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Sun R , Fang P , Jiang J , Huang C , Wang J , Guo Q , Li H , Wu X , Xie X , Jiang Y , Chen Q , Bao J , Wang J , Wang H , Zhang Y
Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes
Cardiovasc Drugs Ther. 2021 Mar 19
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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 [(3)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.
1573-7241 Sun, Runlu Fang, Pu Jiang, Jieyu Huang, Canxia Wang, Junjie Guo, Qi Li, Hongwei Wu, Xiaoying Xie, Xiangkun Jiang, Yuan Chen, Qian Bao, Jinlan Wang, Jingfeng Wang, Hong Zhang, Yuling Orcid: 0000-0001-8805-5249 81700397/National Natural Science Foundation of China/ 81970388/National Natural Science Foundation of China (CN)/ 2019A1515011682/Natural Science Foundation of Guangdong Province/ 201605131212026/Guangzhou Science and Technology Program key projects/ Journal Article United States Cardiovasc Drugs Ther. 2021 Mar 19. doi: 10.1007/s10557-021-07166-2.