Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation

Macrophage foam cells derived from vascular smooth muscle cells (VSMCs) account for 30–70 % of foam cells in atherosclerotic lesions. Liver X receptor (LXR) agonists promote high-density lipoprotein (HDL)-mediated cholesterol efflux from macrophages. This study aimed to investigate the effects of LX...

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Autores: Borràs, Carla, Rotllan, Noemí, Griñán, Raquel, Santos, David, Solé, Arnau, Dong, Chen, Zhao, Qi, Llorente-Cortés, Vicenta, Mourín, Marta, Soto, Begoña, Camacho, Mercedes, Tondo, Mireia, Canyelles, Marina, Blanco-Vaca, Francisco, Escolà-Gil, Joan Carles
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/395517
Acesso em linha:http://hdl.handle.net/10261/395517
https://api.elsevier.com/content/abstract/scopus_id/105005485309
Access Level:acceso abierto
Palavra-chave:Cholesterol
HDL
Liver X receptor
Mice
Reverse cholesterol transport
Vascular smooth muscle cells
id ES_193f96dcd687d659c8d2ef9b41e32b7a
oai_identifier_str oai:digital.csic.es:10261/395517
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
title Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
spellingShingle Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
Borràs, Carla
Cholesterol
HDL
Liver X receptor
Mice
Reverse cholesterol transport
Vascular smooth muscle cells
title_short Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
title_full Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
title_fullStr Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
title_full_unstemmed Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
title_sort Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation
dc.creator.none.fl_str_mv Borràs, Carla
Rotllan, Noemí
Griñán, Raquel
Santos, David
Solé, Arnau
Dong, Chen
Zhao, Qi
Llorente-Cortés, Vicenta
Mourín, Marta
Soto, Begoña
Camacho, Mercedes
Tondo, Mireia
Canyelles, Marina
Blanco-Vaca, Francisco
Escolà-Gil, Joan Carles
author Borràs, Carla
author_facet Borràs, Carla
Rotllan, Noemí
Griñán, Raquel
Santos, David
Solé, Arnau
Dong, Chen
Zhao, Qi
Llorente-Cortés, Vicenta
Mourín, Marta
Soto, Begoña
Camacho, Mercedes
Tondo, Mireia
Canyelles, Marina
Blanco-Vaca, Francisco
Escolà-Gil, Joan Carles
author_role author
author2 Rotllan, Noemí
Griñán, Raquel
Santos, David
Solé, Arnau
Dong, Chen
Zhao, Qi
Llorente-Cortés, Vicenta
Mourín, Marta
Soto, Begoña
Camacho, Mercedes
Tondo, Mireia
Canyelles, Marina
Blanco-Vaca, Francisco
Escolà-Gil, Joan Carles
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Ministerio de Ciencia, Innovación y Universidades (España)
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
China Scholarship Council
Llorente-Cortés, Vicenta [0000-0002-0067-7201]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cholesterol
HDL
Liver X receptor
Mice
Reverse cholesterol transport
Vascular smooth muscle cells
topic Cholesterol
HDL
Liver X receptor
Mice
Reverse cholesterol transport
Vascular smooth muscle cells
description Macrophage foam cells derived from vascular smooth muscle cells (VSMCs) account for 30–70 % of foam cells in atherosclerotic lesions. Liver X receptor (LXR) agonists promote high-density lipoprotein (HDL)-mediated cholesterol efflux from macrophages. This study aimed to investigate the effects of LXR activation on the reverse cholesterol transport (RCT) rate from VSMCs to feces in vivo. Both human and mouse VSMCs exhibited similar levels of cholesterol efflux when exposed to serum and HDL. However, cholesterol efflux was significantly reduced following methyl-β-cyclodextrin (MBD)-cholesterol loading, while treatment with the LXR agonist T090137 markedly enhanced efflux. Radiolabeled foam-like VSMCs injected intraperitoneally into mice exhibited impaired cholesterol transfer to serum, HDL, and feces compared to non-lipid-laden VSMCs. Pre-treatment with the LXR agonist increased radiolabeled cholesterol levels in serum and HDL and doubled its fecal excretion. Furthermore, LXR activation restored RCT from MBD-cholesterol-loaded VSMCs to feces, reaching levels comparable to those of non-lipid-laden cells. Treatment with an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor fully restored RCT rates in foam-like VSMCs, and the combination of the ACAT inhibitor and the LXR agonist further enhanced RCT. These findings indicate that HDL-mediated cholesterol efflux is significantly impaired during the transition of VSMCs into foam cells. Pharmacological activation of LXR enhances RCT from VSMCs to feces in vivo and restores the impaired RCT from transitioning VSMCs. The combination of LXR agonists and ACAT inhibitors holds promise as a synergistic therapeutic approach to restoring cholesterol homeostasis in lipid-laden VSMCs, offering potential strategies to mitigate atherosclerosis.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/395517
https://api.elsevier.com/content/abstract/scopus_id/105005485309
url http://hdl.handle.net/10261/395517
https://api.elsevier.com/content/abstract/scopus_id/105005485309
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-137186OB-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at https://doi.org/10.1016/j.biopha.2025.118178
https://doi.org/10.1016/j.biopha.2025.118178
Sí
dc.rights.none.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 BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activationBorràs, CarlaRotllan, NoemíGriñán, RaquelSantos, DavidSolé, ArnauDong, ChenZhao, QiLlorente-Cortés, VicentaMourín, MartaSoto, BegoñaCamacho, MercedesTondo, MireiaCanyelles, MarinaBlanco-Vaca, FranciscoEscolà-Gil, Joan CarlesCholesterolHDLLiver X receptorMiceReverse cholesterol transportVascular smooth muscle cellsMacrophage foam cells derived from vascular smooth muscle cells (VSMCs) account for 30–70 % of foam cells in atherosclerotic lesions. Liver X receptor (LXR) agonists promote high-density lipoprotein (HDL)-mediated cholesterol efflux from macrophages. This study aimed to investigate the effects of LXR activation on the reverse cholesterol transport (RCT) rate from VSMCs to feces in vivo. Both human and mouse VSMCs exhibited similar levels of cholesterol efflux when exposed to serum and HDL. However, cholesterol efflux was significantly reduced following methyl-β-cyclodextrin (MBD)-cholesterol loading, while treatment with the LXR agonist T090137 markedly enhanced efflux. Radiolabeled foam-like VSMCs injected intraperitoneally into mice exhibited impaired cholesterol transfer to serum, HDL, and feces compared to non-lipid-laden VSMCs. Pre-treatment with the LXR agonist increased radiolabeled cholesterol levels in serum and HDL and doubled its fecal excretion. Furthermore, LXR activation restored RCT from MBD-cholesterol-loaded VSMCs to feces, reaching levels comparable to those of non-lipid-laden cells. Treatment with an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor fully restored RCT rates in foam-like VSMCs, and the combination of the ACAT inhibitor and the LXR agonist further enhanced RCT. These findings indicate that HDL-mediated cholesterol efflux is significantly impaired during the transition of VSMCs into foam cells. Pharmacological activation of LXR enhances RCT from VSMCs to feces in vivo and restores the impaired RCT from transitioning VSMCs. The combination of LXR agonists and ACAT inhibitors holds promise as a synergistic therapeutic approach to restoring cholesterol homeostasis in lipid-laden VSMCs, offering potential strategies to mitigate atherosclerosis.This work was partly funded by the Instituto de Salud Carlos III and FEDER "Una manera de hacer Europa" grants PI2100140 (to F.B-V and M.T), PI2300232 (to M.C and J.E-G), JR22/00003 (to M.C.), PI2101523 (to V.Ll-C.) and the Ministerio de Ciencia, Innovación y Universidades, grants PID2022–137186OB-I00 and CNS2023–144119 (to N.R.). C.B. was funded with a Formación de Profesorado Universitario grant FPU20/07440 from Ministerio de Universidades. N.R was funded by Agencia Estatal de Investigación (AEI/10.13039/501100011033) within the Subprograma Ramón y Cajal (RYC-201722879). Q.Z. and C.D. were supported by the State Scholarship Fund from the China Scholarship Council (Grant Nos. 202406170068 and 202408370068, respectively). CIBERDEM and CIBERCV are Instituto de Salud Carlos III projects. All authors declare that they have no relationships relevant to the contents of this paper to disclose and have approved the final version of the article.Peer reviewedElsevier BVInstituto de Salud Carlos IIIEuropean CommissionMinisterio de Ciencia, Innovación y Universidades (España)Ministerio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)China Scholarship CouncilLlorente-Cortés, Vicenta [0000-0002-0067-7201]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/395517https://api.elsevier.com/content/abstract/scopus_id/105005485309reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-137186OB-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at https://doi.org/10.1016/j.biopha.2025.118178https://doi.org/10.1016/j.biopha.2025.118178Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3955172026-05-22T06:33:51Z
score 15,81155

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