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

Virginia Actis Dato,Gustavo Alberto Chiabrando,Gustavo Bonacci,David De Gonzalo-Calvo,Vicenta Llorente-Cortés,Maximiliano Vazquez,Aleyda Benitez-Amaro

doi:10.3390/cells9010182

Abstract

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.

Highlights

These results indicate that Aggregated LDL (aggLDL) via LDL receptor-related protein 1 (LRP1) impairs the insulin intracellular signaling activation in HL-1 cells
These results indicate that aggLDL/LRP1 complex endocytosis affects insulin-induced glucose transporter type 4 (GLUT4) traffic to the plasma membrane (PM) and, the glucose uptake by HL-1 cells
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Summary

Introduction

Metabolic syndrome (MS) and type-2 diabetes mellitus (T2DM) are chronic metabolic disorders and prevalent diseases adversely impacting health worldwide, which are characterized by increased levels of circulating glucose, insulin, atherogenic lipoprotein subfractions, and inflammatory cytokines [1,2].These mediators of metabolic disease modify multiple molecular pathways, such as ceramide-induced apoptosis, increased formation of reactive oxygen species, mitochondrial dysfunction, and endoplasmic reticulum stress, which drive multiple alterations in different cell types, including cardiomyocytes [1,3].Cardiomyocytes are insulin-responsive cells and impaired insulin-signaling are associated with heartCells 2020, 9, 182; doi:10.3390/cells9010182 www.mdpi.com/journal/cellsCells 2020, 9, 182 failure [4]. Metabolic syndrome (MS) and type-2 diabetes mellitus (T2DM) are chronic metabolic disorders and prevalent diseases adversely impacting health worldwide, which are characterized by increased levels of circulating glucose, insulin, atherogenic lipoprotein subfractions, and inflammatory cytokines [1,2]. These mediators of metabolic disease modify multiple molecular pathways, such as ceramide-induced apoptosis, increased formation of reactive oxygen species, mitochondrial dysfunction, and endoplasmic reticulum stress, which drive multiple alterations in different cell types, including cardiomyocytes [1,3]. Whereas native LDL are recognized by the LDL receptor (LDLR), aggLDL are taken up by the LDL receptor-related protein 1 (LRP1) [10]

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