Abstract：
Mitochondrial fatty acid oxidation (mtFAO) plays an important role in hepatic energy metabolism. Severe mtFAO injury leads to nonalcoholic fatty liver disease (NAFLD) and liver failure. Several drugs have been withdrawn owing to safety issues, such as induction of fatty liver disease through mtFAO disruption. For instance, the antimicrobial triclocarban (TCC), an environmental contaminant that was removed from the market due to its unknown safety in humans, induces NAFLD in rats and promotes hepatic FAO in mice. Therefore, there are no consistent conclusions regarding the effects of TCC on FAO and lipid droplet accumulation. We hypothesized that TCC induces lipid droplet accumulation by inhibiting mtFAO in human hepatocytes. Here, we evaluated mitochondrial respiration in HepaRG cells to investigate the effects of TCC on fatty acid-driven oxidation in cells, electron transport chain parameters, lipid droplet accumulation, and antioxidant genes. The results suggest that TCC increases oxidative stress gene expression (GCLM, p62, HO-1, and NRF2) through lipid droplet accumulation via mtFAO inhibition in HepaRG cells. The results of the present study provide further insights into the effect of TCC on human NAFLD through mtFAO inhibition, and further in vivo studies could be used to validate the mechanisms.
摘要：
线粒体脂肪酸氧化（mtFAO）在肝脏能量代谢中起着重要作用。严重的mtFAO损伤导致非酒精性脂肪性肝病（NAFLD）和肝功能衰竭。由于安全问题，几种药物已被撤回，例如通过mtFAO破坏诱导脂肪肝疾病。例如,抗菌三氯卡班（TCC），一种环境污染物，由于其对人类的未知安全性而从市场上清除，在大鼠中诱导NAFLD并在小鼠中促进肝脏FAO。因此,关于TCC对FAO和脂滴积累的影响，没有一致的结论。我们假设TCC通过抑制人肝细胞中的mtFAO诱导脂滴积累。这里,我们评估了HepaRG细胞的线粒体呼吸，以研究TCC对脂肪酸驱动的细胞氧化的影响，电子传输链参数，脂滴积累，和抗氧化基因。结果表明，TCC增加氧化应激基因表达(GCLM，p62，HO-1和NRF2）通过mtFAO抑制HepaRG细胞中的脂滴积累。本研究的结果为TCC通过mtFAO抑制对人类NAFLD的影响提供了进一步的见解，进一步的体内研究可用于验证机制。
