槲皮素通过Nrf2/MAPK/NF-<i>κ</i>B通路改善LPS诱导的小鼠肝肾氧化应激、炎症及胰岛素抵抗的机制

李雨晨; 陈蔚蔚; 吴海峰; 宿婷

doi:10.13386/j.issn1002-0306.2025090167

槲皮素通过Nrf2/MAPK/NF-κB通路改善LPS诱导的小鼠肝肾氧化应激、炎症及胰岛素抵抗的机制

Mechanistic Study on Quercetin Attenuation of LPS-Induced Hepatic and Renal Oxidative Stress, Inflammation, and Insulin Resistance via the Nrf2/MAPK/NF-κB Signaling Pathways in Mice

摘要

摘要: 本研究旨在探讨槲皮素对脂多糖（LPS）诱导的小鼠肝肾组织氧化应激、炎症反应、胰岛素抵抗的改善作用及其分子机制。实验选用2月龄C57BL/6J雄性小鼠，采用腹腔注射LPS（5 mg/kg/d，持续1周）建立系统性炎症模型，同时给予40 mg/kg/d槲皮素干预，系统探究了槲皮素对小鼠肝肾脏组织中炎症、氧化应激和胰岛素抵抗的干预作用。结果显示，相较LPS组小鼠，摄入槲皮素后，肾脏的Nrf2/HO-1/NQO-1蛋白表达量分别增加32.56%、27.25%、53.53%（P<0.05），肝脏的Nrf2/HO-1/NQO-1蛋白表达量分别增加56.11%、40.23%、39.46%（P<0.05），Nrf2抗氧化防御通路显著激活，抗氧化基因的表达明显上调，有效缓解LPS诱导的氧化应激损伤。此外，槲皮素能够调控丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路，降低促炎因子的释放，减轻肝肾组织的炎症反应。经槲皮素干预，小鼠肾脏和肝脏组织中p-IκB/IκB及p-NFκB/NFκB的比值相较LPS组小鼠明显降低（P<0.01）。进一步研究表明，槲皮素可激活胰岛素受体底物1（IRS-1）/蛋白激酶B（AKT）/糖原合成酶激酶3β（GSK3β）信号通路，相较于LPS组小鼠，槲皮素干预后的小鼠肾脏IRS-1 Ser307磷酸化水平降低（P<0.01），GLUT1、GLUT2和GLUT4等葡萄糖转运蛋白的表达显著提高（P<0.01），而小鼠肝脏IRS-1酪氨酸612位点（Tyr612）的磷酸化水平提高119.52%（P<0.01），GLUT1、GLUT2、GLUT4蛋白的表达分别上调125.39%、81.47%、89.82%（P<0.01），肝肾组织的胰岛素抵抗获得显著改善。本研究揭示了槲皮素通过多靶点调控机制缓解LPS诱导的代谢紊乱，为其在炎症相关疾病中的潜在应用提供了理论依据。

Abstract: This study aimed to investigate the ameliorative effects of quercetin on lipopolysaccharide (LPS)-induced oxidative stress, inflammatory response, and insulin resistance in the liver and kidney tissues of mice, as well as the underlying molecular mechanisms. Two-month-old male C57BL/6J mice were intraperitoneally injected with LPS (5 mg/kg/d for 1 week) to establish a systemic inflammation model, while quercetin (40 mg/kg/d) was administered to evaluate its protective role. The results demonstrated that, compared with the LPS group, quercetin supplementation significantly upregulated the protein expression of Nrf2, HO-1, and NQO-1 in the kidney by 32.56%, 27.25%, and 53.53% (P<0.05), and in the liver by 56.11%, 40.23%, and 39.46% (P<0.05), respectively. This activation of the Nrf2 antioxidant defense pathway effectively alleviated LPS-induced oxidative stress damage. Additionally, quercetin modulated the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, reducing the release of proinflammatory cytokines and attenuating inflammatory responses in hepatic and renal tissues. The ratios of p-IκB/IκB and p-NF-κB/NF-κB were markedly decreased in quercetin-treated mice compared to the LPS group (P<0.01). Further mechanistic studies revealed that quercetin activated the insulin receptor substrate 1 (IRS-1)/protein kinase B (AKT)/glycogen synthase kinase 3β (GSK3β) signaling pathway. In the kidney, quercetin significantly reduced IRS-1 phosphorylation at Ser307 (P<0.01) and enhanced the expression of glucose transporters (GLUT1, GLUT2, and GLUT4). In the liver, it increased IRS-1 phosphorylation at Tyr612 by 119.52% (P<0.01) and upregulated GLUT1, GLUT2, and GLUT4 protein expression by 125.39%, 81.47%, and 89.82% (P<0.01), respectively, thereby ameliorating insulin resistance. These findings elucidate the multi-target regulatory mechanism of quercetin in mitigating LPS-induced metabolic disturbances, providing a theoretical basis for its potential application in inflammation-related diseases.