Health risks caused by crucial environmental carcinogens N-nitrosamines triggered ubiquitous attention. As the liver exerted vital function through metabolic process, lipid metabolism disorders have been confirmed as potential drivers for toxicological effects, and the mechanisms of lipid regulation related to hepatotoxicity induced by N-nitrosamines remained largely unclear. In this study, we comprehensively explored the disturbance of hepatic lipid homeostasis in mice induced by nitrosamines. The results implied that nitrosamines exposure induced hepatotoxicity accompanied by liver injury, inflammatory infiltration, and hepatic edema. Lipidomics profiling analysis indicated the decreased levels of phosphatidic acids (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), lyso-phosphatidylcholines (LPC), lyso-phosphatidylethanolamines (LPE), diacylglycerols (DAG) and triacylglycerols (TAG), the elevation of ceramides (Cer) and decomposition of free fatty acids (FFA) in high-dose nitrosamines exposure group. Importantly, nitrosamines exposure promoted fatty acid oxidation (FAO) by facilitating fatty acid uptake and decomposition, together with the upregulation of genes associated with FAO accompanied by the activation of inflammatory cytokines TNF-α, IL-1β and NLRP3. Furthermore, fatty acid translocase CD36-mediated fatty acid oxidation was correlated with the enhancement of oxidative stress in the liver caused by nitrosamines exposure. Overall, our results contributed to the new strategies to interpret the early toxic effects of nitrosamines exposure.

由重要的环境致癌物N-亚硝胺引起的健康风险引起了广泛关注。由于肝脏通过代谢过程发挥重要功能，脂质代谢紊乱已被证实是毒理学效应的潜在驱动因素，以及与N诱导的肝毒性相关的脂质调节机制-亚硝胺在很大程度上仍不清楚。在本研究中，我们全面探讨了亚硝胺对小鼠肝脏脂质稳态的干扰。结果表明亚硝胺暴露会引起肝毒性，并伴有肝损伤、炎症浸润和肝水肿。脂质组学分析表明磷脂酸 (PA)、磷脂酰胆碱 (PC)、磷脂酰乙醇胺 (PE)、溶血磷脂酰胆碱 (LPC)、溶血磷脂酰乙醇胺 (LPE)、二酰基甘油 (DAG) 和三酰基甘油 (TAG) 水平降低，高剂量亚硝胺暴露组中神经酰胺 (Cer) 和游离脂肪酸 (FFA) 的分解。重要的是，亚硝胺暴露通过促进脂肪酸吸收和分解来促进脂肪酸氧化（FAO），连同与FAO相关的基因的上调，伴随着炎性细胞因子TNF-α、IL-1β和NLRP3的激活。此外，脂肪酸转位酶 CD36 介导的脂肪酸氧化与亚硝胺暴露引起的肝脏氧化应激增强相关。总体而言，我们的结果有助于解释亚硝胺暴露的早期毒性作用的新策略。