胰岛素通过 ABCA1、ABCG1、SR-BI 和 PI3K/Akt 激活拯救脂肪细胞中 MCP-1 抑制的胆固醇向大 HDL2 颗粒的流出。
Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes.
机构信息
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China.
Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China.
出版信息
Cardiovasc Drugs Ther. 2022 Aug;36(4):665-678. doi: 10.1007/s10557-021-07166-2. Epub 2021 Mar 19.
PURPOSE
Intracellular cholesterol imbalance plays an important role in adipocyte dysfunction of obesity. However, it is unclear whether obesity induced monocyte chemoattractant protein-1 (MCP-1) causes the adipocyte cholesterol imbalance. In this study, we hypothesize that MCP-1 impairs cholesterol efflux of adipocytes to HDL2 and insulin rescues this process.
METHODS
We recruited coronary artery disease (CAD) patients with obesity and overweight to analyze the association between MCP-1 and HDL2-C by Pearson correlation coefficients. We performed [H]-cholesterol efflux assay to demonstrate the effect of MCP-1 and insulin on cholesterol efflux from 3T3-L1 adipocytes to large HDL2 particles. Western blot, RT-qPCR, cell-surface protein assay, and confocal microscopy were performed to determine the regulatory mechanism.
RESULTS
Plasma MCP-1 concentrations were negatively correlated with HDL2-C in CAD patients with obesity and overweight (r = -0.60, p < 0.001). In differentiated 3T3-L1 adipocytes, MCP-1 reduced cholesterol efflux to large HDL2 particles by 55.4% via decreasing ATP-binding cassette A1 (ABCA1), ABCG1, and scavenger receptor class B type I (SR-BI) expression. Intriguingly, insulin rescued MCP-1 mediated-inhibition of cholesterol efflux to HDL2 in an Akt phosphorylation-dependent manner. The rescue efficacy of insulin was 138.2% for HDL2. Moreover, insulin increased mRNA and protein expression of ABCA1, ABCG1, and SR-BI at both transcriptional and translational levels via the PI3K/Akt activation.
CONCLUSIONS
These findings indicate that MCP-1 impairs cholesterol efflux to large HDL2 particles in adipocytes, which is reversed by insulin via the upregulation of ABCA1, ABCG1, and SR-BI. Therefore, insulin might improve cholesterol imbalance by an anti-inflammatory effect in adipocytes.
CLINICAL TRIAL REGISTRATION NUMBER
ChiCTR2000033297; Date of registration: 2020/05/ 27; Retrospectively registered.
目的
细胞内胆固醇失衡在肥胖导致的脂肪细胞功能障碍中起着重要作用。然而，目前尚不清楚肥胖诱导的单核细胞趋化蛋白-1（MCP-1）是否导致脂肪细胞胆固醇失衡。在本研究中，我们假设 MCP-1 会损害脂肪细胞向 HDL2 的胆固醇外排，而胰岛素则可以挽救这一过程。
方法
我们招募了患有肥胖症和超重的冠心病（CAD）患者，通过皮尔逊相关系数分析 MCP-1 与 HDL2-C 之间的关系。我们通过 [H]-胆固醇外排实验来证明 MCP-1 和胰岛素对 3T3-L1 脂肪细胞向大 HDL2 颗粒的胆固醇外排的影响。我们通过 Western blot、RT-qPCR、细胞表面蛋白检测和共聚焦显微镜来确定调控机制。
结果
在患有肥胖症和超重的 CAD 患者中，血浆 MCP-1 浓度与 HDL2-C 呈负相关（r=-0.60，p<0.001）。在分化的 3T3-L1 脂肪细胞中，MCP-1 通过降低 ATP 结合盒转运体 A1（ABCA1）、ABCG1 和清道夫受体 B 类 I 型（SR-BI）的表达，使胆固醇向大 HDL2 颗粒的外排减少了 55.4%。有趣的是，胰岛素通过 Akt 磷酸化依赖性方式挽救了 MCP-1 介导的 HDL2 胆固醇外排抑制。胰岛素对 HDL2 的挽救效率为 138.2%。此外，胰岛素通过激活 PI3K/Akt 通路，在转录和翻译水平上增加了 ABCA1、ABCG1 和 SR-BI 的 mRNA 和蛋白表达。
结论
这些发现表明，MCP-1 损害了脂肪细胞向大 HDL2 颗粒的胆固醇外排，而胰岛素通过上调 ABCA1、ABCG1 和 SR-BI 来逆转这种作用。因此，胰岛素可能通过抗炎作用改善脂肪细胞中的胆固醇失衡。
临床试验注册号
ChiCTR2000033297；注册日期：2020/05/27；回顾性注册。
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