基于1H NMR的代谢组学分析糖尿病肾病小鼠血清的代谢模式

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摘要目的：通过基于1H NMR的代谢组学方法结合相关性分析探索db/db糖尿病肾病（DN）小鼠血清代谢物的改变和相关代谢途径。方法：8只DN模型db/db小鼠和9只C57BL/6J野生型小鼠饲养至17周时，收集尿液和血清。检测血糖、尿肌酐（UCr）和尿白蛋白肌酐比（UACR）。采集血清的1H NMR谱，采用偏最小二乘判别分析比较2种小鼠血清的代谢模式变化，采用Pearson相关性分析探索UACR、UCr与血清代谢物的相关性。结果：17周时，db/db小鼠体质量均超过野生型小鼠的2倍，呈现明显的肥胖状态；db/db小鼠的血糖、UACR均超过野生型小鼠的2倍，而UCr则显著降低，表明在17周时db/db小鼠呈现出典型的DN症状。2种小鼠的血清代谢模式在第一主成分上明显分开。与野生型小鼠相比，db/db小鼠血清中的丙酮酸、乳酸、柠檬酸降低，低密度脂蛋白/极低密度脂蛋白水平升高，3-羟基丁酸和乙酰乙酸水平降低，异亮氨酸/亮氨酸水平升高，甘氨酸、谷氨酰胺、酪氨酸和苯丙氨酸水平显著降低，肌酸、胆碱水平降低，差异均有统计学意义（P＜
0.05）。仅在db/db小鼠中，血清胆碱与UACR呈正相关（r=0.717，P＜0.05）。结论：在DN的发病过程中三羧酸循环、糖酵解途径和脂类代谢途径均受到不同程度抑制，糖异生作用增强。胆碱可能是与DN相关的潜在生物标记物。

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	魏婷婷
	赵良才
	高红昌

关键词 ： , 糖尿病肾病, db/db小鼠, 血清, 核磁共振氢谱, 代谢组学

Abstract：Objective: To study the characteristic metabolites and the related pathways in serum of db/db
diabetic mice by 1H nuclear magnetic resonance (1H NMR)-based metabonomics with correlative analysis. Methods: The urine and serum of eight db/db mice and nine C57BL/6J mice were collected at week 17. Then the blood glucose, urine creatinine (UCr) and urinary albumin to creatinine ratio (UACR) were measured. The characteristic alterations in serum metabolites were explored by the projection to latent structure discriminant analysis based on the 1H NMR spectra. The correlation between UACR, UCr and serum metabolites was performed by Pearson correlation analysis. Results: At 17-week, db/db mice showed apparent obesity, with the weight more than twice that of wild type mice. The blood glucose and UACR of db/db mice were also doubled compared with wild type mice, but the UCr decreased. It was demonstrated that the db/db mice showed typical symptoms of diabetic nephropathy at week 17. The metabolic profile of the two kinds of mice showed clear differences along the PC1 direction. Compared with wild type mice, pyruvate, lactate, citrate, 3-hydroxybutyrate, acetoacetate, glycine, glutamine, tyrosine, phenylalanine, creatine, choline were reduced, LDL/VLDL and isoleucine/leucine were increased in db/db mice (P<0.05). UACR showed a positive correlation with choline in the serum of db/db mice (r=0.717, P<0.05). Conclusion: In the pathogenic process of diabetic nephropathy, the tricarboxylic acid cycle, glycolysis and lipid metabolic pathways are suppressed and glycogenesis is elevated. Choline may be a potential biomarker of diabetic nephropathy.

Key words： diabetic nephropathies db/db mice serum 1H nuclear magnetic resonance metabonomics

收稿日期: 2018-01-25

基金资助:国家自然科学基金资助项目（81600653）。

通讯作者: 高红昌，教授，博士生导师，Email：gaohc27@wmu.edu.cn。

作者简介: 魏婷婷（1990-），女，浙江金华人，硕士。

链接本文:

https://xb.wmu.edu.cn/CN/ 或 https://xb.wmu.edu.cn/CN/Y2018/V48/I5/313

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