RT Journal Article
SR Electronic
T1 Differential Roles of Unsaturated and Saturated Fatty Acids on Autophagy and Apoptosis in Hepatocytes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.184341
DO 10.1124/jpet.111.184341
A1 Shuang Mei
A1 Hong-Min Ni
A1 Sharon Manley
A1 Abigail Bockus
A1 Karen M Kassel
A1 James P Luyendyk
A1 Bryan L Copple
A1 Wen-Xing Ding
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/08/19/jpet.111.184341.abstract
AB Fatty acid-induced lipotoxicity plays a critical role in the pathogenesis of non-alcoholic liver disease. Saturated fatty acids and unsaturated fatty acids have differential effects on cell death and steatosis but the mechanisms responsible for these differences are not known. Using cultured HepG2 cells and primary mouse hepatocytes, we found that unsaturated and saturated fatty acids differentially regulate autophagy and apoptosis. The unsaturated fatty acid, oleic acid, promoted the formation of triglyceride-enriched lipid droplets and induced autophagy but had a minimal effect on apoptosis. In contrast, the saturated fatty acid, palmitic acid, was poorly converted into triglyceride enriched lipid droplets, suppressed autophagy and significantly induced apoptosis. Subsequent studies revealed that palmitic acid-induced apoptosis suppressed autophagy by inducing caspase-dependent Beclin 1 cleavage, indicating crosstalk between apoptosis and autophagy. Moreover, our data suggest that the formation of triglyceride enriched lipid droplets and induction of autophagy are protective mechanisms against fatty acid-induced lipotoxicity. In line with our in vitro findings, we found that high fat diet-induced hepatic steatosis was associated with autophagy in the mouse liver. Potential modulation of autophagy may be a novel approach that has therapeutic benefits for obesity-induced steatosis and liver injury.