GPER通过阻断氧化应激-炎症恶性循环改善内毒素诱导肝细胞损伤的机制研究

doi:10.3870/j.issn.1672-8009.2026.03.002

摘要/Abstract

摘要： 目的探讨G蛋白偶联雌激素受体(G protein-coupled estrogen receptor,GPER)在内毒素诱导肝细胞损伤中的保护作用及其分子机制,并评估其作为性别差异化治疗策略的潜力。方法采用脂多糖(lipopolysaccharide,LPS)诱导的AML-12小鼠肝细胞模型模拟脓毒性肝损伤的早期病理过程,设空白对照组、LPS组、LPS+G1(GPER激动剂)组和LPS+G15(GPER拮抗剂)组。通过流式细胞术、蛋白质印迹、RT-qPCR、ELISA、透射电镜等技术检测细胞凋亡率、GPER表达、线粒体活性氧(mitochondrial reactive oxygen species,mtROS)、丙二醛(malondialdehyde,MDA)、NLRP3炎症小体活化、炎症因子(白细胞介素1β,IL-1β)、ATP/AMP比值、线粒体膜电位(ΔΨm)及超微结构的变化。结果与LPS组相比,G1处理可显著降低细胞凋亡率,抑制mtROS和MDA生成,下调NLRP3/Caspase-1/IL-1β信号通路活化,提高ATP水平和降低AMP/ATP比值,并改善线粒体膜电位与超微结构;而G15则加重上述损伤。相关性分析显示,GPER表达与细胞凋亡率呈负相关(R²=0.8970),mtROS水平与凋亡率及IL-1β含量均呈正相关。结论 GPER通过抑制mtROS生成,阻断NLRP3炎症体活化及下游炎症反应,改善线粒体能量代谢和结构完整性,从而减轻脓毒症肝细胞损伤,其作用机制为临床性别差异化治疗提供了新靶点与理论依据。

关键词: 脓毒症肝损伤, G蛋白偶联雌激素受体, 氧化应激, NLRP3炎症小体, 线粒体功能障碍, 性别差异

Abstract: Objective To investigate the protective effect of the G protein-coupled estrogen receptor(GPER)against endotoxin-induced hepatocyte injury and its underlying molecular mechanism,and to evaluate its potential as a sex-specific therapeutic strategy. Methods An AML-12 mouse hepatocyte model induced by lipopolysaccharide(LPS)was used to simulate the early pathological processes of septic liver injury.The cells were divided into four groups:blank control,LPS,LPS+G1(a GPER agonist),and LPS+G15(a GPER antagonist).Techniques including flow cytometry,Western blot,RT-qPCR,ELISA,and transmission electron microscopy were employed to assess apoptosis rate,GPER expression,mtROS,MDA,NLRP3 inflammasome activation,IL-1β levels,ATP/AMP ratio,ΔΨm,and ultrastructural changes. Results Compared with the LPS group,G1 treatment significantly reduced the apoptosis rate,suppressed mtROS and MDA production,downregulated the NLRP3/Caspase-1/IL-1β signaling pathway,increased ATP level,decreased the AMP/ATP ratio,and ameliorated mitochondrial membrane potential and ultrastructure.In contrast,G15 exacerbated these injuries.Correlation analysis showed that GPER expression was negatively correlated with the apoptosis rate(R²=0.8970),while mtROS levels were positively correlated with both apoptosis rate and IL-1β content. Conclusion GPER activation alleviates septic liver injury by inhibiting mtROS production,blocking NLRP3 inflammasome activation and subsequent inflammatory responses,and improving mitochondrial energy metabolism and structural integrity.This mechanism provides a novel target and theoretical basis for sex-specific treatment strategies in clinical practice.

Key words: septic liver injury, G protein-coupled estrogen receptor, oxidative stress, NLRP3 inflammasome, mitochondrial dysfunction, gender difference

中图分类号:

R631.2

杨镭镭, 彭坚, 冯小静, 高珊, 陈真. GPER通过阻断氧化应激-炎症恶性循环改善内毒素诱导肝细胞损伤的机制研究[J]. 医学分子生物学杂志, 2026, 23(3): 242-249.

YANG Leilei, PENG Jian, FENG Xiaojing, GAO Shan, CHEN Zhen. The Protective Role of GPER Against Endotoxin-Induced Hepatocyte Injury via Disruption of Oxidative Stress-Inflammation Cycle[J]. Journal of Medical Molecular Biology, 2026, 23(3): 242-249.

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