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目的:通过网络药理学及动物实验验证探究降脂轻身胶囊治疗高脂血症的作用机制。方法:通过网络药理学获取降脂轻身胶囊治疗高脂血症可能的作用靶点，并对核心靶点进行基因本体(GO)功能富集和京都基因与基因组百科全书(KEGG)通路富集分析，筛选其可能参与的生物过程及信号通路。将50只小鼠随机分为正常对照组、模型对照组、降脂轻身胶囊0.6、2.4 g/kg组和瑞舒伐他汀1.3 mg/kg组，采用高脂饲料喂养诱导高脂血症模型，药物干预10 w后，称取小鼠体质量、肝脏质量并计算肝脏指数、Lee's指数；采用苏木精-伊红(HE)染色、油红O染色法观察肝组织病理学变化；用生化试剂盒检测血清生化指标；实时荧光定量聚合酶链式反应(Real-time PCR)、蛋白免疫印迹(Western blot)法检测Pparα、Pgc1α、Acox1、Cpt1α mRNA及蛋白表达。结果:网络药理学筛选出中药成分相关靶点787个，脂质标记物相关靶点共计341个，疾病相关靶点2 060个，三者交集靶点39个；GO功能分析与KEGG富集分析提示降脂轻身胶囊与脂肪酸β氧化的生物过程相关，PPARα信号通路可能是作用的途径之一。动物实验结果显示：与正常对照组比较，模型对照组小鼠体质量、肝湿质量、肝指数和Lee's指数明显升高(P<0.05),血清TC、TG、LDL-C、HDL-C含量、ALT及AST活力明显升高，HDL-C含量明显降低(P<0.05),肝组织出现炎性浸润和坏死灶，脂质沉积明显增加，肝组织PPARα、PGC-1α、CPT1α、ACOX1的表达明显下调(P<0.05);与模型对照组比较，降脂轻身胶囊小鼠体质量、肝湿质量、肝指数和Lee's指数降低(P<0.05),小鼠TC、TG、LDL-C、HDL-C含量、ALT及AST的活力降低(P<0.05),肝组织炎症及脂质沉积改善，肝组织PPARα、PGC-1α、CPT1α、ACOX1的表达上调(P<0.05)。结论:降脂轻身胶囊能够改善高脂血症小鼠的血脂水平，恢复肝功能，其作用机制可能是通过上调肝组织PPARα通路的活性，上调其下游蛋白PGC-1α、CPT1α、ACOX1的表达，促进脂肪酸β氧化的进程而实现的。
Abstract：Objective:To investigate the therapeutic mechanism of Jiangzhiqingshen(降脂轻身) capsules for hyperlipidaemia based on network pharmacology and animal experiments. Methods:The possible targets of Jiangzhiqingshen capsules for hyperlipidaemia were obtained through network pharmacology, and the core targets were subjected to gene ontology(GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis for screening of the biological processes and signaling pathways that might be involved. Fifty mice were randomly assigned into normal control, model control, Jiangzhiqingshen capsules(2.4 g/kg and 0.6 g/kg),and rosuvastatin(1.3 mg/kg) groups. A hyperlipidemia model was established by feeding with a high-fat diet. After 10 weeks of pharmacological interventions, the body mass, liver mass, liver index, and Lee's index were weighed or calculated. Histopathological changes of the liver tissue were observed by hematoxylin-eosin(HE) staining and oil red O staining. Serum levels of biochemical indexes were measured by biochemical kits, and real-time PCR and Western blot were used to determine the mRNA and protein levels, respectively, of peroxisome proliferator-activated receptor alpha(PPARα),peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1α),acyl-CoA oxidase 1(ACOX1),and carnitine palmitoyltransferase 1 alpha(CPT1α). Results:A total of 787 targets related to the components of Jiangzhiqingshen capsules, 341 lipid marker-related targets, and 2 060 disease-related targets were screened by network pharmacology, with 39 common targets. GO functional enrichment and KEGG enrichment analysis suggested that Jiangzhiqingshen capsules exerted therapeutic effects via fatty acid β-oxidation, and the PPARα signaling pathway might be one of the action pathways. The results of animal experiments showed that compared with the normal control group, the model control group showed increased body mass, liver wet mass, liver index, and Lee's index(P<0.05),raised serum levels of total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),alanine aminotransferase(ALT),and aspartate aminotransferase(AST) but declined serum level of high-density lipoprotein cholesterol(HDL-C)(P<0.05),inflammatory infiltration, necrotic foci, and increased lipid deposition in the liver tissue, and down-regulated expression levels of PPARα,PGC-1α,CPT1α,and ACOX1(P<0.05). Compared with the model control group, Jiangzhiqingshen capsules decreased the body mass, liver wet mass, liver index, and Lee's index(P<0.05),lowered the serum levels of TC,TG,LDL-C,ALT,and AST(P<0.05),alleviated the hepatic inflammation and lipid deposition, and up-regulated the expression levels of PPARα,PGC-1α,CPT1α,and ACOX1 in the liver tissue(P<0.05). Conclusion:Jiangzhiqingshen capsules can restore the blood lipid levels and the liver function in hyperlipidemic mice by up-regulating the PPARα pathway in the liver tissue to promote the expression of downstream proteins(PGC-1α,CPT1α,and ACOX1) and enhance fatty acid β-oxidation.
[1]Arvanitis M,Lowenstein C J.Dyslipidemia[J].Annals of Internal Medicine,2023,176(6):ITC81-ITC96.
[2]Cosentino F,Verma S,Ambery P,et al.Cardiometabolic risk management:insights from a European Society of Cardiology Cardiovascular Round Table[J].European Heart Journal,2023,44(39):4141-4156.
[3]Marais A D,Blom D J,Raal F J.Management of hyperlipidaemia[J].South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde,2024,114(3):e1016.
[4]中国血脂管理指南修订联合专家委员会.中国血脂管理指南(2023年)[J].中国循环杂志，2023,38(3):237-271.
[5]韩文杰，张赤道，李兰馨，等.中医药防治高脂血症临床研究的证据图分析[J].中药新药与临床药理，2024,35(10):1611-1620.
[6]庞琳琳，李峥，王钰，等.健脾祛痰法治疗血脂异常研究概况[J].世界中医药，2024,19(8):1209-1214.
[7]徐学功.降脂轻身胶囊干预痰浊阻遏型血脂异常临床观察[J].世界中西医结合杂志，2009,4(1):26-28.
[8]徐变玲，王楠，张理，等.降脂轻身方对高脂血症小鼠调节作用的分子机制[J].中成药，2021,43(1):219-224.
[9]XU B,WANG N,XU X,et al.Unraveling the molecular mechanisms of hyperlipidemia using integrated lncRNA and mRNA microarray data[J].Experimental and therapeutic medicine,2022,23(2):160.
[10]徐学功，刘燕，苏东东，等.基于转录组学与加权基因共表达网络分析探讨降脂轻身胶囊介导NF-κB/NLRP3/Caspase-1信号轴改善高脂血症的作用机制[J].中药新药与临床药理，2024,35(12):1816-1826.
[11]WANG X,WANG Z Y,ZHENG J H,et al.TCM network pharmacology:A new trend towards combining computational,experimental and clinical approaches[J].Chinese journal of natural medicines,2021,19(1):1-11.
[12]刘应，唐子惟，陶鹏，等.黄精与黑苦荞、发芽糙米配伍对高脂血症小鼠的辅助降血脂研究[J].中药药理与临床，2023,39(9):66-69.
[13]江勉君，史忠亮，古惠文，等.基于痰瘀理论探讨动脉粥样硬化的发病机制[J].中西医结合心脑血管病杂志，2022,20(11):2098-2100.
[14]王洋，刘悦，孔德昭，等.基于“脾气散精”理论探讨从脾论治冠心病调节血脂水平效果研究[J].辽宁中医药大学学报，2022,24(2):41-44.
[15]Feingold K R.Lipid and Lipoprotein Metabolism[J].Endocrinology and metabolism clinics of North America,2022,51(3):437-458.
[16]Houten S M,Violante S,Ventura F V,et al.The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders[J].Annual review of physiology,2016,78:23-44.
[17]Samovski D,Jacome-sosa M,Abumrad N A.Fatty Acid Transport and Signaling:Mechanisms and Physiological Implications[J].Annual review of physiology,2023,85:317-337.
[18]Dambrova M,Makrecka-kuka M,Kuka J,et al.Acylcarnitines:Nomenclature,Biomarkers,Therapeutic Potential,Drug Targets,and Clinical Trials[J].Pharmacol Rev,2022,74(3):506-551.
[19]Schlaepfer I R,Joshi M.CPT1A-mediated Fat Oxidation,Mechanisms,and Therapeutic Potential[J].Endocrinology,2020,161(2):bqz046.
[20]HE Q,CHEN Y,WANG Z,et al.Cellular Uptake,Metabolism and Sensing of Long-Chain Fatty Acids[J].Frontiers in bioscience (Landmark edition),2023,28(1):10.
[21]Joshi P R,Zierz S.Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency:A Conceptual Approach[J].Molecules (Basel,Switzerland),2020,25(8):1784.
[22]ZENG S,WU F,CHEN M,et al.Inhibition of Fatty Acid Translocase (FAT/CD36) Palmitoylation Enhances Hepatic Fatty Acid β-Oxidation by Increasing Its Localization to Mitochondria and Interaction with Long-Chain Acyl-CoA Synthetase 1[J].Antioxidants & redox signaling,2022,36(16-18):1081-1100.
[23]Wanders R J A,Vaz F M,Waterham H R,et al.Fatty Acid Oxidation in Peroxisomes:Enzymology,Metabolic Crosstalk with Other Organelles and Peroxisomal Disorders[J].Advances in experimental medicine and biology,2020,1299:55-70.
[24]Tahri-joutey M,Andreoletti P,Surapureddi S,et al.Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα[J].Int J Mol Sci,2021,22(16):8969.
[25]Pawlak M,Lefebvre P,Staels B.Molecular mechanism of PPARα action and its impact on lipid metabolism,inflammation and fibrosis in non-alcoholic fatty liver disease[J].Journal of Hepatology,2015,62(3):720-733.
[26]Montaigne D,Butruille L,Staels B.PPAR control of metabolism and cardiovascular functions[J].Nature Reviews Cardiology,2021,18(12):809-823.
[27]CHEN Z,SUN X,LI X,et al.Oleoylethanolamide alleviates hyperlipidaemia-mediated vascular calcification via attenuating mitochondrial DNA stress triggered autophagy-dependent ferroptosis by activating PPARα[J].Biochemical pharmacology,2023,208:115379.
[28]XU Y,WANG M,LUO Y,et al.PPARα is one of the key targets for dendrobine to improve hepatic steatosis in NAFLD[J].Journal of Ethnopharmacology,2024:323.
[29]XU Y,DENNING K L,LU Y.PPARα agonist WY-14,643 induces the PLA2/COX-2/ACOX1 pathway to enhance peroxisomal lipid metabolism and ameliorate alcoholic fatty liver in mice[J].Biochemical and biophysical research communications,2022,613:47-52.
[30]WANG Y,CHEN C,CHEN J,et al.Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation[J].Redox biology,2022,52:102322.
[31]LIAO J,XIE X,WANG N,et al.Formononetin promotes fatty acid β-oxidation to treat non-alcoholic steatohepatitis through SIRT1/PGC-1α/PPARα pathway[J].Phytomedicine :international journal of phytotherapy and phytopharmacology,2024,124:155285.
基本信息:
DOI：10.13412/j.cnki.zyyl.20251029.001
中图分类号:R285.5
引用信息:
[1]赵梦,陈晓阳,刘燕,等.基于网络药理学与动物实验验证降脂轻身胶囊调控PPARα通路治疗高脂血症的作用机制[J].中药药理与临床,2026,42(08):22-30.DOI:10.13412/j.cnki.zyyl.20251029.001.
基金信息:
国家中医药管理局“张仲景传承与创新专项”(编号：GZY-KJS-2022-042-1); 河南省科技攻关项目(编号：242102311280、232102311192); 河南省中医药科学研究专项课题(编号：2023ZY1026、2023ZY2147、2022ZYZD、2018ZY3008)
2025-10-29
2025-10-29
2025-10-29