Zn Induces Lipophagy Via the Deacetylation of Beclin1 and Alleviates Cu-Induced Lipotoxicity at Their Environmentally Relevant Concentrations

In this study, the mechanisms of environmentally relevant doses of Cu and Zn mixtures influencing lipid deposition and metabolism were investigated in freshwater teleost yellow catfish (2 months old, 4.95 (t0.01 g, mean ± SEM). Our study indicated that waterborne Cu exposure increased lipid content, while Zn activated lipophagic flux and alleviated Cu-induced lipid accumulation. Yellow catfish hepatocytes treated with Zn or Zn + Cu activated autophagy-specific lipophagy, decreased lipid storage, and increased nonesterified fatty acid (NEFA) release, suggesting a causal relationship between lipophagy and lipid droplet (LD) breakdown under Zn and Zn + Cu conditions. Our further investigation found that Beclin1 deacetylation by sirtuin 1 (SIRT1) was required for Zn- and Zn + Cu-induced lipophagy and lipolysis, and lysine residues 427 and 434 were key sites for Beclin1 deacetylation. Taken together, these findings show that the Zn-induced deacetylation of Beclin1 promotes lipophagy as an important pathway to alleviate Cu-induced lipid accumulation in fish, which reveals a previously unidentified mechanism for understanding the antagonistic effects of Cu and Zn on metabolism at their environmentally relevant concentrations. Our results highlight the importance of combined exposure when the biological effects of heavy metals are evaluated during environmental risk assessments.