Abstract：
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by abnormal lipid deposition, with oxidative stress being a risk factor in its onset and progression. Haloacetamides (HAcAms), as unregulated disinfection by-products in drinking water, may alter the incidence and severity of NAFLD through the production of oxidative stress. We explored whether HAcAms at 1, 10, and 100-fold concentrations in Shanghai drinking water perturbed lipid metabolism in normal human liver LO-2 cells. CRISPR/Cas9 was used to construct a LO-2 line with stable NRF2 knock-down (NRF2-KD) to investigate the mechanism underlying abnormal lipid accumulation and hepatocyte damage caused by mixed exposure to HAcAms. At 100-fold real-world concentration, HAcAms caused lipid deposition and increased triglyceride accumulation in LO-2 cells, consistent with altered de novo lipogenesis. Differences in responses to HAcAms in normal and NRF2-KD LO-2 cells indicated that HAcAms caused hepatocyte lipid deposition and triglyceride accumulation by activation of the NRF2/PPARγ pathway and aggravated liver cell toxicity by inducing ferroptosis. These results indicate that HAcAms are important risk factors for NAFLD. Further observations and verifications of the effect of HAcAms on NAFLD in the population are warranted in the future.
摘要：
非酒精性脂肪性肝病(NAFLD)是一种以异常脂质沉积为特征的代谢紊乱,氧化应激是其发病和进展的危险因素。卤乙酰胺（HAcAms），作为饮用水中不受管制的消毒副产品，可能通过氧化应激的产生改变NAFLD的发生率和严重程度。我们探讨了上海饮用水中1、10和100倍浓度的HAcAms是否会干扰正常人肝脏LO-2细胞的脂质代谢。使用CRISPR/Cas9构建具有稳定NRF2敲低的LO-2系(NRF2-KD),以研究混合暴露于HAcAms引起的异常脂质积累和肝细胞损伤的潜在机制。在现实世界的100倍浓度下，HAcAms在LO-2细胞中引起脂质沉积和增加的甘油三酯积累，与从头脂肪生成改变一致。正常和NRF2-KDLO-2细胞对HAcAms的反应差异表明，HAcAms通过激活NRF2/PPARγ途径引起肝细胞脂质沉积和甘油三酯积累，并通过诱导铁性凋亡加重肝细胞毒性。这些结果表明HAcAms是NAFLD的重要危险因素。将来有必要进一步观察和验证HAcAms对人群NAFLD的影响。
