Mechanistic insights into dietary CuO nanoparticle (CuO NP)-induced hepatic lipotoxicity: the critical role of the Ccs/Mek1/Erk1/2/Pparα pathway and mitochondrial oxidative stress

Abstract

Copper oxide nanoparticles (CuO NPs) are widely used in industry and agriculture, leading to their persistent occurrence and accumulation in aquatic environments and posing potential environmental risks. However, the specific role and underlying mechanisms of CuO NPs in the health risks of aquatic organisms remain unclear. This study revealed that dietary exposure to high levels of CuO NPs elevated hepatic Cu content, inducing oxidative stress and mitochondrial dysfunction that exacerbate hepatic lipotoxicity. Mechanistically, high dietary CuO NPs enhanced the interaction between domains 1 and 3 of the Cu chaperone for superoxide dismutase (Ccs) and mitogen-activated protein kinase kinase 1 (Mek1), which subsequently activated the phosphorylation of extracellular signal-regulated protein kinase 1/2 (Erk1^T202/Y204 and Erk2^T185/Y187). The activated Erk1/2 mediated CuO NP-induced lipotoxicity by suppressing the expression of peroxisome proliferator-activated receptor α (Pparα) and promoting its phosphorylation at the S77 site. Further investigation demonstrated that Pparα phosphorylation impaired fatty acid β-oxidation by downregulating the promoter activities of long chain acyl-coA dehydrogenase (acadl) and carnitine palmitoyl transferase Ia1b (cptIa1b). For the first time, this study elucidated the novel mechanism by which CuO NPs induced metabolic disorder via the Ccs/Mek1/Erk1/2/Pparα signaling axis. These findings provide critical evidence for the toxicological and environmental risk assessment of nanoparticles, while also deepening the mechanistic understanding of nanometal exposure-induced health effects in aquatic animals within complex environments.