Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells

• DOI: 10.1016/j.jlr.2024.100692
• Publication Date: 2024-11-05T01:50:44Z
• Authors: Camilla Moliterni; Francesco Vari; Emily Schifano; Stefano Tacconi; Eleonora Stanca; Marzia Friuli; Serena Longo; Maria Conte; Stefano Salvioli; Davide Gnocchi; Antonio Mazzocca; Daniela Uccelletti; Daniele Vergara; Luciana Dini; Anna Maria Giudetti
• Keywords: Lipotoxicity

Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending type involved. Saturated unsaturated exhibit distinct effects, though precise mechanisms behind these differences remain unclear. Here, we investigated lipotoxicity palmitic acid (PA), a saturated acid, compared with oleic (OA), monounsaturated in hepatic cell line HuH7.Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, autophagy inhibition. Compared PA treatment leads less lipid droplet (LD) accumulation significant reduction mRNA protein level diacylglycerol acyltransferase 1 (DGAT1), key enzyme triacylglycerol synthesis. Using modulators ER stress autophagy, established DGAT1 downregulation by is closely linked cellular pathways. Notably, inhibitor 4-phenylbutyrate suppress PA-induced downregulation. Furthermore, knockdown siRNA or A922500, specific inhibitor, resulted death, even OA. Both OA increased oxygen consumption rate; however, increase associated was only partially coupled ATP Importantly, GW7647 PPARα agonist mitigated lipotoxic restoring block, suppression. In conclusion, our study highlights crucial role broadening knowledge underlying providing basis for potential therapeutic interventions.