Li Dan, Zhang Lulu, Dong Fangcong, Liu Yan, Li Ning, Li Huihui, Lei Hehua, Hao Fuhua, Wang Yulan, Zhu Yi, Tang Huiru
†Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China.
‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
J Proteome Res. 2015 May 1;14(5):2237-54. doi: 10.1021/acs.jproteome.5b00032. Epub 2015 Mar 27.
Atherosclerosis resulting from hyperlipidemia causes many serious cardiovascular diseases. To understand the systems changes associated with pathogenesis and progression of atherosclerosis, we comprehensively analyzed the dynamic metabonomic changes in multiple biological matrices of LDLR(-/-) mice using NMR and GC-FID/MS with gene expression, clinical chemistry, and histopathological data as well. We found that 12 week "Western-type" diet (WD) treatment caused obvious aortic lesions, macrophage infiltration, and collagen level elevation in LDLR(-/-) mice accompanied by up-regulation of inflammatory factors including aortic ICAM-1, MCP-1, iNOS, MMP2, and hepatic TNFα and IL-1β. The WD-induced atherosclerosis progression was accompanied by metabonomic changes in multiple matrices including biofluids (plasma, urine) and (liver, kidney, myocardial) tissues involving multiple metabolic pathways. These included disruption of cholesterol homeostasis, disturbance of biosynthesis of amino acids and proteins, altered gut microbiota functions together with metabolisms of vitamin-B3, choline, purines, and pyrimidines. WD treatment caused down-regulation of SCD1 and promoted oxidative stress reflected by urinary allantoin elevation and decreases in hepatic PUFA-to-MUFA ratio. When switching to normal diet, atherosclerotic LDLR(-/-) mice reprogrammed their metabolisms and reversed the atherosclerosis-associated metabonomic changes to a large extent, although aortic lesions, inflammation parameters, macrophage infiltration, and collagen content were only partially alleviated. We concluded that metabolisms of fatty acids and vitamin-B3 together with gut microbiota played crucially important roles in atherosclerosis development. These findings offered essential biochemistry details of the diet-induced atherosclerosis and demonstrated effectiveness of the integrated metabonomic analysis of multiple biological matrices for understanding the molecular aspects of cardiovascular diseases.
高脂血症引发的动脉粥样硬化会导致许多严重的心血管疾病。为了解与动脉粥样硬化发病机制和进展相关的系统变化，我们使用核磁共振（NMR）和气相色谱 - 火焰离子化检测/质谱联用（GC - FID/MS）技术，全面分析了低密度脂蛋白受体基因敲除（LDLR(-/-)）小鼠多种生物基质中的动态代谢组学变化，并结合基因表达、临床化学和组织病理学数据进行研究。我们发现，12周的“西式”饮食（WD）处理导致LDLR(-/-)小鼠出现明显的主动脉病变、巨噬细胞浸润以及胶原蛋白水平升高，同时伴有包括主动脉细胞间黏附分子 - 1（ICAM - 1）、单核细胞趋化蛋白 - 1（MCP - 1）、诱导型一氧化氮合酶（iNOS）、基质金属蛋白酶2（MMP2）以及肝脏肿瘤坏死因子α（TNFα）和白细胞介素 - 1β（IL - 1β）等炎症因子的上调。WD诱导的动脉粥样硬化进展伴随着多种基质（包括生物流体（血浆、尿液）和（肝脏、肾脏、心肌）组织）的代谢组学变化，涉及多个代谢途径。这些变化包括胆固醇稳态的破坏、氨基酸和蛋白质生物合成的紊乱、肠道微生物群功能的改变以及维生素B3、胆碱、嘌呤和嘧啶的代谢变化。WD处理导致硬脂酰辅酶A去饱和酶1（SCD1）下调，并通过尿中尿囊素升高和肝脏多不饱和脂肪酸与单不饱和脂肪酸比值降低反映出氧化应激增强。当改为正常饮食时，动脉粥样硬化的LDLR(-/-)小鼠重新编程其代谢，在很大程度上逆转了与动脉粥样硬化相关的代谢组学变化，尽管主动脉病变、炎症参数、巨噬细胞浸润和胶原蛋白含量仅得到部分缓解。我们得出结论，脂肪酸和维生素B3的代谢以及肠道微生物群在动脉粥样硬化发展中起着至关重要的作用。这些发现提供了饮食诱导动脉粥样硬化的重要生物化学细节，并证明了对多种生物基质进行综合代谢组学分析对于理解心血管疾病分子层面的有效性。
