药学学报, 2021, 56(4): 1109-1119
引用本文:
刘启凤, 吕雪琪, 郭聪聪, 孙珊珊, 王亚男, 靳香菊, 王映红*. 基于核磁代谢流和代谢组技术对二甲双胍改善脂代谢紊乱作用的研究[J]. 药学学报, 2021, 56(4): 1109-1119.
LIU Qi-feng, L� Xue-qi, GUO Cong-cong, SUN Shan-shan, WANG Ya-nan, JIN Xiang-ju, WANG Ying-hong*. The effect of metformin on lipid disorders as measured by nuclear magnetic metabolomics and metabolic flux analysis[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 1109-1119.

基于核磁代谢流和代谢组技术对二甲双胍改善脂代谢紊乱作用的研究
刘启凤, 吕雪琪, 郭聪聪, 孙珊珊, 王亚男, 靳香菊, 王映红*
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
近十几年的研究发现二甲双胍不仅是降糖首选药,而且具有良好的降脂减肥作用,本研究旨在用高脂血症金黄地鼠模型探讨二甲双胍的降脂作用以及其对脂代谢紊乱中的关键代谢通路改变的作用。采用50只金黄地鼠,分为空白对照组、模型组、二甲双胍低高剂量组和辛伐他汀组,高脂膳食造模1周后连续给药11周,给药2、6、9周取金黄地鼠血清测血脂血糖,取金黄地鼠的3、5、9周的粪便和尿液以及9周的血清进行1H NMR代谢组学测试,11周静脉注射给予金黄地鼠[U-13C6]葡萄糖后收集血清进行13C NMR代谢流测试。结果表明,二甲双胍给药后能显著降低血脂和血糖水平,且能显著影响与能量代谢密切相关的糖代谢、脂质代谢、酮体生成、氨基酸代谢、肠道菌群代谢等代谢通路。代谢流结果显示高脂膳食干预使三羧酸循环通量降低37.48%,二甲双胍低剂量和高剂量干预后,三羧酸循环通量分别增加98.14%和143.10%,辛伐他汀干预后三羧酸循环通量增加33.18%,表明二甲双胍具有显著地促进能量代谢的作用。本研究采用代谢组学和代谢流结合的方法探讨二甲双胍对脂代谢紊乱的调节作用,在发现热点代谢途径的同时对能量代谢关键途径-三羧酸循环的变化进行量化,为其药效和作用机制的研究提供了有用的信息,也为基于金黄地鼠模型上的调脂药物的筛选提供了实用的技术方法。
关键词:    高脂血症      代谢组学      代谢流      二甲双胍     
The effect of metformin on lipid disorders as measured by nuclear magnetic metabolomics and metabolic flux analysis
LIU Qi-feng, L� Xue-qi, GUO Cong-cong, SUN Shan-shan, WANG Ya-nan, JIN Xiang-ju, WANG Ying-hong*
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Studies have found that metformin is not only the preferred drug for lowering blood sugar, but also shows lipid-lowering and weight-loss effects. The purpose of this study was to use a hyperlipidemia hamster model to investigate the lipid-lowering effect of metformin and its effect on important metabolic pathways in lipid metabolism disorders. Fifty golden hamsters were divided into a control group, a model group, metformin high- and low-dose groups, and a simvastatin group. A high-fat diet was fed for 1 week to create the model, and then drug was administered for 11 weeks with the high-fat diet. Serum was taken for measurement of blood lipid and blood glucose at 2, 6, and 9 weeks after administration, and at weeks 3, 5, and 9 feces and urine were collected for 1H NMR metabolomics tests. After 11 weeks of intravenous injection of[U-13C6] glucose, serum was collected for a 13C NMR metabolic flux test. The results showed that the administration of metformin can significantly reduce blood lipids and glucose levels and can significantly affect metabolic pathways such as sugar metabolism, lipid metabolism, ketone metabolism, amino acid metabolism, and intestinal flora metabolism. The results of the metabolic flux analysis showed that the high-fat diet reduced the metabolism of tricarboxylic acids by 37.48%. After administration of low and high doses of metformin the metabolism of tricarboxylic acid increased by 98.14% and 143.10%, respectively. After administration of simvastatin tricarboxylic acid metabolism increased by 33.18%. The results indicate that metformin has a significant effect on promoting energy metabolism. This study used a combination of metabolomics and metabolic flow to explore the effect of metformin on lipid metabolism disorders and quantifies changes in the key pathway of energy metabolism-the tricarboxylic acid cycle. This study provides useful information for the study of the efficacy and mechanism of metformin, as well as a practical technical method for the screening of lipid-lowering drugs based on a hamster model.
Key words:    hyperlipidemia    metabolomics    metabolic flux    metformin   
收稿日期: 2020-11-08
DOI: 10.16438/j.0513-4870.2020-1774
基金项目: 中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-009);国家科技重大专项项目(2018ZX09711001-002-004).
通讯作者: 王映红,Tel:86-10-63165216,E-mail:wyh@imm.ac.cn
Email: wyh@imm.ac.cn
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