Insulin resistance has been shown to be the common pathogenesis of many metabolic diseases. Metainflammation is one of the important characteristics of insulin resistance. Macrophage polarization mediates the production and development of metainflammation. Toll-like receptor 4 (TLR4) mediates macrophage activity and is probably the intersection of immunity and metabolism, but the detailed mechanism is probably not fully understood. Activated protein 1 (AP1) signaling pathway is very important in macrophage activation-mediated inflammation. However, it is unclear whether AP1 signaling pathway mediates metabolic inflammation in the liver. We aimed to investigate the effects of macrophage TLR4-AP1 signaling pathway on hepatocyte metabolic inflammation, insulin sensitivity, and lipid deposition, as well as to explore the potential of TLR4-AP1 as new intervention targets of insulin resistance and liver steatosis. TLR4 and AP1 were silenced in the RAW264.7 cells by lentiviral siRNA transfection. In vivo transduction of lentivirus was administered in mice fed with high-fat diet. Insulin sensitivity and inflammation were evaluated in the treated cells or animals. Our results indicated that TLR4/AP-1 siRNA transfection alleviated high-fat diet-induced systemic and hepatic inflammation, obesity, and insulin resistance in mice. Additionally, TLR4/AP-1 siRNA transfection mitigated palmitic acid- (PA-) induced inflammation in RAW264.7 cells and metabolic abnormalities in cocultured AML hepatocytes. Herein, we propose that TLR4-AP1 signaling pathway activation plays a crucial role in high fat- or PA-induced metabolic inflammation and insulin resistance in hepatocytes. Intervention of the TLR4 expression regulates macrophage polarization and metabolic inflammation and further alleviates insulin resistance and lipid deposition in hepatocytes.

中文翻译：

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TLR4/AP-1 靶向抗炎干预减弱胰岛素敏感性和肝脂肪变性

胰岛素抵抗已被证明是许多代谢疾病的常见发病机制。Metainflammation 是胰岛素抵抗的重要特征之一。巨噬细胞极化介导了金属炎症的产生和发展。Toll 样受体 4 (TLR4) 介导巨噬细胞活性，可能是免疫和代谢的交叉点，但详细机制可能尚未完全了解。活化蛋白 1 (AP1) 信号通路在巨噬细胞活化介导的炎症中非常重要。然而，AP1信号通路是否介导肝脏代谢炎症尚不清楚。我们旨在研究巨噬细胞 TLR4-AP1 信号通路对肝细胞代谢炎症、胰岛素敏感性和脂质沉积的影响，以及探索 TLR4-AP1 作为胰岛素抵抗和肝脂肪变性的新干预靶点的潜力。TLR4 和 AP1 通过慢病毒 siRNA 转染在 RAW264.7 细胞中沉默。在高脂肪饮食喂养的小鼠中进行慢病毒的体内转导。在处理过的细胞或动物中评估胰岛素敏感性和炎症。我们的结果表明，TLR4/AP-1 siRNA 转染减轻了小鼠高脂饮食诱导的全身和肝脏炎症、肥胖和胰岛素抵抗。此外，TLR4/AP-1 siRNA 转染减轻了棕榈酸 (PA-) 诱导的 RAW264.7 细胞炎症和共培养 AML 肝细胞的代谢异常。在此处，我们提出 TLR4-AP1 信号通路激活在肝细胞中高脂肪或 PA 诱导的代谢炎症和胰岛素抵抗中起着至关重要的作用。TLR4 表达的干预调节巨噬细胞极化和代谢炎症，并进一步减轻肝细胞中的胰岛素抵抗和脂质沉积。