模式识别受体CD36在脂肪组织代谢性炎症发生中的作用及分子机制

Both adipocytes and macrophages in adipose tissues were involved in the development of metabolic inflammation. Metabolic inflammation in adipose tissues is implicated in development of metabolic diseases, such as type 2 diabetes and atherosclerotic cardiovascular disease..Previous studies indicated that pattern recognition receptor CD36 might be the crosslink of lipid metabolism and inflammation. Our previous studies also has shown that high-fat diet upregulated serum free fatty acids (FFAs) levels (a CD36 ligand) and CD36 expression in adipose tissues of C57BL/6J mice, accompanied with increase levels of inflammatory cytokines in adipose tissues and blood. CD36 gene knock-out significantly ameliorated the high-fat diet induced metabolic inflammation in mice. However the molecular mechanisms by which CD36 activate metabolic inflammation remain unclear..It has been demonstrated that amyloid-β (a CD36 ligand) stimulates sterile inflammation in microglia by activation of CD36-TLR4-TLR6/Lyn pathway. We hypothesize that under metabolic disorders, the increased oxidized LDL and FFAs stimulate CD36 protein expression in adipose tissues which activates NF-κB mediated inflammatory response by recuiting kinase Lyn to the TLR4-TLR6 complex..In this project, the CD36 gene knockout / wild-type mice, adipocytes / macrophages will be used to investigate the molecular mechanisms and roles of CD36 in the occurrence of adipose tissues metabolic inflammation in vivo and in vitro.

代谢性炎症主要指营养物和代谢过剩所触发的慢性低峰度炎症，与代谢性疾病的发生发展密切相关。代谢性炎症产生的主要器官是脂肪组织，模式识别受体白细胞分化抗原36（CD36）是介导代谢性炎症的重要蛋白。课题组前期发现：高脂状态下，脂肪组织CD36表达上调且伴炎症因子增加；而CD36基因敲除显著降低炎症水平。然而，目前尚不清楚CD36激活脂肪组织代谢性炎症的具体分子机制。有研究报道在小胶质细胞中，CD36能与Lyn激酶和Toll样受体(TLRs)结合而活化NF-κB炎症信号通路，启动无菌性炎症反应。在脂肪组织中，CD36能否也通过与Lyn和TLRs结合而启动代谢性炎症的发生，至今未见报道，值得深入探讨。.本项目拟使用已有的野生型和CD36基因敲除小鼠、脂肪/巨噬细胞体内外模型，深入探讨脂肪组织内CD36/Lyn/TLRs激活代谢性炎症反应的信号转导机制，从一个新的角度阐释代谢性炎症发生的分子机制。

代谢性炎症主要指营养物和代谢过剩所触发的慢性低峰度炎症，与代谢性疾病的发生发展密切相关。代谢性炎症产生的主要器官是脂肪组织，模式识别受体白细胞分化抗原36（CD36）是介导代谢性炎症的重要蛋白。.课题组使用已有的野生型和CD36 基因敲除小鼠、脂肪/巨噬细胞体内外模型，初步证明：①棕榈酸作为CD36 的配体能上调脂肪细胞和巨噬细胞的CD36 表达，同时促进CD36融入脂筏中，随后CD36与TLR4形成CD36/TLRs共聚体，激活JNK信号通路和NF-κB信号通路，促使下游多种炎症和趋化因子的转录，启动代谢性炎症反应；② 抑制CD36 基因的表达能有效降低棕榈酸诱导的脂肪细胞和巨噬细胞的炎症反应；③CD36 基因缺失能降低脂肪组织代谢性炎症的发生并改善高脂诱导的小鼠胰岛素抵抗；而超表达CD36能进一步加重高脂导致的胰岛素抵抗。.项目深入探讨了脂肪组织内CD36激活代谢性炎症反应的信号转导机制，从一个新的角度阐释代谢性炎症发生的分子机制。相关研究结果已发表SCI论文6篇，CSCD核心期刊论文4篇。