In obese patients, free fatty acids ectopically accumulated in non-adipose tissues cause cell death. Saturated fatty acids are more deleterious to non-adipose cells, and supplementation with mono-unsaturated fatty acids has been proposed to rescue cells from saturated fatty acid-induced cytotoxicity; however, the mechanisms are not well understood. To understand the cytoprotective role of mono-unsaturated fatty acids in lipotoxic cell death of macrophages, we investigated the antagonizing effect of oleate and the underlying mechanisms in palmitate-treated RAW264.7 cells. Palmitate strongly induced apoptosis in macrophages by increasing CD36 expression, which was identified to mediate both endoplasmic reticulum stress and the generation of reactive oxygen species. Co-treatment with oleate significantly reduced CD36 expression and its downstream signaling pathways of apoptosis in palmitatetreated cells. These findings provide a novel mechanism by which oleate protects macrophages from palmitate-induced lipotoxicity. (C) 2017 Elsevier Inc. All rights reserved.