title: HDL inhibits endoplasmic reticulum stress by stimulating apoE and CETP secretion from lipid-loaded macrophages.
abstract: 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-2α (eIF2α), 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-2α 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-2α 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.
authors.affiliation: Institute of Cellular Biology and Pathology N. Simionescu of the Romanian Academy, Bucharest, Romania.
authors.forename: Loredan S
authors.initials: LS
authors.lastname: Niculescu
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Sanda
authors.forename: Anca V
authors.initials: AV
authors.lastname: Sima
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D001057:Apolipoproteins E / Q000378:metabolism*; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D044243:Linoleic Acids, Conjugated / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids / Q000008:administration & dosage; D053440:Lipoproteins, HDL3 / Q000378:metabolism* / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000447:Aldehydes; D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D044243:Linoleic Acids, Conjugated; D008055:Lipids; D053440:Lipoproteins, HDL3; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C024347:9-hydroxy-10,12-octadecadienoic acid; C027576:4-hydroxy-2-nonenal