title: Endoplasmic reticulum stress promotes macrophage-derived foam cell formation by up-regulating cluster of differentiation 36 (CD36) expression.
abstract: Oxidized low-density lipoprotein (ox-LDL) up-regulates CD36, a scavenger receptor responsible for macrophage uptake of ox-LDL without limitation. However, the precise underlying mechanism is not completely understood. Our previous study has demonstrated that ox-LDL induces endoplasmic reticulum (ER) stress in macrophages. The goal of this study was to explore the exact relationship between ER stress and macrophage-derived foam cell formation and whether ER stress would be involved in ox-LDL-induced CD36 up-regulation. Our results showed that ox-LDL-induced lipid accumulation in macrophages was promoted synergistically by ER stress inducer tunicamycin (TM), while attenuated by ER stress inhibitor 4-phenylbutyric acid (PBA). Ox-LDL caused CD36 up-regulation with concomitant activation of ER stress as assessed by phosphorylation of inositol-requiring kinase/endonuclease-1 (IRE-1) and protein kinase-like ER kinase (PERK), up-regulation of X-box-binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP 78), and nuclear translocation of activating transcription factor 6 (ATF6). TM not only up-regulated CD36 alone but also synergized with ox-LDL to increase CD36 expression. Alleviation of ER stress with PBA and siRNA against ATF6, IRE1, and GRP78 mitigated ox-LDL-induced CD36 protein up-regulation. Moreover, administration of apoE(-/-) mice with PBA suppressed the up-regulation of CD36, phospho-IRE1, and GRP78 in macrophage-dense atherosclerotic lesions and in peritoneal macrophages. Additionally, CD36 silencing attenuated ox-LDL-induced nuclear translocation of ATF6, phosphorylation of IRE1 and up-regulation of XBP1 and GRP78. These data indicate that CD36-mediated ox-LDL uptake in macrophages triggers ER stress response, which, in turn, plays a critical role in CD36 up-regulation, enhancing the foam cell formation by uptaking more ox-LDL.
authors.affiliation: From the Key Laboratory of Atherosclerosis in Universities of Shandong, Institute of Atherosclerosis and.
authors.forename: Shutong
authors.initials: S
authors.lastname: Yao
authors.forename: Cheng
authors.initials: C
authors.lastname: Miao
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.forename: Hui
authors.initials: H
authors.lastname: Sang
authors.forename: Nana
authors.initials: N
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Jiao
authors.forename: Jiju
authors.initials: J
authors.lastname: Han
authors.forename: Chuanlong
authors.initials: C
authors.lastname: Zong
authors.forename: Shucun
authors.initials: S
authors.lastname: Qin
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010654:Phenylbutyrates / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001057:Apolipoproteins E; C497112:Atf6 protein, mouse; D018955:CD36 Antigens; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D010654:Phenylbutyrates; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C099252:oxidized low density lipoprotein; D014415:Tunicamycin; C075773:4-phenylbutyric acid; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: Atherosclerosis; CD36; Endoplasmic Reticulum Stress; Foam Cell; Low Density Lipoprotein (LDL); Macrophages; Oxidized Low-density Lipoprotein; Unfolded Protein Response