Lipotoxicity refers to cellular toxicity in the presence of excessive free fatty acids. Fatty acid-induced lipotoxicity plays a critical role in the pathogenesis of nonalcoholic liver disease. In this study, Mei et al. investigated the differential effects of unsaturated and saturated fatty acid-induced lipotoxicity through the regulation of autophagy and apoptosis. Unsaturated fatty acids [oleic acid (OA)] promoted the formation of triglyceride-enriched lipid droplets and induced autophagy with minimal effects on apoptosis. Saturated fatty acids [palmitic acid (PA)], on the other hand, promoted lipid droplet formation poorly and suppressed autophagy but significantly induced apoptosis. OA-induced autophagy was independent of mammalian target of rapamycin but dependent on reactive oxygen species and phosphatidylinositol 3-kinase. PA-induced apoptosis suppressed autophagy by inducing caspase-dependent Beclin 1 cleavage, indicating cross-talk between apoptosis and autophagy. Induction of autophagy through the formation of triglyceride-enriched lipid droplets may be the protective mechanism against fatty acid-induced lipotoxicity. Even in vivo, a high-fat diet-induced hepatic steatosis was associated with autophagy in the liver. Overall, the results reveal a novel mechanism underlying the differential role of saturated versus unsaturated fatty acids in hepatotoxicity, and could suggest new therapeutic approaches for treating fatty liver diseases by modulating autophagy.
See article at J Pharmacol Exp Ther 2011, 339:487–498
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics