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Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation
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 redu...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797718/ https://www.ncbi.nlm.nih.gov/pubmed/24146768 http://dx.doi.org/10.1371/journal.pone.0075650 |
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author | Zhou, Chao Lei, Han Chen, Yaxi Liu, Qing Li, Lung-Chih Moorhead, John F. Varghese, Zac Ruan, Xiong Z. |
author_facet | Zhou, Chao Lei, Han Chen, Yaxi Liu, Qing Li, Lung-Chih Moorhead, John F. Varghese, Zac Ruan, Xiong Z. |
author_sort | Zhou, Chao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3797718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37977182013-10-21 Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation Zhou, Chao Lei, Han Chen, Yaxi Liu, Qing Li, Lung-Chih Moorhead, John F. Varghese, Zac Ruan, Xiong Z. PLoS One Research Article 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. Public Library of Science 2013-10-16 /pmc/articles/PMC3797718/ /pubmed/24146768 http://dx.doi.org/10.1371/journal.pone.0075650 Text en © 2013 Zhou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Zhou, Chao Lei, Han Chen, Yaxi Liu, Qing Li, Lung-Chih Moorhead, John F. Varghese, Zac Ruan, Xiong Z. Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation |
title | Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation |
title_full | Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation |
title_fullStr | Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation |
title_full_unstemmed | Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation |
title_short | Enhanced SCAP Glycosylation by Inflammation Induces Macrophage Foam Cell Formation |
title_sort | enhanced scap glycosylation by inflammation induces macrophage foam cell formation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797718/ https://www.ncbi.nlm.nih.gov/pubmed/24146768 http://dx.doi.org/10.1371/journal.pone.0075650 |
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