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Open AccessArticle

LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

1
Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina
2
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba 5000, Argentina
3
Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), 08025 Barcelona, Spain
4
Biomedical Research Institute Sant Pau (IIB Sant Pau), 08025 Barcelona, Spain
5
CIBERCV, Institute of Health Carlos III, 28029 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(1), 182; https://doi.org/10.3390/cells9010182 (registering DOI)
Received: 17 October 2019 / Revised: 23 December 2019 / Accepted: 6 January 2020 / Published: 10 January 2020
(This article belongs to the Special Issue Cells in Cardiovascular Disease)
The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosis. View Full-Text
Keywords: glucose; signaling; lipid; membranes; intracellular traffic glucose; signaling; lipid; membranes; intracellular traffic
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MDPI and ACS Style

Actis Dato, V.; Benitez-Amaro, A.; de Gonzalo-Calvo, D.; Vazquez, M.; Bonacci, G.; Llorente-Cortés, V.; Chiabrando, G.A. LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells. Cells 2020, 9, 182.

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