Original Article:
TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway
Xide Chen, et al.
Toxicological Sciences,2018, 163(2), 374-384.
10.1155/2019/5487962
TAK-875 is a selective G protein-coupled receptor 4 (GPR40) agonist. Metabolic inflammation is an important pathophysiology of obesity-induced diabetes. Toll-like receptor 4 (TLR4), a key factor in the activation of innate immunity in inflammatory signaling pathways, plays a key role in the pathogenesis of metabolic inflammation in type 2 diabetes.
This work aims to investigate the relationship between the protective effect of GPR40 against lipotoxicity-induced metabolic inflammatory injury and the TLR4-NF-κB pathway by using a β-cell line, HFD-induced obese rats. In vitro, TAK-875 inhibits lipotoxicity and LPS-induced β-cell apoptosis, improves insulin secretion, and inhibits the expression of TLR4 and NF-κB subunit P65 in a concentration-dependent manner. Furthermore, silencing of TLR4 expression enhanced the protective effect of TAK-875, whereas TLR4 overexpression attenuated this protective effect. The findings suggest that GPR40 agonists antagonize lipotoxic β-cell injury by inhibiting the TLR4-NF-κB pathway.
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