TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells.
TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells.
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DOI：
10.1042/bsr20120098
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发表时间：
2012-11-30
影响因子：
4
通讯作者：
Musi N
中科院分区：
文献类型：
--
作者：
Hussey SE;Liang H;Costford SR;Klip A;DeFronzo RA;Sanchez-Avila A;Ely B;Musi N
新的证据表明TLR4(Toll样受体)及其下游通路[丝裂原活化蛋白激酶(MAPKs)和核因子κB(核因子κB)]在胰岛素抵抗的发病机制中起重要作用。脂多糖(LPs)和饱和的NEFA(非酯化脂肪酸)激活TLR4，肥胖和2型糖尿病患者血浆中这些TLR4配体浓度升高。我们的目标是明确TLR4在脂多糖和饱和NEFA引起的胰岛素抵抗中的作用，并通过使用TLR4的特异性抑制剂TAK-242来剖析LPS和NEFA在TLR4驱动的通路激活中的独立贡献。脂多糖导致L6肌管中丝裂原活化蛋白激酶和核因子-κB通路的强烈激活，以及胰岛素信号和葡萄糖运输的受损。TAK-242可完全阻断脂多糖引起的炎症反应(丝裂原活化蛋白激酶和核因子-κB活化)，进而改善脂多糖诱导的胰岛素抵抗。与脂多糖类似，硬脂酸对MAPK有强烈的激活作用，但对NF-κB轴的刺激较弱。与脂多糖一样，硬脂酸盐引起的炎症反应伴随着胰岛素作用的减弱。TAK-242也可减弱硬脂酸诱导的炎症反应；然而，TAK-242的保护作用是部分的，仅在MAPK上观察到。因此，TAK-242只能部分改善硬脂酸盐引起的胰岛素抵抗。综上所述，TAK-242对脂多糖和NEFA诱导的炎症和胰岛素抵抗分别提供了完全和部分保护作用。因此，脂多糖诱导的胰岛素抵抗完全依赖于TLR4，而NEFA通过TLR4依赖和非依赖的机制来削弱胰岛素的作用。
Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action.