Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.
Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.
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DOI：
10.1016/j.redox.2023.102771
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发表时间：
2023-08
期刊：
影响因子：
11.4
通讯作者：
Yang, Xiaofeng
中科院分区：
文献类型：
--
作者：
Xu, Keman;Saaoud, Fatma;Shao, Ying;Lu, Yifan;Wu, Sheng;Zhao, Huaqing;Chen, Kaifu;Vazquez-Padron, Roberto;Jiang, Xiaohua;Wang, Hong;Yang, Xiaofeng
关键词：
为了确定早期高脂血症中的代谢组学重编程，在喂食高脂饮食（HFD）3周的ApoE−/−小鼠的4种组织中筛选了无偏倚的代谢组。主动脉、心脏、肝脏和血浆中分别有30、122、67和97种代谢物上调。9种上调的代谢产物为尿毒症毒素，13种代谢产物（包括棕榈酸酯）促进训练的免疫力，增加乙酰辅酶A和胆固醇的合成，增加S-腺苷高半胱氨酸（SAH）和低甲基化，减少糖酵解。交叉组学分析发现ApoE腹主动脉/腹主动脉中11种代谢物合成酶的上调，其促进ROS、胆固醇生物合成和炎症。12种上调的代谢产物与ApoE腹主动脉中37种基因上调的统计学相关性表明，9种上调的新代谢产物是促动脉粥样硬化的。抗氧化转录因子NRF 2 −/−转录组分析表明，NRF 2抑制训练免疫代谢组学重编程。我们的研究结果提供了新的见解代谢组学重编程在多个组织在早期高脂血症面向三个共存的新型训练免疫。差异代谢重编程促进动脉粥样硬化形成，主要在主动脉中，但不在心脏、肝脏或血浆中。第一个代谢组学数据确定了早期高脂血症诱导的炎症增强的训练免疫。我们的研究结果首次强调了致动脉粥样硬化代谢物促进代谢物-传感器伴侣信号传导。交叉组学分析表明，代谢重编程不仅是酶促反应，也是转录组调控。抗氧化转录因子NRF 2作为一种新的抑制剂训练免疫代谢重编程。
To identify metabolomic reprogramming in early hyperlipidemia, unbiased metabolome was screened in four tissues from ApoE−/− mice fed with high fat diet (HFD) for 3 weeks. 30, 122, 67, and 97 metabolites in the aorta, heart, liver, and plasma, respectively, were upregulated. 9 upregulated metabolites were uremic toxins, and 13 metabolites, including palmitate, promoted a trained immunity with increased syntheses of acetyl-CoA and cholesterol, increased S-adenosylhomocysteine (SAH) and hypomethylation and decreased glycolysis. The cross-omics analysis found upregulation of 11 metabolite synthetases in ApoE‾/‾ aorta, which promote ROS, cholesterol biosynthesis, and inflammation. Statistical correlation of 12 upregulated metabolites with 37 gene upregulations in ApoE‾/‾ aorta indicated 9 upregulated new metabolites to be proatherogenic. Antioxidant transcription factor NRF2−/− transcriptome analysis indicated that NRF2 suppresses trained immunity-metabolomic reprogramming. Our results have provided novel insights on metabolomic reprogramming in multiple tissues in early hyperlipidemia oriented toward three co-existed new types of trained immunity. Differential metabolic reprogramming promoted atherogenesis, mainly in the aorta but not in the heart, liver, or plasma. The first metabolomic data identified that early hyperlipidemia-induced trained immunity for inflammatory enhancement. Our findings highlighted for the first time that atherogenic metabolites facilitate metabolite-sensor partner signaling. Cross-omic analysis identified that metabolic reprogramming is not only enzymatic reactions but also transcriptomic regulation. Antioxidant transcription factor NRF2 acts as a new inhibitor for trained immunity-metabolic reprogramming.
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