Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/49051 |
Resumo: | Rationale: Cholesteryl hemiesters are oxidation products of polyunsaturated fatty acid esters of cholesterol. Their oxo-ester precursors have been identified as important components of the "core aldehydes" of human atheromata and in oxidized lipoproteins (Ox-LDL). We had previously shown, for the first time, that a single compound of this family, cholesteryl hemisuccinate (ChS), is sufficient to cause irreversible lysosomal lipid accumulation (lipidosis), and is toxic to macrophages. These features, coupled to others such as inflammation, are typically seen in atherosclerosis. Objective: To obtain insights into the mechanism of cholesteryl hemiester-induced pathological changes in lysosome function and induction of inflammation in vitro and assess their impact in vivo. Methods and results: We have examined the effects of ChS on macrophages (murine cell lines and primary cultures) in detail. Specifically, lysosomal morphology, pH, and proteolytic capacity were examined. Exposure of macrophages to sub-toxic ChS concentrations caused enlargement of the lysosomes, changes in their luminal pH, and accumulation of cargo in them. In primary mouse bone marrow-derived macrophages (BMDM), ChS-exposure increased the secretion of IL-1 beta, TNF-alpha and IL-6. In zebrafish larvae (wild-type All and PU.1:EGFP), fed with a ChS-enriched diet we observed lipid accumulation, myeloid cell-infiltration in their vasculature and decrease in larval survival. Under the same conditions the effects of ChS were more profound than the effects of free cholesterol (FC). Conclusions: Our data strongly suggest that cholesteryl hemiesters are pro-atherogenic lipids able to mimic features of Ox-LDL both in vitro and in vivo. |
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Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophagesAtherosclerosisCholesteryl hemiestersLysosome malfunctionInflammationOxidized lipidsZebrafish larvaeCiências Médicas::Medicina ClínicaScience & TechnologyRationale: Cholesteryl hemiesters are oxidation products of polyunsaturated fatty acid esters of cholesterol. Their oxo-ester precursors have been identified as important components of the "core aldehydes" of human atheromata and in oxidized lipoproteins (Ox-LDL). We had previously shown, for the first time, that a single compound of this family, cholesteryl hemisuccinate (ChS), is sufficient to cause irreversible lysosomal lipid accumulation (lipidosis), and is toxic to macrophages. These features, coupled to others such as inflammation, are typically seen in atherosclerosis. Objective: To obtain insights into the mechanism of cholesteryl hemiester-induced pathological changes in lysosome function and induction of inflammation in vitro and assess their impact in vivo. Methods and results: We have examined the effects of ChS on macrophages (murine cell lines and primary cultures) in detail. Specifically, lysosomal morphology, pH, and proteolytic capacity were examined. Exposure of macrophages to sub-toxic ChS concentrations caused enlargement of the lysosomes, changes in their luminal pH, and accumulation of cargo in them. In primary mouse bone marrow-derived macrophages (BMDM), ChS-exposure increased the secretion of IL-1 beta, TNF-alpha and IL-6. In zebrafish larvae (wild-type All and PU.1:EGFP), fed with a ChS-enriched diet we observed lipid accumulation, myeloid cell-infiltration in their vasculature and decrease in larval survival. Under the same conditions the effects of ChS were more profound than the effects of free cholesterol (FC). Conclusions: Our data strongly suggest that cholesteryl hemiesters are pro-atherogenic lipids able to mimic features of Ox-LDL both in vitro and in vivo.NOVA4Health - UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. FCT fellowship references: SFRH/BPD/26843/2006, SFRH/BD/62126/2009, SFRH/BD/90258/2012, SFRH/BD/84685/2012, SFRH/BPD/102229/2014, SFRH/BD/52293/2013info:eu-repo/semantics/publishedVersionElsevierUniversidade do MinhoDomingues, NeuzaEstronca, Luís M.B.B.Silva, JoãoEncarnação, Marisa R.Mateus, RitaSilva, Diogo Pinto Lobo JesusSantarino, Inês B.Saraiva, MargaridaSoares, Maria I.L.Melo, Teresa M.V.D. Pinho eet. al.2017-02-012017-02-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/49051engDomingues, N., Estronca, L. M., Silva, J., Encarnação, M. R., Mateus, R., Silva, D., ... & Jacinto, A. (2017). Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1862(2), 210-2201388-198110.1016/j.bbalip.2016.10.00927793708http://www.sciencedirect.com/science/article/pii/S1388198116302839info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:42:12Zoai:repositorium.sdum.uminho.pt:1822/49051Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:39:23.781180Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
title |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
spellingShingle |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages Domingues, Neuza Atherosclerosis Cholesteryl hemiesters Lysosome malfunction Inflammation Oxidized lipids Zebrafish larvae Ciências Médicas::Medicina Clínica Science & Technology |
title_short |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
title_full |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
title_fullStr |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
title_full_unstemmed |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
title_sort |
Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages |
author |
Domingues, Neuza |
author_facet |
Domingues, Neuza Estronca, Luís M.B.B. Silva, João Encarnação, Marisa R. Mateus, Rita Silva, Diogo Pinto Lobo Jesus Santarino, Inês B. Saraiva, Margarida Soares, Maria I.L. Melo, Teresa M.V.D. Pinho e et. al. |
author_role |
author |
author2 |
Estronca, Luís M.B.B. Silva, João Encarnação, Marisa R. Mateus, Rita Silva, Diogo Pinto Lobo Jesus Santarino, Inês B. Saraiva, Margarida Soares, Maria I.L. Melo, Teresa M.V.D. Pinho e et. al. |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Domingues, Neuza Estronca, Luís M.B.B. Silva, João Encarnação, Marisa R. Mateus, Rita Silva, Diogo Pinto Lobo Jesus Santarino, Inês B. Saraiva, Margarida Soares, Maria I.L. Melo, Teresa M.V.D. Pinho e et. al. |
dc.subject.por.fl_str_mv |
Atherosclerosis Cholesteryl hemiesters Lysosome malfunction Inflammation Oxidized lipids Zebrafish larvae Ciências Médicas::Medicina Clínica Science & Technology |
topic |
Atherosclerosis Cholesteryl hemiesters Lysosome malfunction Inflammation Oxidized lipids Zebrafish larvae Ciências Médicas::Medicina Clínica Science & Technology |
description |
Rationale: Cholesteryl hemiesters are oxidation products of polyunsaturated fatty acid esters of cholesterol. Their oxo-ester precursors have been identified as important components of the "core aldehydes" of human atheromata and in oxidized lipoproteins (Ox-LDL). We had previously shown, for the first time, that a single compound of this family, cholesteryl hemisuccinate (ChS), is sufficient to cause irreversible lysosomal lipid accumulation (lipidosis), and is toxic to macrophages. These features, coupled to others such as inflammation, are typically seen in atherosclerosis. Objective: To obtain insights into the mechanism of cholesteryl hemiester-induced pathological changes in lysosome function and induction of inflammation in vitro and assess their impact in vivo. Methods and results: We have examined the effects of ChS on macrophages (murine cell lines and primary cultures) in detail. Specifically, lysosomal morphology, pH, and proteolytic capacity were examined. Exposure of macrophages to sub-toxic ChS concentrations caused enlargement of the lysosomes, changes in their luminal pH, and accumulation of cargo in them. In primary mouse bone marrow-derived macrophages (BMDM), ChS-exposure increased the secretion of IL-1 beta, TNF-alpha and IL-6. In zebrafish larvae (wild-type All and PU.1:EGFP), fed with a ChS-enriched diet we observed lipid accumulation, myeloid cell-infiltration in their vasculature and decrease in larval survival. Under the same conditions the effects of ChS were more profound than the effects of free cholesterol (FC). Conclusions: Our data strongly suggest that cholesteryl hemiesters are pro-atherogenic lipids able to mimic features of Ox-LDL both in vitro and in vivo. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-02-01 2017-02-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/49051 |
url |
http://hdl.handle.net/1822/49051 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Domingues, N., Estronca, L. M., Silva, J., Encarnação, M. R., Mateus, R., Silva, D., ... & Jacinto, A. (2017). Cholesteryl hemiesters alter lysosome structure and function and induce proinflammatory cytokine production in macrophages. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1862(2), 210-220 1388-1981 10.1016/j.bbalip.2016.10.009 27793708 http://www.sciencedirect.com/science/article/pii/S1388198116302839 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
dc.source.none.fl_str_mv |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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