The role of HDL in the modulation of endoplasmic reticulum (ER) stress in macrophage-derived foam cells is not completely understood. Therefore, we aimed to investigate whether HDL may inhibit ER stress in correlation with the secretion of apoE and CETP from lipid-loaded macrophages. To this purpose, THP-1 macrophages were loaded with lipids by incubation with human oxidized LDL (oxLDL) and then exposed to human HDL3. ER stress signaling markers, protein kinase/Jun-amino-terminal kinase (SAPK/JNK p54/p46) and eukaryotic initiation factor-2 alpha (eIF2 alpha), as well as the secreted apoE and CETP, were evaluated by immunoblot analysis. Out of the many different bioactive lipids of oxLDL, we tested the effect of 9-hydroxy-octadecadienoic acid (9-HODE) and 4-hydroxynonenal (4-HNE) on ER stress. Tunicamycin was used as positive control for ER stress induction. Results showed that oxLDL, 9-HODE and 4-HNE induce ER stress in human macrophages by activation of eIF-2 alpha and SAPK/JNK (p54/p46) signaling pathways. OxLDL stimulated apoE and CETP secretion, while tunicamycin determined a reduction of the secreted apoE and CETP, both in control and lipid-loaded macrophages. The addition of HDL3 to the culture medium of tunicamycin-treated cells induced: (i) the reduction of ER stress, expressed as decreased levels of eIF-2 alpha and SAPK/JNK, and (ii) a partial recovery of the secreted apoE and CETP levels in lipid-loaded macrophages. These data suggest a new mechanism by which HDL3 diminish ER stress and stimulate cholesterol efflux from lipid-loaded macrophages. (C) 2013 Elsevier Inc. All rights reserved.