Mitochondrial oxidative stress inhibited Sirt3/Foxo3/PPARα pathway and aggravated copper and zinc co-deficiency-induced hepatic lipotoxicity in a fish model.

Copper (Cu) and zinc (Zn) are essential trace elements for terrestrial animals. Studies suggested that single dietary Cu- or Zn- deficiency lead to liver lipid deposition and cause metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms by which dietary Cu and Zn co-deficiency promote hepatic lipid deposition and metabolism remain unknown. Our study found that, compared to single Cu- or Zn- deficiency, Cu and Zn co-deficiency significantly increased lipid deposition, induced mitochondrial oxidative stress, disrupted mitochondrial structure and function, and inhibited lipolysis in hepatocytes and whole liver tissue. Mechanistically, Cu and Zn co-deficiency-induced lipotoxicity was mediated by sirtuin 3 (Sirt3). Sirt3 inhibited the acetylation and degradation of forkhead box O3 (Foxo3), preventing its binding to the peroxisome proliferator-activated receptor alpha (PPARα) promoter, which accordingly increased lipid deposition. Overall, for the first time, we elucidated the mechanism by which Cu and Zn co-deficiency aggravates hepatic lipotoxicity and identified the critical regulatory role of the Sirt3/Foxo3/PPARα pathway during this process, with the fish as the model.