Involvement of sarco/endoplasmic reticulum calcium ATPase-mediated calcium flux in the protective effect of oleic acid against lipotoxicity in hepatocytes.

Elevated free fatty acids, particularly saturated ones such as palmitic acid, may play an important role in the lipotoxic mechanism of nonalcoholic fatty liver disease (NAFLD). Saturated fatty acids induce autophagy dysfunction and endoplasmic reticulum (ER) stress leading to apoptosis in hepatocytes. However, unsaturated fatty acids, such as oleic acid, are nontoxic and can even prevent saturated fatty acid-induced toxicity in vitro. Although emerging evidence has suggested that ER calcium flux disruption in hepatocytes is involved in NAFLD pathogenesis, the roles of fatty acids in autophagy and ER calcium flux still remain unclear. We demonstrated that oleic acid ameliorated palmitic acid-induced autophagy arrest and ER stress in parallel with ER calcium depletion in hepatocytes. Moreover, we found that the effect of oleic acid against autophagy arrest was reversed by the pharmacological inhibition of sarcoplasmic reticulum Ca2+-ATPase (SERCA), which influxes calcium to ER. These data suggest that SERCA-mediated ER calcium flux is greatly involved in fatty acid-induced lipotoxicity in hepatocytes, and the prevention of ER calcium depletion may restore saturated fatty acid-induced autophagy arrest in hepatocytes.