基于代谢组学研究阿托伐他汀致非酒精性脂肪肝模型鼠肝损伤的作用机制  

Study on the mechanism of atorvastatin‐induced liver injury in non-alcoholic fatty liver model hamster based on metabolomics

作　　者：郗有丽 赵重博[3] 杨娜[1,2] 金路 朱怀军[1,2] 沈纪中 王敏[1,2] Xi Youli;Zhao Chongbo;Yang Na;Jin Lu;Zhu Huaijun;Shen Jizhong;Wang Min(Department of Pharmacy,the Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing 210008,China;Nanjing Medical Center for Clinical Pharmacy,Nanjing 210008,China;School of Pharmacy,Shaanxi University of Traditional Chinese Medicine,Xianyang 712046,China)

机构地区：[1]南京大学医学院附属鼓楼医院药学部,江苏南京210008 [2]南京临床药学中心,江苏南京210008 [3]陕西中医药大学药学院,陕西咸阳712046

出　　处：《实用药物与临床》2024年第4期241-247,共7页Practical Pharmacy and Clinical Remedies

基　　金：国家自然科学基金(82204846);南京鼓楼医院临床研究专项资金(2022‐LCYJ‐PY‐14);江苏省研究型医院学会精益化用药科研基金(JY202213);江苏省南京鼓楼医院-中西医协同特色技术发展项目(CZXM2022110)。

摘　　要：目的采用代谢组学技术考察阿托伐他汀对非酒精性脂肪肝模型鼠内源性代谢物的影响,探讨其致肝损伤的代谢调控机制。方法以高脂饲料喂养金黄地鼠构建非酒精性脂肪肝动物模型,并将其随机分成正常对照组、模型对照组和阿托伐他汀干预组,检测血清甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、天冬氨酸氨基转移酶(AST)和丙氨酸氨基转移酶(ALT)。采用基于超高效液相色谱-四极杆/飞行时间质谱的非靶向代谢组学方法筛查阿托伐他汀致肝损伤相关的代谢物及代谢通路。结果与模型对照组相比,阿托伐他汀干预组的TG、TC和LDL-C水平显著降低,AST和ALT水平显著升高。代谢组学研究结果显示,模型对照组与阿托伐他汀干预组代谢轮廓谱差异明显,共筛选出43个差异代谢物,主要涉及胆汁酸类、甘油磷脂类和脂肪酸类等代谢物。结论阿托伐他汀在改善非酒精性脂肪肝模型鼠血脂紊乱的同时,可引起肝功能损伤,其机制可能与胆汁酸类、甘油磷脂类和脂肪酸类等内源性代谢物水平紊乱相关。Objective Metabolomics was adopted to investigate the effect of atorvastatin on endogenous metabolites in non-alcoholic fatty liver model hamster and explore its hepatotoxicity mechanism.Methods Hamsters were fed with high-fat diet to establish non-alcoholic fatty liver models,which were divided into three groups,namely normal group,model group and atorvastatin-treated group.The serum levels of total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein-cholesterol(HDL-C),aspartate aminotransferase(AST)and alanine aminotransferase(ALT)were measured.Afterwards,the ultra-performance liquid chromatography quadrupole/time-of-flight mass spectrometry-based metabolomics was adopted to find out the metabolites and metabolic pathways related to the hepatotoxicity of atorvastatin.Results Compared with model group,the serum levels of TC,TG,LDL-C decreased significantly,while those of AST and ALT increased significantly in atorvastatin-treated group.Furthermore,the metabolomics results showed that there were obvious differences in the serum metabolic profile between model group and atorvastatin-treated group.A total of 43 differential metabolites,were screened out mainly covering bile acids,glycerophospholipids,fatty acids and so on.Conclusion Atorvastatin can improve the abnormal serum lipid levels but cause liver injury in non-alcoholic fatty liver model hamster.Its hepatotoxicity mechanism may be related to the disorder of endogenous metabolites,such as bile acids,glycerol phospholipids,and fatty acids.

关 键 词：阿托伐他汀 非酒精性脂肪肝 肝毒性 代谢组学 

分 类 号：R575.5[医药卫生—消化系统]