Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response

Background: Antibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin re...

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Autores: Actis Dato, Virginia|||0000-0002-9071-8045, Benitez Amaro, Aleyda|||0000-0002-1106-3125, García Rodríguez, Jesús Eduardo|||0000-0002-7758-6789, Claudi, Lene, La Chica Lhoëst, María Teresa|||0000-0002-9070-5973, Iborra Obiols, Antoni|||0000-0002-8984-5151, Escolà-Gil, Joan Carles|||0000-0001-9021-2485, Guerra Ramos, José María|||0000-0001-5397-9177, Samouillan, Valerie|||0000-0003-0571-3985, Enrich, Carlos|||0000-0003-0382-2993, Chiabrando, Gustavo Alberto, Llorente-Cortés, Vicenta|||0000-0002-0067-7201
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:277697
Acceso en línea:https://ddd.uab.cat/record/277697
https://dx.doi.org/urn:doi:10.1016/j.biopha.2022.113270
Access Level:acceso abierto
Palabra clave:High-fat diet
Lipid droplets
Cholesteryl esters
Heart
Lipoprotein
Insulin
LRP1
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spelling Targeting cholesteryl ester accumulation in the heart improves cardiac insulin responseActis Dato, Virginia|||0000-0002-9071-8045Benitez Amaro, Aleyda|||0000-0002-1106-3125García Rodríguez, Jesús Eduardo|||0000-0002-7758-6789Claudi, LeneLa Chica Lhoëst, María Teresa|||0000-0002-9070-5973Iborra Obiols, Antoni|||0000-0002-8984-5151Escolà-Gil, Joan Carles|||0000-0001-9021-2485Guerra Ramos, José María|||0000-0001-5397-9177Samouillan, Valerie|||0000-0003-0571-3985Enrich, Carlos|||0000-0003-0382-2993Chiabrando, Gustavo AlbertoLlorente-Cortés, Vicenta|||0000-0002-0067-7201High-fat dietLipid dropletsCholesteryl estersHeartLipoproteinInsulinLRP1Background: Antibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin response are largely unknown. Here, the effects of P3 peptide immunization on the alterations induced by a high-fat diet (HFD) in cardiac insulin response were evaluated. Methods: Irrelevant (IrP)- or P3 peptide-immunized rabbits were randomized into groups fed either HFD or normal chow. Cardiac lipid content was characterized by thin-layer chromatography, confocal microscopy, and electron microscopy. LRP1, InsR and glucose transporter type 4 (GLUT4) levels were determined in membranes and total lysates from rabbit heart. The interaction between InsR and LRP1 was analyzed by immunoprecipitation and confocal microscopy. Insulin signaling activity and glucose uptake were evaluated in HL-1 cells exposed to rabbit serum from the different groups. Findings: HFD reduces cardiac InsR and GLUT4 membrane levels and the interactions between LRP1/InsR. Targeting the P3 sequence on LRP1 through anti-P3 Abs specifically reduces CE accumulation in the heart independently of changes in the circulating lipid profile. This restores InsR and GLUT4 levels in cardiac membranes as well as the LRP1/InsR interactions of HFD-fed rabbits. In addition, anti-P3 Abs restores the insulin signaling cascade and glucose uptake in HL-1 cells exposed to hypercholesterolemic rabbit serum. Interpretation: LRP1-immunotargeting can block CE accumulation within the heart with specificity, selectivity, and efficacy, thereby improving the cardiac insulin response; this has important therapeutic implications for a wide range of cardiac diseases. Funding: Fundació MARATÓ TV3: grant 101521-10, Instiuto de Salud Carlos III (ISCIII) and ERDF PI18/01584, Fundación BBVA Ayudas a Equipos de Investigación 2019. SECyT-UNC grants PROYECTOS CONSOLIDAR 2018-2021; FONCyT, Préstamo BID PICT grant 2015-0807 and grant 2017-4497.Universitat Autònoma de Barcelona 22022-01-0120222022-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/277697https://dx.doi.org/urn:doi:10.1016/j.biopha.2022.113270reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/01584Fundació la Marató de TV3 https://doi.org/10.13039/100008666 101521-10open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2776972026-06-06T12:50:31Z
dc.title.none.fl_str_mv Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
title Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
spellingShingle Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
Actis Dato, Virginia|||0000-0002-9071-8045
High-fat diet
Lipid droplets
Cholesteryl esters
Heart
Lipoprotein
Insulin
LRP1
title_short Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
title_full Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
title_fullStr Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
title_full_unstemmed Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
title_sort Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response
dc.creator.none.fl_str_mv Actis Dato, Virginia|||0000-0002-9071-8045
Benitez Amaro, Aleyda|||0000-0002-1106-3125
García Rodríguez, Jesús Eduardo|||0000-0002-7758-6789
Claudi, Lene
La Chica Lhoëst, María Teresa|||0000-0002-9070-5973
Iborra Obiols, Antoni|||0000-0002-8984-5151
Escolà-Gil, Joan Carles|||0000-0001-9021-2485
Guerra Ramos, José María|||0000-0001-5397-9177
Samouillan, Valerie|||0000-0003-0571-3985
Enrich, Carlos|||0000-0003-0382-2993
Chiabrando, Gustavo Alberto
Llorente-Cortés, Vicenta|||0000-0002-0067-7201
author Actis Dato, Virginia|||0000-0002-9071-8045
author_facet Actis Dato, Virginia|||0000-0002-9071-8045
Benitez Amaro, Aleyda|||0000-0002-1106-3125
García Rodríguez, Jesús Eduardo|||0000-0002-7758-6789
Claudi, Lene
La Chica Lhoëst, María Teresa|||0000-0002-9070-5973
Iborra Obiols, Antoni|||0000-0002-8984-5151
Escolà-Gil, Joan Carles|||0000-0001-9021-2485
Guerra Ramos, José María|||0000-0001-5397-9177
Samouillan, Valerie|||0000-0003-0571-3985
Enrich, Carlos|||0000-0003-0382-2993
Chiabrando, Gustavo Alberto
Llorente-Cortés, Vicenta|||0000-0002-0067-7201
author_role author
author2 Benitez Amaro, Aleyda|||0000-0002-1106-3125
García Rodríguez, Jesús Eduardo|||0000-0002-7758-6789
Claudi, Lene
La Chica Lhoëst, María Teresa|||0000-0002-9070-5973
Iborra Obiols, Antoni|||0000-0002-8984-5151
Escolà-Gil, Joan Carles|||0000-0001-9021-2485
Guerra Ramos, José María|||0000-0001-5397-9177
Samouillan, Valerie|||0000-0003-0571-3985
Enrich, Carlos|||0000-0003-0382-2993
Chiabrando, Gustavo Alberto
Llorente-Cortés, Vicenta|||0000-0002-0067-7201
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv High-fat diet
Lipid droplets
Cholesteryl esters
Heart
Lipoprotein
Insulin
LRP1
topic High-fat diet
Lipid droplets
Cholesteryl esters
Heart
Lipoprotein
Insulin
LRP1
description Background: Antibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin response are largely unknown. Here, the effects of P3 peptide immunization on the alterations induced by a high-fat diet (HFD) in cardiac insulin response were evaluated. Methods: Irrelevant (IrP)- or P3 peptide-immunized rabbits were randomized into groups fed either HFD or normal chow. Cardiac lipid content was characterized by thin-layer chromatography, confocal microscopy, and electron microscopy. LRP1, InsR and glucose transporter type 4 (GLUT4) levels were determined in membranes and total lysates from rabbit heart. The interaction between InsR and LRP1 was analyzed by immunoprecipitation and confocal microscopy. Insulin signaling activity and glucose uptake were evaluated in HL-1 cells exposed to rabbit serum from the different groups. Findings: HFD reduces cardiac InsR and GLUT4 membrane levels and the interactions between LRP1/InsR. Targeting the P3 sequence on LRP1 through anti-P3 Abs specifically reduces CE accumulation in the heart independently of changes in the circulating lipid profile. This restores InsR and GLUT4 levels in cardiac membranes as well as the LRP1/InsR interactions of HFD-fed rabbits. In addition, anti-P3 Abs restores the insulin signaling cascade and glucose uptake in HL-1 cells exposed to hypercholesterolemic rabbit serum. Interpretation: LRP1-immunotargeting can block CE accumulation within the heart with specificity, selectivity, and efficacy, thereby improving the cardiac insulin response; this has important therapeutic implications for a wide range of cardiac diseases. Funding: Fundació MARATÓ TV3: grant 101521-10, Instiuto de Salud Carlos III (ISCIII) and ERDF PI18/01584, Fundación BBVA Ayudas a Equipos de Investigación 2019. SECyT-UNC grants PROYECTOS CONSOLIDAR 2018-2021; FONCyT, Préstamo BID PICT grant 2015-0807 and grant 2017-4497.
publishDate 2022
dc.date.none.fl_str_mv 2
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/277697
https://dx.doi.org/urn:doi:10.1016/j.biopha.2022.113270
url https://ddd.uab.cat/record/277697
https://dx.doi.org/urn:doi:10.1016/j.biopha.2022.113270
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18/01584
Fundació la Marató de TV3 https://doi.org/10.13039/100008666 101521-10
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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