Multiple pathways are involved in palmitic acid-induced toxicity.

In this study, we identified the toxic mechanism following the accumulation of palmitic acid (PA), a saturated fatty acid, in human Chang liver cells. After PA exposure for 24 h, the mitochondria and the endoplasmic reticulum (ER) became dilated, and lipid droplets and organelles were observed within autophagosomes. Cell viability decreased with an ATP reduction and the G2/M phase arrest. The expression of SOD-2, but not of SOD-1, markedly increased after PA exposure, which also elevated the number of cells generating ROS. PA enhanced the levels of proteins related to apoptosis, necroptosis, autophagy, and ER stress. Moreover, the inhibition of caspases, p53, necroptosis, or ER stress substantially rescued PA-induced cytotoxicity and, similarly, the inhibition of caspases and ER stress counteracted PA-induced changes in the cell cycle. Conversely, the inhibition of necroptosis and p53 signaling accelerated the changes in the cell cycle triggered by PA exposure. Blocking autophagy exacerbated PA-induced cytotoxicity and alterations in the cell cycle and caused disappearance of cellular components. These results suggest that PA induces apoptosis accompanied by autophagy through mitochondrial dysfunction and ER stress, which are triggered by oxidative stress in Chang liver cells and that blocking autophagy accelerates cell damage following PA exposure.