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 knock-down (-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 lipogenesis. Differences in responses to HAcAms in normal and -KD LO-2 cells indicated that HAcAms caused hepatocyte lipid deposition and triglyceride accumulation by activation of the NRF2/PPAR 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.

中文翻译：

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卤代乙酰胺消毒副产物，非酒精性脂肪肝的潜在危险因素


非酒精性脂肪性肝病（NAFLD）是一种以脂质沉积异常为特征的代谢性疾病，氧化应激是其发病和进展的危险因素。卤代乙酰胺 (HAcAms) 作为饮用水中不受管制的消毒副产品，可能通过产生氧化应激来改变 NAFLD 的发病率和严重程度。我们探讨了上海饮用水中 1、10 和 100 倍浓度的 HAcAm 是否会扰乱正常人肝 LO-2 细胞的脂质代谢。利用CRISPR/Cas9构建稳定敲低（-KD）的LO-2系，以研究HAcAms混合暴露引起异常脂质积累和肝细胞损伤的机制。在 100 倍真实浓度下，HAcAm 会导致 LO-2 细胞中的脂质沉积并增加甘油三酯的积累，这与脂肪生成的改变一致。正常细胞和-KD LO-2细胞对HAcAms反应的差异表明HAcAms通过激活NRF2/PPAR途径引起肝细胞脂质沉积和甘油三酯积累，并通过诱导铁死亡而加重肝细胞毒性。这些结果表明 HAcAm 是 NAFLD 的重要危险因素。未来有必要进一步观察和验证 HAcAms 对人群中 NAFLD 的影响。