Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, the Secondary Military Medical University, Shanghai, China.
Graduate School, Ningxia Medical University, Ningxia, China.
J Cell Physiol. 2018 Oct;233(10):6814-6824. doi: 10.1002/jcp.26547. Epub 2018 Apr 18.
Elevated plasma statured fatty acids (FFAs) cause TLR4/MD2 activation-dependent inflammation and insulin tolerance, which account for the occurrence and development of obesity. It has been confirmed that statured palmitic acid (PA) (the most abundant FFA) could bind MD2 to cause cellular inflammation. The natural compound celastrol could improve obesity, which is suggested via inhibiting inflammation, yet the detailed mechanism for celastrol is still unclear. As celastrol is reported to directly target MD2, we thought disrupting the binding between FFAs and MD2 might be one of the ways for celastrol to inhibit FFAs-caused inflammation and insulin resistance. In this study, we found evidence to support our hypothesis: celastrol could reverse PA-caused TLR4/MD2 activation-dependent insulin resistance, as determined by glucose-lowering ability, cellular glucose uptake, insulin action-related proteins and TLR4/MD2/NF-κB activation. Bioinformatics and cellular experiments showed that both celastrol and PA could bind MD2, and that celastrol could expel PA from cells. Finally, celastrol could reverse high fat diet caused hyperglycemia and obesity, and liver NF-kB activations. Taking together, we proved that celastrol could reverses PA-caused TLR4-MD2 activation-dependent insulin resistance via disrupting PA binding to MD2.
血浆中升高的长链饱和脂肪酸（FFAs）导致 TLR4/MD2 激活依赖性炎症和胰岛素抵抗，这是肥胖发生和发展的原因。已经证实，长链饱和脂肪酸（PA）（最丰富的 FFA）可与 MD2 结合导致细胞炎症。天然化合物雷公藤红素可改善肥胖，其通过抑制炎症来实现，但雷公藤红素的详细机制仍不清楚。由于雷公藤红素被报道可直接靶向 MD2，我们认为破坏 FFAs 与 MD2 之间的结合可能是雷公藤红素抑制 FFAs 引起的炎症和胰岛素抵抗的一种方式。在这项研究中，我们找到了支持我们假设的证据：通过降低血糖能力、细胞葡萄糖摄取、胰岛素作用相关蛋白和 TLR4/MD2/NF-κB 激活，我们发现雷公藤红素可以逆转 PA 引起的 TLR4/MD2 激活依赖性胰岛素抵抗。生物信息学和细胞实验表明，雷公藤红素和 PA 均可与 MD2 结合，并且雷公藤红素可将 PA 从细胞中排出。最后，雷公藤红素可以逆转高脂肪饮食引起的高血糖和肥胖以及肝脏 NF-κB 激活。综上所述，我们证明了雷公藤红素可以通过破坏 PA 与 MD2 的结合来逆转 PA 引起的 TLR4-MD2 激活依赖性胰岛素抵抗。
