Effects of palmitic acid on TNF-α-induced cytotoxicity in SK-Hep-1 cells.

Non-alcoholic steatohepatitis (NASH) is an increasingly common cause of chronic liver disease; however, no specific pharmacologic therapy has been shown to be effective in its treatment. The present study was designed to develop an experimental cell culture model of NASH using four kinds of fatty acids - palmitic acid (PA), stearic acid (SA), linoleic acid (LA), and oleic acid (OA) - and TNF-α, according to the "two-hit" hypothesis. The saturated fatty acids PA and SA are more cytotoxic than the unsaturated fatty acids OA and LA. Cellular lipid accumulation without cytotoxicity was more easily induced with the unsaturated fatty acids than with the saturated fatty acids. PA augmented TNF-α-induced cytotoxicity, while the unsaturated fatty acids attenuated TNF-α-induced cytotoxicity. In a mechanistic study, PA enhanced TNF-α-mediated apoptosis in the absence of oxidative stress, as determined by measuring the cellular glutathione and malondialdehyde levels. Moreover, PA inhibited the TNF-α-induced phosphorylation of AKT, but not c-Jun N-terminal kinase, indicating that inhibition of survival signaling pathways activated by TNF-α may explain the effects of PA on TNF-α-induced cytotoxicity. The in vitro NASH model established in this study may be used to screen drug candidates for suitability for the treatment of NASH.