Department of Pharmacy, The Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan Eastern Road, Shenyang, Liaoning, China.
School of Pharmacy, China Medical University, No. 77 Puhe Road, Shenyang, Liaoning, China.
Anal Methods. 2020 May 14;12(18):2355-2362. doi: 10.1039/d0ay00305k.
To better understand the mechanism of hyperlipidemia and discover potential biomarkers, we have used targeted metabolomics to analyze eight amino acid profiles of control and hyperlipidemia rats by a liquid chromatography-mass spectrometry method. With high fat diet, the concentrations of serum of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) were increased by 666.7%, 99.0%, 61.7% and 51.0%, whereas the concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) were decreased by 46.3% and 58.9%. The concentrations of alanine, arginine, lysine, methionine, serine, tyrosine and valine in hyperlipidemia rats were significantly decreased by 21.8%, 19.72%, 26.5%, 19.6%, 48.7%, 19.8% and 24.91%, while there was no striking change in threonine. Combined with experimental results and previous literature, we inferred that alanine and serine were gradually disordered and subsequently generated abundant acetyl-CoA through pyruvate, which resulted in energy metabolism deficiency. Furthermore, Spearman correlation analysis shows that TC was negatively associated with methionine (r = -0.640, p < 0.05), suggesting that the lowered level of methionine caused by the homocysteine pathway enhances absorption and synthesis of TC. Meanwhile, the reduction of tyrosine demonstrated that rapid metabolism of cholesterol in vivo was caused by high levels of exogenous cholesterol. Furthermore, the observed ApoB and lysine changes indicated that lysine was largely incorporated into ApoB particles during the disease process. In addition, the levels of arginine, SOD and MDA reflected the behavior of oxidative stress. Finally, the metabolism fluctuation of valine demonstrated that abnormal lipid metabolism could cause abnormal glucose metabolism. In general, disordered energy metabolism, lipid metabolism, glucose metabolism and elevated oxidative stress were important characteristics of metabolic perturbations in hyperlipidemia. Herein, the discovery of biomarkers and the biological explanations mentioned above could be used to analyze the pathogenesis of hyperlipidemia through metabolic pathways, and these results could play an important role in assisting the clinical diagnosis of hyperlipidemia.
为了更好地理解高血脂症的发病机制，寻找潜在的生物标志物，我们采用靶向代谢组学方法，利用液相色谱-质谱联用法分析了高脂饮食诱导的高血脂症大鼠和正常大鼠的 8 种氨基酸谱。结果显示，与正常大鼠相比，高脂饮食组大鼠血清总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）和载脂蛋白 B（ApoB）的浓度分别升高了 666.7%、99.0%、61.7%和 51.0%，高密度脂蛋白胆固醇（HDL-C）和载脂蛋白 A-I（ApoA-I）的浓度分别降低了 46.3%和 58.9%。与正常大鼠相比，高血脂症大鼠血清中丙氨酸、精氨酸、赖氨酸、蛋氨酸、丝氨酸、酪氨酸和缬氨酸的浓度分别降低了 21.8%、19.72%、26.5%、19.6%、48.7%、19.8%和 24.91%，而苏氨酸的浓度没有明显变化。结合实验结果和以往文献，我们推测丙氨酸和丝氨酸逐渐紊乱，随后通过丙酮酸生成大量乙酰辅酶 A，导致能量代谢不足。此外，Spearman 相关分析显示 TC 与蛋氨酸呈负相关（r=-0.640，p<0.05），提示同型半胱氨酸通路降低的蛋氨酸水平增强了 TC 的吸收和合成。同时，酪氨酸的减少表明体内胆固醇的快速代谢是由外源性胆固醇水平升高引起的。此外，观察到的 ApoB 和赖氨酸的变化表明，在疾病过程中，赖氨酸大量掺入 ApoB 颗粒中。此外，精氨酸、SOD 和 MDA 的水平反映了氧化应激的行为。最后，缬氨酸代谢的波动表明异常的脂质代谢可能导致异常的葡萄糖代谢。总的来说，能量代谢、脂质代谢、葡萄糖代谢紊乱和氧化应激升高是高血脂症代谢紊乱的重要特征。在此，生物标志物的发现和上述生物学解释可用于通过代谢途径分析高血脂症的发病机制，这些结果可能在辅助高血脂症的临床诊断方面发挥重要作用。
