Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba 5000, Argentina.
Cells. 2020 Jan 10;9(1):182. doi: 10.3390/cells9010182.
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.
代谢综合征和 2 型糖尿病常并发心血管疾病（CVD），与聚集倾向小 LDL 颗粒水平升高有关。聚集的 LDL（aggLDL）通过 LDL 受体相关蛋白 1（LRP1）介导内化，促进细胞内胆固醇酯（CE）积累。此外，LRP1 在胰岛素受体（IR）和葡萄糖转运蛋白 4（GLUT4）活性的调节中起关键作用。然而，LRP1、CE 积累和胰岛素反应之间的联系在心肌细胞中尚未得到研究。我们旨在确定 aggLDL 通过与 LRP1 的相互作用产生 CE 积累并影响 HL-1 细胞中胰岛素诱导的细胞内信号转导和 GLUT4 易位的机制。我们证明 LRP1 介导 aggLDL 的内吞作用，并促进这些细胞中的 CE 积累。此外，aggLDL 减少了 IR 和 LRP1 之间的分子结合，并损害了胰岛素诱导的细胞内信号转导激活。最后，aggLDL 影响了胰岛素刺激细胞中 GLUT4 向质膜的易位和 2-NBDG 的摄取。我们得出结论，LRP1 是胰岛素反应的关键调节剂，通过 LRP1 介导的 aggLDL 内吞作用，CE 积累可以改变其功能。
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