TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway. (19th December 2019) - Chen, Xide
Abstract : Metabolic inflammatory damage, characterized by Toll-like receptor 4 (TLR4) signaling activation, is a major mechanism underlying lipotoxicity-induced β -cell damage. The present study is aimed at determining whether G protein-coupled receptor 4 (GPR40) agonist can improve β -cell lipotoxicity-induced damage by inhibiting the TLR4-NF- κ B pathway. Lipotoxicity, inflammation-damaged β -cells, obese SD, and TLR4 KO rat models were used in the study. In vitro, TAK-875 inhibited the lipotoxicity- and LPS-induced β -cell apoptosis in a concentration-dependent manner, improved the insulin secretion, and inhibited the expression of TLR4 and NF- κ 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- κ 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 α or β -cells, inhibited the apoptosis of islet cells, and inhibited the expression of TLR4 and NF- κ 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 β -cell damage by inhibiting the TLR4-NF- κ B pathway.