靶向心脏中的胆固醇酯积累可改善心脏胰岛素反应。
Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response.
机构信息
Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Córdoba, Argentina.
Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
出版信息
Biomed Pharmacother. 2022 Aug;152:113270. doi: 10.1016/j.biopha.2022.113270. Epub 2022 Jun 13.
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 ERDFPI18/01584, 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.
背景
针对 LRP1 第 P3 序列（Gly1127-Cys1140）的抗体（抗-P3 Abs）特异性地阻止血管细胞中胆固醇酯（CE）的积累。LRP1 是不同细胞类型中胰岛素受体（InsR）转运的关键调节剂。CE 积累与胰岛素反应之间的联系在很大程度上尚不清楚。在这里，评估了 P3 肽免疫接种对高脂肪饮食（HFD）引起的心脏胰岛素反应改变的影响。
方法
将无关（IrP）或 P3 肽免疫接种的兔子随机分为 HFD 或正常饲料喂养的组。通过薄层层析、共聚焦显微镜和电子显微镜来描述心脏脂质含量。从兔心膜和总裂解物中测定 LRP1、InsR 和葡萄糖转运蛋白 4（GLUT4）水平。通过免疫沉淀和共聚焦显微镜分析 InsR 和 LRP1 之间的相互作用。在暴露于来自不同组的兔血清的 HL-1 细胞中评估胰岛素信号转导活性和葡萄糖摄取。
结果
HFD 降低了心脏 InsR 和 GLUT4 膜水平以及 LRP1/InsR 的相互作用。通过抗-P3 Abs 靶向 LRP1 的 P3 序列可特异性地降低心脏中的 CE 积累，而不改变循环脂质谱。这恢复了 HFD 喂养兔子心脏膜中的 InsR 和 GLUT4 水平以及 LRP1/InsR 的相互作用。此外，抗-P3 Abs 恢复了暴露于高胆固醇兔血清的 HL-1 细胞中的胰岛素信号级联和葡萄糖摄取。
解释
LRP1 免疫靶向可以特异性、选择性和有效性地阻止心脏内的 CE 积累，从而改善心脏胰岛素反应；这对广泛的心脏疾病具有重要的治疗意义。
资金
Fundació MARATÓ TV3：资助 101521-10，西班牙卡洛斯三世健康研究所（ISCIII）和欧洲区域发展基金 PI18/01584，BBVA 基金会 2019 年研究团队资助。SECyT-UNC 巩固项目 2018-2021 年；阿根廷国家科学技术研究委员会（CONICET），BID PICT 贷款 2015-0807 和 2017-4497 年。
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