治疗肥胖性胰岛素抵抗的新靶点PPARδ通过GSTP1-NLRP3炎性体通路抗炎的作用和机制研究

Peroxisome proliferator-activated receptor (PPAR) δ is a nuclear receptor that has represented as a potential new therapeutic target for obesity-induced insulin resistance (IR). Emerging evidence suggests that PPARδ attenuates IR by repression of IL-1β production in macrophages; however, the mechanisms underpinning this anti-inflammatory property of PPARδ have not been fully understood. Previously, it is shown that NLRP3 inflammasome activation is required for IL-1β production in macrophages; however, we found that PPARδ activation could attenuate NLRP3 mRNA level. We also found that, activation of PPARδ resulted in a highly enriched gene expression of GSTP1. Moreover, overexpress GSTP1 in macrophages repressed NLRP3 gene expression as indicated by our preliminary data. Therefore, we propose that PPARδ exerts inhibitory effect on IL-1β production through transcriptional induction of GSTP1 which further suppresses NLRP3 inflammasome activation in macrophages. In the present study, we will first induce-or-reduce PPARδ expression in macrophages to investigate its role in regulating NLRP3 inflammasome activation. Secondly, luciferase reporter gene will be used to identify regulatory mechanism of PPARδ on GSTP1 expression. Thirdly, we will test if GSTP1 could modulate the activation process of NLRP3 inflammasome. At last, our hypothesis will be verified in obesity-induced IR mice model using the PPARδ-deficient bone marrow chimaeras mice. This study will provide a new mechanism underlying PPARδ inhibitory effect on obesity-induced IR, and also offer new evidence for development and application of PPARδ agonists as an anti-obesity-induced IR drug.

核转录因子PPARδ是肥胖性胰岛素抵抗（IR）的新型治疗靶点，其作用机理与抑制巨噬细胞产生IL-1β有关，但PPARδ抑制巨噬细胞产生IL-1β的机制不完全清楚。IL-1β的产生依赖NLRP3炎性体的活化，而我们发现激活PPARδ可抑制NLRP3的基因表达；我们还发现激活PPARδ后，GSTP1是表达量升高最显著的基因之一，其过表达可使NLRP3的表达降低。故推测：PPARδ可通过上调GSTP1的表达，抑制NLRP3炎性体的活化，从而抑制IL-1β产生。本研究首先改变PPARδ的表达，探寻其对NLRP3炎性体的调控作用；然后用荧光素酶报告基因揭示PPARδ对GSTP1的调控机制；再考察GSTP1对NLRP3炎性体的影响；最后在骨髓细胞敲除PPARδ基因的小鼠中建立肥胖性IR模型，验证体外试验的结果。本项目旨在完善PPARδ抑制肥胖性IR的机制，为PPARδ激动剂的开发应用提供新的科学依据。