title: Enhanced SCAP glycosylation by inflammation induces macrophage foam cell formation.
abstract: Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation.
authors.affiliation: Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, Chongqing Medical University, Chongqing, P.R. China ; Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China ; John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, United Kingdom.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhou
authors.forename: Han
authors.initials: H
authors.lastname: Lei
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Lung-Chih
authors.initials: LC
authors.lastname: Li
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D008078:Cholesterol, LDL / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D005487:Foam Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006031:Glycosylation; D006056:Golgi Apparatus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008361:Mannosidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis; D011973:Receptors, LDL / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D008361:Mannosidases; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase