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Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response

Actis Dato, Virginia and Benitez-Amaro, Aleyda and Garcia, Eduardo and Claudi, Lene and Lhoëst, Maria Teresa LaChica and Iborra, Antoni and Escola-Gil, Joan Carles and Guerra, Jose Maria and Samouillan, Valérie and Enrich, Carlos and Chiabrando, Gustavo and Llorente-Cortés, Vicenta Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response. (2022) Biomedicine & Pharmacotherapy, 152. 113270. ISSN 0753-3322

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Official URL: https://doi.org/10.1016/j.biopha.2022.113270

Abstract

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.

Item Type:Article
Additional Information:Under a Creative Commons license
HAL Id:hal-03714200
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:Other partners > Institute of Health Carlos III - CIBERCV (SPAIN)
French research institutions > Centre National de la Recherche Scientifique - CNRS (FRANCE)
Other partners > Institut d′Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS (SPAIN)
Other partners > Institute of Biomedical Research of Barcelona of the Spanish National Research Council - IIBB-CSIC (SPAIN)
Université de Toulouse > Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE)
Other partners > Universidad Nacional de Cordoba - UNC (ARGENTINA)
Université de Toulouse > Université Toulouse III - Paul Sabatier - UT3 (FRANCE)
Other partners > Universitat Autònoma de Barcelona - UAB (SPAIN)
Other partners > Universitat de Barcelona - UB (SPAIN)
Other partners > Consejo Nacional de Investigaciones Científicas y Técnicas - CONICET (ARGENTINA)
Other partners > Hospital de la Santa Creu i Sant Pau (SPAIN)
Laboratory name:
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Deposited On:05 Jul 2022 10:42

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