TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway
TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway
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TAK-875 通过抑制 TLR4-NF-kappa B 途径减轻 β 细胞脂毒性诱导的炎症损伤
DOI：
10.1155/2019/5487962
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发表时间：
2019-12-19
影响因子：
4.3
通讯作者：
Yang, Liyong
中科院分区：
文献类型：
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作者：
Chen, Xide;Yan, Yuanli;Yang, Liyong
以Toll样受体4（TLR 4）信号传导激活为特征的代谢性炎症损伤是脂毒性诱导的β细胞损伤的主要机制。本研究旨在确定G蛋白偶联受体4（GPR40）激动剂是否可以通过抑制TLR4-NF-κ B通路来改善脂毒性诱导的β细胞损伤。在研究中使用脂毒性、炎症损伤的β细胞、肥胖SD和TLR4（KO）大鼠模型。在体外，TAK-875以浓度依赖性方式抑制脂毒性和LPS诱导的β细胞凋亡，改善胰岛素分泌，并抑制TLR 4和NF-κ B亚基P65的表达。此外，TLR4表达的沉默增强了TAK-875的保护作用，而TLR4过表达减弱了这种保护作用。TLR 4或NF-κ B的活化减弱了TAK-875对PA诱导的损伤的拮抗作用。此外，TAK-875的上述过程部分不依赖于GPR40表达。TAK-875可降低肥胖大鼠的体重和炎症因子，重新平衡α或β细胞的数量和分布，抑制胰岛细胞凋亡，并抑制TLR 4和NF-κ B亚基P65的表达。进一步敲除大鼠TLR4基因延迟了高脂饮食诱导的损伤，并与TAK-875的作用协同。这些数据表明，GPR40激动剂通过抑制TLR 4-NF-κ B途径拮抗脂毒性β细胞损伤。
Metabolic inflammatory damage, characterized by Toll-like receptor 4 (TLR4) signaling activation, is a major mechanism underlying lipotoxicity-induced beta-cell damage. The present study is aimed at determining whether G protein-coupled receptor 4 (GPR40) agonist can improve beta-cell lipotoxicity-induced damage by inhibiting the TLR4-NF-kappa B pathway. Lipotoxicity, inflammation-damaged beta-cells, obese SD, and TLR4(KO) rat models were used in the study. In vitro, TAK-875 inhibited the lipotoxicity- and LPS-induced beta-cell apoptosis in a concentration-dependent manner, improved the insulin secretion, and inhibited the expression of TLR4 and NF-kappa B subunit P65. Besides, silencing of TLR4 expression enhanced the protective effects of TAK-875, while TLR4 overexpression attenuated this protective effect. Activation of TLR4 or NF-kappa B attenuated the antagonism of TAK-875 on PA-induced damage. Moreover, the above process of TAK-875 was partially independent of GPR40 expression. TAK-875 reduced the body weight and inflammatory factors, rebalanced the number and distribution of alpha or beta-cells, inhibited the apoptosis of islet cells, and inhibited the expression of TLR4 and NF-kappa B subunit P65 in obese rats. Further knockout of the rat TLR4 gene delayed the damage induced by the high-fat diet and synergy with the action of TAK-875. These data suggest that GPR40 agonists antagonized the lipotoxicity beta-cell damage by inhibiting the TLR4-NF-kappa B pathway.