Abstract：
As an efficient alternative copper (Cu) source, copper nanoparticles (nano-Cu) have been widely supplemented into animal-producing food. Therefore, it is necessary to assess the effect of nano-Cu exposure on the biological health risk. Recently, the toxic effects of nano-Cu have been confirmed but the underlying mechanism remains unclear. This study reveals the impact of nano-Cu on endoplasmic reticulum autophagy (ER-phagy) in chicken hepatocytes and further identifies Drp1 and its downstream gene FAM134B as crucial regulators of nano-Cu-induced hepatotoxicity. Nano-Cu exposure can induce Cu ion overaccumulation and pathological injury in the liver, trigger excessive mitochondrial fission and mitochondria-associated membrane (MAM) integrity damage, and activate ER-phagy in vivo and in vitro. Interestingly, the knockdown of Drp1 markedly decreases the expression of FAM134B induced by nano-Cu. Furthermore, the expression levels of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I induced by nano-Cu exposure are decreased by inhibiting the expression of Drp1. Simultaneously, the inhibition of FAM134B effectively alleviates nano-Cu-induced ER-phagy by downregulating the expression of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I. Overall, these results suggest that Drp1-mediated impairment of MAM integrity leads to ER-phagy as a novel molecular mechanism involved in the regulation of nano-Cu-induced hepatotoxicity. These findings provide new ideas for future research on the mechanism of nano-Cu-induced hepatotoxicity.
摘要：
作为一种有效的替代铜（Cu）源，纳米铜(nano-Cu)已被广泛地添加到动物生产食品中。因此,有必要评估纳米铜暴露对生物健康风险的影响。最近,纳米铜的毒性作用已得到证实，但潜在的机制仍不清楚。这项研究揭示了纳米Cu对鸡肝细胞内质网自噬（ER-phagy）的影响，并进一步确定了Drp1及其下游基因FAM134B是纳米Cu诱导的肝毒性的关键调节因子。纳米Cu暴露可引起肝脏Cu离子过度积累和病理损伤,引发过度的线粒体裂变和线粒体相关膜（MAM）完整性损伤，并在体内和体外激活ER-吞噬。有趣的是,Drp1的敲除显著降低了纳米Cu诱导的FAM134B的表达。此外，纳米Cu暴露诱导的ATL3，CCPG1，SEC62，TEX264和LC3II/LC3I的表达水平通过抑制Drp1的表达而降低。同时,FAM134B的抑制通过下调ATL3，CCPG1，SEC62，TEX264和LC3II/LC3I的表达，有效减轻纳米Cu诱导的ER吞噬。总的来说,这些结果表明,Drp1介导的MAM完整性受损导致ER-吞噬作为一种新的分子机制参与调节纳米Cu诱导的肝毒性.这些发现为进一步研究纳米铜诱导肝毒性的机制提供了新思路。
