Autophagy and Endoplasmic Reticulum Stress-Related Protein Homeostasis Links Palmitic Acid to Hepatic Lipotoxicity in Zebrafish (Danio rerio), Counteracted by Linoleic Acid

Saturated fatty acids (SFAs) are the primary contributors to hepatic lipotoxic injuries accompanied by the accumulation of hepatic insoluble protein inclusions that are composed of ubiquitinated proteins and p62, but the role of these inclusions in the SFA-induced hepatic lipotoxic injuries and their regulatory mechanisms are incompletely understood. In this study, we demonstrated that palmitic acid (PA), a dietary SFA, induced aberrant accumulation of hepatic insoluble protein inclusions, leading to hepatic lipotoxic injuries in zebrafish. Mechanistically, the accumulation of hepatic insoluble protein inclusions and the subsequent lipotoxic injuries induced by PA were attributed to reduced Autophagy activity and increased endoplasmic reticulum (ER) stress. In addition, the upregulation of p62 by the ER stress response factor XBP1s and ATF4 further exacerbated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries. Importantly, the ω-6 PUFA linoleic acid (LA) attenuated PA-induced accumulation of hepatic insoluble protein inclusions and subsequent lipotoxic injuries by improving defective Autophagy and reducing ER stress induced by PA. Overall, the present study provides new mechanisms by which SFAs and ω-6 PUFA influence hepatic lipotoxic injuries. These findings advance the understanding of hepatic lipotoxic injuries induced by SFAs and provide new insights for optimizing the rational substitution of fish oil by vegetable oils in aquaculture and the balance of fatty acid intake in human diets.

autophagy; endoplasmic reticulum stress; hepatic insoluble protein inclusions; hepatic lipotoxic injuries; linoleic acid; palmitic acid.