维生素A在肥胖慢性炎症状态下NLRP3炎症小体活化中的作用及机制研究

The activation of NLRP3 inflammasome plays an important role in the chronic inflammation caused by obesity, and thus the inhibition of NLRP3 inflammasome activation may help to prevent or lessen the chronic inflammatory reaction. It has been demonstrated that the lower levels of vitamin A are closely associated with chronic inflammation in obesity and associated chronic metabolic disorders. However, the underlying mechanisms are far from being fully understood. In our previous work, based on the compound library screening and cell culture study in vitro, vitamin A has been found to be able to significantly inhibit the activation of NLRP3 inflammasome. Therefore, we hypothesize that vitamin A deficiency may be involved in the activation of NLRP3 inflammasome in obesity associated chronic inflammation, and that the vitamin A supplementation may inhibit its activation leading to the alleviation of chronic inflammation. In this project, using the high fat diet induced obese (DIO) mice, dietary vitamin A intervention will be conducted to observe the relationship between different vitamin A status and the NLRP3 inflammasome and associated chronic inflammation. Then the causal relationship between the NLRP3 inflammasome and vitamin A will be investigated to examine the role of NLRP3 in mediating the effect of vitamin A on chronic inflammation, by using Nlrp3 gene knockout (Nlrp3-/-) mice. Furthermore, the specific regulatory mechanisms of vitamin A in the activation of NLRP3 inflammasome will be studied in vitro. Finally, it will be clarified whether the vitamin A receptors are involved in assembly, aggregation and activation of the proteins associated with NLRP3 inflammasome. This project will have great significance in elucidating the mechanisms of vitamin A’s regulation on the chronic inflammation and exploring the potential methods in prevention and treatment for chronic inflammation related metabolic diseases.

NLRP3炎症小体活化在肥胖慢性炎症的发生中起重要作用，抑制其活化有助于减轻慢性炎症。维生素A在肥胖及相关慢病状态下的低水平与慢性炎症发生密切相关，但作用机制尚不明确。我们前期化合物文库筛选和细胞实验发现--维生素A能够显著抑制NLRP3炎症小体活化，故我们假设：维生素A缺乏或不足可能参与肥胖慢性炎症状态下NLRP3炎症小体的活化，补充维生素A可抑制其活化进而减轻慢性炎症。本项目拟以高脂饲料诱导肥胖小鼠为对象，首先观察饲料中不同维生素A营养状态与慢性炎症和NLRP3炎症小体的关系，再利用NLRP3的基因缺陷小鼠观察NLRP3炎症小体在介导维生素A抑制慢性炎症中的因果效应；然后细胞实验探讨维生素A调控NLRP3炎症小体活化的特异机制，并深入观察维生素A受体在NLRP3炎症小体相关蛋白组装、多聚和活化中的作用。项目对于揭示维生素A影响肥胖慢性炎症的机制及探索相关代谢疾病的防治措施，有重要意义。

NLRP3炎症小体活化在肥胖慢性炎症的发生中起重要作用，抑制其活化有助于减轻慢性炎症。维生素A在肥胖及相关慢病状态下的低水平与慢性炎症发生密切相关，但作用机制尚不明确。我们的研究发现，维生素A能够显著抑制高脂食物诱导的肥胖、代谢紊乱和慢性炎症，表现为维生素A显著抑制高脂饲料诱导的小鼠的体重增加、糖脂代谢紊乱和脂肪组织及肝脏组织中炎性细胞的浸润和组织中IL-1β等炎性因子的水平。细胞实验表明维生素A显著抑制巨噬细胞中激动剂诱导的NLRP3炎症小体的激活，表现为caspase-1激活和IL-1β分泌增加。但是维生素对poly(dA:dT)诱导的AIM2炎症小体的激活没有影响。探究机制，我们发现维生素A不影响炎症小体活化中钾离子的外流，但是抑制了炎症小体活化中线粒体ROS的增强，进而抑制NLRP3炎症小体的组装和活化。因此，我们的研究结果表明，维生素A通过抑制巨噬细胞中线粒体ROS的增强抑制NLRP3炎症小体的活化，进而减轻高脂饮食诱导的组织慢性炎症，减少肥胖和代谢紊乱的发生。我们的研究对于揭示维生素A影响肥胖慢性炎症的机制及探索相关代谢疾病的防治措施，有重要意义。