Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis

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.