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目的 探究草甘膦诱导胆固醇结石的加重作用及其分子机制。方法 以C57BL/6雄性小鼠为实验对象，通过致石性膳食构建胆固醇结石病模型。小鼠随机分为4组(n=10):正常对照组(CON)、草甘膦暴露组(GLY)、胆固醇结石造模组(CS)及造模+草甘膦暴露联合组(CS+GLY),实验周期为6周。观察小鼠体重变化及胆囊结石形成状况；检测血清生化指标；对肝和胆囊组织HE染色，通过RT-qPCR法对肝脏中参与胆固醇代谢通路的基因表达进行定量分析；利用分子对接预测草甘膦与胆固醇结石病相关靶点的结合程度。结果 CS+GLY组小鼠体质量增长最快，胆囊内可见结石，血清ALT、AST、TC、LDL-C水平均显著升高(与CS组比，P<0.01),血脂异常加剧；病理学结果显示CS+GLY组肝细胞肿大、肝小叶中央静脉管腔增大和胆囊黏膜增厚。RT-qPCR结果表明，CS+GLY组肝组织FXR mRNA表达降低，而LRH-1、SR-B1 mRNA表达升高(与CS组比，P<0.01)。分子对接结果表明，草甘膦与FXR、LRH-1及SR-B1均有良好的对接活性，结合能分别为-10.46、-5.10、-9.29kJ/mol。结论 草甘膦可加重胆固醇结石的发生，作用机制或与其可能通过抑制肝脏组织FXR表达、进而干扰LRH-1/SR-B1通路，导致血清脂质代谢异常和肝胆损伤有关。
Abstract：Objective To investigate the exacerbating effect of glyphosate on cholesterol gallstone and elucidate its underlying mechanisms.Methods The experimental protocol was conducted on male C57BL/6 mice, in which a lithogenic diet was administered to establish a cholesterol gallstone disease model.Mice were randomly allocated into four groups: normal control(CON),glyphosate-exposed(GLY),cholesterol stone model(CS),and combined model+glyphosate(CS+GLY) groups, with a 6-week experimental duration.Parameters evaluated included body weight changes and gallstone formation status.Serum biochemical profiles were quantified, and hepatic and gallbladder tissues were conducted by Hematoxylin-Eosin(HE) staining.The transcriptional levels of cholesterol metabolism-associated genes in hepatic tissue were analyzed by quantitative real-time polymerase chain reaction(RT-qPCR).The binding affinities between glyphosate and cholesterol gallstone-related molecular targets were predicted by molecular docking simulations.Results The CS+GLY group exhibited accelerated body mass gain, gallstone occurrence, and significantly elevated serum ALT,AST,TC,and LDL-C levels(vs.CS,P<0.01),indicating exacerbated dyslipidemia.Histopathological analysis revealed distinct pathological alterations in the CS+GLY group, characterized by hepatocyte hypertrophy, enlargement of central venous lumina in hepatic lobules, and thickening of gallbladder mucosa.RT-qPCR results showed that the down-regulated hepatic FXR mRNA level, and upregulated LRH-1 and SR-B1 mRNA levels in CS+GLY group(vs.CS,P<0.01).Molecular docking confirmed robust binding interactions between glyphosate and FXR/LRH-1/SR-B1,with binding energies of-10.46,-5.10,-9.29kJ/mol, respectively.Conclusion Glyphosate can aggravate cholesterol gallstone pathogenesis through inhibiting FXR expression in liver tissue, thereby interfering with the LRH-1/SR-B1 pathway, resulting in abnormal serum lipid metabolism and liver and hepatobiliary damage.
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基本信息:
DOI：10.16751/j.cnki.2095-4646.2025032010
中图分类号:R994
引用信息:
[1]王贝贝,赵雪,徐旭龙,等.草甘膦经LRH-1/SR-B1通路加重小鼠胆固醇结石的机制[J].湖北科技学院学报(医学版),2025,39(05):374-379.DOI:10.16751/j.cnki.2095-4646.2025032010.
基金信息:
湖北省自然科学基金青年项目(2023AFB478); 国家自然科学基金青年项目(42307547)