目的 基于代謝組學(xué)探究四物湯改善自然衰老小鼠脂代謝失調(diào)的機(jī)制。方法 采用自然增齡造模，以3月齡小鼠作為對(duì)照組，自然生長(zhǎng)至18月齡為模型組，將造模小鼠隨機(jī)分為模型組和四物湯（4.68 g·kg^-1）組，對(duì)照組和模型組ig給予蒸餾水，四物湯組ig給予四物湯藥液，每天固定時(shí)間給藥1次，連續(xù)給藥4周。試劑盒法檢測(cè)血清總膽固醇（TC）、三酰甘油（TG）、低密度脂蛋白-膽固醇（LDL-C）、高密度脂蛋白-膽固醇（HDL-C）水平；油紅O染色和蘇木精-伊紅（HE）染色觀察肝臟病理變化；采用非靶代謝組學(xué)對(duì)不同組別的血清樣本進(jìn)行檢測(cè)，以多元統(tǒng)計(jì)分析篩選各組之間的差異代謝物，結(jié)合質(zhì)譜信息和公共數(shù)據(jù)庫(kù)檢索對(duì)差異代謝物進(jìn)行鑒定；將篩選出的12個(gè)代謝標(biāo)志物ID輸入MetaboAnalyst6.0中進(jìn)行代謝通路富集。結(jié)果 與對(duì)照組比較，模型組血清中TC、TG、LDL-C水平均顯著升高（P＜0.001），HDL-C水平顯著降低（P＜0.01）；與模型組相比，四物湯組能明顯降低TC、TG、LDL-C水平（P＜0.05、0.01），HDL-C呈升高趨勢(shì)并趨于對(duì)照組。與對(duì)照組比較，模型組肝臟出現(xiàn)明顯炎癥細(xì)胞簇和脂肪沉積，四物湯干預(yù)后均明顯減少。模型組和對(duì)照組小鼠有31種內(nèi)源性物質(zhì)發(fā)生了顯著性變化（P＜0.05），經(jīng)四物湯干預(yù)后沒(méi)食子酸、溶血磷脂膽堿、植物鞘氨醇、?；侨パ跄懰帷⒛I上腺甾酮等12種代謝物水平顯著回調(diào)（P＜0.05），最終富集到鞘脂代謝、甘油磷脂代謝和類固醇激素生物合成3條脂代謝通路。結(jié)論 四物湯對(duì)自然衰老脂代謝紊亂小鼠體內(nèi)的差異代謝物有一定的回調(diào)作用，其調(diào)節(jié)脂質(zhì)代謝紊亂的作用機(jī)制主要與鞘脂代謝、甘油磷脂代謝和類固醇激素生物合成代謝通路有關(guān)。

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

國(guó)家自然科學(xué)基金項(xiàng)目（81473563）；寧夏自然科學(xué)基金優(yōu)青項(xiàng)目（2023AAC05041）；寧夏醫(yī)科大學(xué)特殊人才啟動(dòng)項(xiàng)目（XT2022017）