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组小鼠显著降低（P<0.01）。进一步研究表明，槲皮素可有效调节IRS-1关键位点的磷酸化状态，上调下游葡萄糖转运蛋白（GLUTs）的表达。相较于LPS组小鼠，槲皮素干预后的小鼠肾脏IRS-1丝氨酸307位点（Ser³⁰⁷）磷酸化水平显著降低（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）的磷酸化水平显著提高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 its modulatory effects on inflammation, oxidative stress, and insulin resistance in hepatic and renal tissues. 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. The Nrf2-mediated antioxidant defense pathway was markedly activated, leading to increased expression of antioxidant genes and effectively alleviating LPS-induced oxidative stress injury. 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 investigation revealed that quercetin effectively regulated the phosphorylation state of IRS-1 at key residues and upregulated the expression of downstream glucose transporters (GLUTs). 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)(P<0.01). 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.