目的 基于代谢组学探究四物汤改善自然衰老小鼠脂代谢失调的机制。方法 采用自然增龄造模，以3月龄小鼠作为对照组，自然生长至18月龄为模型组，将造模小鼠随机分为模型组和四物汤（4.68 g·kg^-1）组，对照组和模型组ig给予蒸馏水，四物汤组ig给予四物汤药液，每天固定时间给药1次，连续给药4周。试剂盒法检测血清总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白-胆固醇（LDL-C）、高密度脂蛋白-胆固醇（HDL-C）水平；油红O染色和苏木精-伊红（HE）染色观察肝脏病理变化；采用非靶代谢组学对不同组别的血清样本进行检测，以多元统计分析筛选各组之间的差异代谢物，结合质谱信息和公共数据库检索对差异代谢物进行鉴定；将筛选出的12个代谢标志物ID输入MetaboAnalyst6.0中进行代谢通路富集。结果 与对照组比较，模型组血清中TC、TG、LDL-C水平均显著升高（P＜0.001），HDL-C水平显著降低（P＜0.01）；与模型组相比，四物汤组能明显降低TC、TG、LDL-C水平（P＜0.05、0.01），HDL-C呈升高趋势并趋于对照组。与对照组比较，模型组肝脏出现明显炎症细胞簇和脂肪沉积，四物汤干预后均明显减少。模型组和对照组小鼠有31种内源性物质发生了显著性变化（P＜0.05），经四物汤干预后没食子酸、溶血磷脂胆碱、植物鞘氨醇、牛磺去氧胆酸、肾上腺甾酮等12种代谢物水平显著回调（P＜0.05），最终富集到鞘脂代谢、甘油磷脂代谢和类固醇激素生物合成3条脂代谢通路。结论 四物汤对自然衰老脂代谢紊乱小鼠体内的差异代谢物有一定的回调作用，其调节脂质代谢紊乱的作用机制主要与鞘脂代谢、甘油磷脂代谢和类固醇激素生物合成代谢通路有关。

Objective This experiment uses metabolomics technology to explore the mechanism by which Siwu Decoction improves lipid metabolism disorders in naturally aging mice. Methods A natural aging model was established, with 3-month-old mice as the control group and naturally aged to 18 months as the model group. The model mice were randomly divided into the model group and the Siwu Decoction (4.68 g·kg^-1) group. The control group and the model group were ig administered distilled water, while the Siwu Decoction group was ig administered Siwu Decoction solution once a day for four weeks. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were detected by kits, liver pathological changes were observed by Oil Red O staining and hematoxylin-eosin (HE) staining, non-targeted metabolomics was used to detect serum samples from different groups, and multivariate statistical analysis was used to screen for differential metabolites between groups. The IDs of the 12 selected metabolic markers were input into MetaboAnalyst 6.0 for metabolic pathway enrichment. Results Compared with control group, the levels of TC, TG, and LDL-C in the serum of model group were significantly increased (P<0.001), and the level of HDL-C was significantly decreased (P<0.01). Compared with the model group, the Siwu Decoction could significantly reduce the levels of TC, TG, and LDL-C (P<0.05, 0.01), and HDL-C showed an increasing trend and tended to be similar to the control group. Compared with the control group, the model group showed obvious inflammatory cell clusters and fat deposition in the liver, which were significantly reduced after Siwu Decoction intervention. There were 31 endogenous substances that changed significantly (P<0.05) in the model group and the control group. After Siwu Decoction intervention, the levels of 12 metabolites such as gallic acid, lysophosphatidylcholine, sphingosine, taurodeoxycholic acid, and adrenosterone were significantly restored (P<0.05), and were finally enriched in three lipid metabolism pathways: sphingolipid metabolism, glycerophospholipid metabolism, and steroid hormone biosynthesis. Conclusion Siwu Decoction has a certain regulatory effect on differential metabolites in naturally aging mice with lipid metabolism disorders. Its mechanism of regulating lipid metabolism disorders is mainly related to the metabolism pathways of sphingolipids, glycerophospholipids, and steroid hormone biosynthesis.

R285.5

国家自然科学基金项目（81473563）；宁夏自然科学基金优青项目（2023AAC05041）；宁夏医科大学特殊人才启动项目（XT2022017）