ATG7类E1泛素激活酶活性调控SIRT1泛素化修饰及其对衰老进程中脂肪细胞代谢紊乱影响机制研究

过度脂质沉积及脂肪异常分布是导致老年机体代谢紊乱及相关疾病发生的重要原因。衰老进程中，脂肪细胞自噬增强，长寿基因-组蛋白去乙酰化酶SIRT1表达减少并诱发脂质代谢功能紊乱，二者之间的关联机制尚不十分清楚。我们近期研究工作发现：1）自噬相关蛋白ATG7在老年小鼠脂肪组织中高表达；2）ATG7作为类E1泛素激活酶，参与SIRT1的泛素化修饰；3）Atg7基因敲除减低脂质生成。据此，我们推测：衰老进程中脂肪组织微环境改变ATG7表达，调控SIRT1蛋白降解，影响脂质代谢。本课题拟通过衰老脂肪细胞模型及脂肪条敲Atg7基因小鼠模型，进一步探索ATG7对SIRT1泛素化的调控规律，阐明ATG7介导的SIRT1表达减少与脂质代谢功能紊乱的分子机制，为衰老相关脂质代谢紊乱以及代谢类疾病的预防及治疗提供新思路和理论依据。

Excessive lipid accumulation and abnormal fat distribution are the important causes of metabolic disorders and related diseases in the elderly. In the process of aging, increased autophagy, decreased SIRT1 expression and lipid metabolism dysfunction was co-observed in adipocytes. The mechanism of the relationship between SIRT1 and autophagy remains unclear. Our recent work showed that: 1) autophagy related protein ATG7 is highly expressed in the adipose tissue of old mice; 2) ATG7, as an E1-like ubiquitin activating enzyme, participates in the ubiquitinated modification of SIRT1; 3) Atg7 knockout reduces lipid production. Therefore, we speculate that the microenvironment of adipose tissue upregulates the expression of ATG7, which regulates SIRT1 protein degradation and affects lipid metabolism. The aim of this study is to further explore the regulation of ATG7 on the ubiquitination of SIRT1, and to elucidate the molecular mechanism of ATG7-induced SIRT1 reduction in regulating lipid metabolism disorder, which would provide new ideas and theoretical basis for the prevention and treatment of aging related lipid metabolism disorder and metabolic diseases.