Zinc oxide nanoparticles disrupt peroxisome-endoplasmic reticulum contacts and increase very-long-chain fatty acid content.

Very-long-chain fatty acids (VLCFAs) are vital for growth, development, and overall health. Zinc oxide nanoparticles (ZnO NPs), recognized for their high bioavailability and wide use in medicine and nutrition, have an unclear impact on lipid metabolism. This study explores how ZnO NPs impact VLCFA metabolism using yellow catfish (Pelteobagrus fulvidraco) as a model organism. In vivo, 240 yellow catfish were divided into a control group and a group fed 10 mg/kg ZnO NPs diet for 10 weeks. Administration of ZnO NPs significantly increased hepatic VLCFA content, accompanied by elevated triglyceride (TG) and total cholesterol (T-CHO) levels. Additionally, ZnO NPs reduced peroxisomal β-oxidation and peroxisome-ER (Po-ER) contacts. In vitro studies with yellow catfish hepatocytes confirmed these findings and explored the underlying mechanisms. ZnO NPs reduced Po-ER attachment and significantly decreased peroxisomal β-oxidation levels. ZnO NPs markedly decreased the expression and localization of ACBD5, a key protein involved in Po-ER interactions and VLCFA degradation. Overexpression of ACBD5 counteracted these effects, whereas knockdown mimicked them. Further experiments revealed that FOXO3 directly regulates ACBD5 by binding to its promoter. ZnO NPs increased the acetylation level of hepatocytes, inhibited the nuclear entry of FOXO3, and reduced the protein level of SIRT1. SIRT1 directly regulates FOXO3 deacetylation at lysine 243. Overall, ZnO NPs disrupt lipid homeostasis by downregulating ACBD5 via the SIRT1/FOXO3 axis, impairing peroxisomal function and Po-ER contacts. This study highlights the significance of the SIRT1 - FOXO3 - ACBD5 axis in managing VLCFA-related metabolic disorders.