β氧化、动物模型的脂肪细胞及脂肪组织都产生了显著的影响，这些结果提示FADD对脂肪细胞具有重要的生物学功能，而且FADD调节脂代谢的功能很可能与其细胞凋亡功能无关，其表型及机制迄今尚未有报道。本课题拟采用FADD基因改造的细胞和动物模型，系统地研究FADD在脂代谢中的作用及其相关机制，拓宽对FADD生物学功能和脂代谢的认识和理解，探索将FADD及其调控作为肥胖治疗靶点的可能性，为肥胖症的预防和治疗提供新理论和新途径。

FADD是死亡受体介导的凋亡通路中的接头蛋白。近年来的研究发现FADD还参与其它许多非凋亡生物学过程。本课题通过构建ad-FADD、FADD-D、FADD-D/ob/ob三种基因改造小鼠模型，首次揭示了FADD参与脂代谢调控的新功能。研究发现FADD-D突变或者脂肪组织特异性敲除FADD（ad-FADD）均能逆转高脂饮食诱导的小鼠肥胖表型，降低小鼠体内脂肪含量。此外，FADD-D突变可以逆转严重的遗传性肥胖ob/ob小鼠的表型，增加其能量消耗，改善其胰岛素抵抗。分子机制分析表明，FADD可以与PPARα的抑制蛋白RIP140相互作用，FADD-D突变或者FADD缺失可消除RIP140介导的转录抑制，引发PPARα的转录激活，增强脂肪酸的氧化代谢。本课题系统地研究了FADD在脂代谢中的作用及其相关机制，拓宽了对FADD生物学功能和脂代谢的认识和理解，探索了将FADD及其调控作为肥胖治疗靶点的可能性，为肥胖症的预防和治疗提供了新理论和新途径。