Differential Effects of Cholesterol and Palmitic Acid on Autophagy, Cell Death, and Metabolic Pathways in HepG2 Cells (Research Article)

Author(s): A. Shima and J. Kamishikiryo* Department of Biochemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, 985-1, Sanzo, Higashimura-Cho, Fukuyama, Hiroshima 729-0292, Japan.

Abstract: The increase in high-calorie diets, notably those rich in animal fats, has contributed to an increased prevalence of obesity, metabolic syndrome, and related diseases. This study investigates the cellular effects of palmitic acid and cholesterol, which are significant components of animal fats, on HepG2 cells, focusing on autophagy, cell death, and key metabolic pathways. Our results demonstrate that treatment with 80 μM cholesterol resulted in significant intracellular cholesterol accumulation and a marked decrease in cell viability. Similarly, 800 μM palmitic acid increased lipid droplet formation and reduced the cell viability. Although cholesterol promoted autophagy and inhibited p70S6 kinase activity, it did not affect AMP-activated protein kinase (AMPK) or acetyl-CoA carboxylase (ACC) phosphorylation. Conversely, palmitic acid suppressed autophagy, inhibited p70S6 kinase activity, activated AMPK, and decreased ACC phosphorylation. Oleic acid, a monounsaturated fatty acid, increased lipid droplet size, but did not adversely affect cell viability or autophagy. These findings suggest that the cytotoxic effects of cholesterol and palmitic acid are mediated by distinct mechanisms involving autophagy regulation and metabolic pathway disruption. These insights will pave the way for future research further to elucidate lipid-specific pathways and their implications in metabolic health. Emphasizing the reduction in dietary palmitic acid and the inclusion of less harmful fatty acids holds promise for mitigating cholesterol toxicity and preventing lifestyle-related diseases.

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