The epoxy triglycerides generated by oxidation, cyclization, and free radical chain reaction of unsaturated dietary oils during deep-frying are demonstrated to have cytotoxicity and can induce lipid metabolism related diseases. Metabolic diseases are usually characterized by metabolic abnormalities in different tissues, however, the relationship between changes in intratissue coordination and communication induced by epoxy triglycerides and specific pathogenic mechanisms remains largely unknown. We conducted lipid metabolomics analysis across six different tissues in C57BL/6J mice, including the medial prefrontal cortex, interscapular brown adipose tissue, epididymal white adipose tissue, liver, intestine, and heart. Normal diet intake demonstrated a high degree of association between lipid metabolites, indicative of cross-communication and cooperation among various tissues and organs, while, a global correlation that was disrupted and restructured by epoxy triglycerides intake. Examination of blood samples revealed that epoxy triglycerides enhanced bacterial translocation from the gut to the systemic circulation, consequently stimulating the TLR4/CD36/NF-κB pathway. In summary, this study found that epoxy triglyceride upsets the comprehensive coordination and information exchange of lipid metabolism, providing a fresh perspective for future research on the systemic metabolic network and identifying metabolic disease markers and associated mechanisms induced by deep-frying oil.