Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARĪ± activation in liver cells
Lipotoxicity refers to the detrimental effects of excess fatty acids on metabolic health, which can vary based on the specific types of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct impacts, though the mechanisms underlying these differences are not fully understood. In this study, we compared the lipotoxicity of palmitic acid (PA), a saturated fatty acid, and oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our findings revealed that PA, in contrast to OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and inhibition of autophagy.
PA treatment resulted in reduced lipid droplet (LD) accumulation and a significant decrease in the mRNA and protein expression of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in triacylglycerol synthesis. Further analysis demonstrated that the downregulation of DGAT1 by PA is closely linked to ER stress and autophagy pathways. Notably, the ER stress inhibitor 4-phenylbutyrate effectively suppressed PA-induced DGAT1 downregulation. Additionally, silencing DGAT1 via siRNA or pharmacological inhibition with A922500 caused cell death, even in the presence of OA. Both PA and OA enhanced the oxygen consumption rate, but the increase associated with PA was only partially coupled to ATP synthesis.
Importantly, treatment with GW7647, a selective PPARĪ± agonist, mitigated the lipotoxic effects of PA by alleviating ER stress, restoring autophagy, and preventing DGAT1 suppression. These findings underscore the pivotal role of DGAT1 in PA-induced lipotoxicity, advancing our understanding of the mechanisms driving hepatic lipotoxicity and identifying potential therapeutic targets for intervention.