PMID- 33740174 OWN - NLM STAT- MEDLINE DCOM- 20220712 LR - 20220726 IS - 1573-7241 (Electronic) IS - 0920-3206 (Print) IS - 0920-3206 (Linking) VI - 36 IP - 4 DP - 2022 Aug TI - Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes. PG - 665-678 LID - 10.1007/s10557-021-07166-2 [doi] AB - 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. CI - (c) 2021. The Author(s). FAU - Sun, Runlu AU - Sun R AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Fang, Pu AU - Fang P AD - Centers for Metabolic & Cardiovascular Research, Department of Pharmacology, Temple University, Medical Education & Research Building, Rm. 1060 3500 North Broad Street, Philadelphia, PA, USA. FAU - Jiang, Jieyu AU - Jiang J AD - Graceland Medical Center, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Huang, Canxia AU - Huang C AD - Intensive Care Unit, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Wang, Junjie AU - Wang J AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Guo, Qi AU - Guo Q AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Li, Hongwei AU - Li H AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Wu, Xiaoying AU - Wu X AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Xie, Xiangkun AU - Xie X AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Jiang, Yuan AU - Jiang Y AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Chen, Qian AU - Chen Q AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. FAU - Bao, Jinlan AU - Bao J AD - Comprehensive Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. FAU - Wang, Jingfeng AU - Wang J AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. wjingf@mail.sysu.edu.cn. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. wjingf@mail.sysu.edu.cn. FAU - Wang, Hong AU - Wang H AD - Centers for Metabolic & Cardiovascular Research, Department of Pharmacology, Temple University, Medical Education & Research Building, Rm. 1060 3500 North Broad Street, Philadelphia, PA, USA. hongw@temple.edu. FAU - Zhang, Yuling AU - Zhang Y AUID- ORCID: 0000-0001-8805-5249 AD - Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, the West of Yanjiang Road, Yuexiu District, Guangzhou, 510120, China. zhyul@mail.sysu.edu.cn. AD - Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China. zhyul@mail.sysu.edu.cn. LA - eng GR - 81700397/National Natural Science Foundation of China/ GR - 81970388/National Natural Science Foundation of China (CN)/ GR - 2019A1515011682/Natural Science Foundation of Guangdong Province/ GR - 201605131212026/Guangzhou Science and Technology Program key projects/ PT - Journal Article DEP - 20210319 PL - United States TA - Cardiovasc Drugs Ther JT - Cardiovascular drugs and therapy JID - 8712220 RN - 0 (ABCA1 protein, human) RN - 0 (ABCG1 protein, human) RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1) RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Chemokine CCL2) RN - 0 (Cholesterol, HDL) RN - 0 (Insulin) RN - 0 (Scavenger Receptors, Class B) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - ATP Binding Cassette Transporter 1/genetics/metabolism MH - ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics/metabolism MH - ATP-Binding Cassette Transporters/genetics/metabolism MH - Adipocytes/metabolism MH - Chemokine CCL2/metabolism MH - Cholesterol/metabolism MH - Cholesterol, HDL MH - Humans MH - Insulin MH - Obesity/drug therapy/metabolism MH - Overweight/metabolism MH - *Phosphatidylinositol 3-Kinases/metabolism MH - *Proto-Oncogene Proteins c-akt/metabolism MH - Scavenger Receptors, Class B/genetics/metabolism PMC - PMC9270268 OTO - NOTNLM OT - Adipocytes OT - Cholesterol efflux; large HDL2 particles OT - Insulin OT - MCP-1 COIS- The authors declare no conflicts of interest. EDAT- 2021/03/20 06:00 MHDA- 2022/07/14 06:00 PMCR- 2021/03/19 CRDT- 2021/03/19 17:30 PHST- 2021/02/24 00:00 [accepted] PHST- 2021/03/20 06:00 [pubmed] PHST- 2022/07/14 06:00 [medline] PHST- 2021/03/19 17:30 [entrez] PHST- 2021/03/19 00:00 [pmc-release] AID - 10.1007/s10557-021-07166-2 [pii] AID - 7166 [pii] AID - 10.1007/s10557-021-07166-2 [doi] PST - ppublish SO - Cardiovasc Drugs Ther. 2022 Aug;36(4):665-678. doi: 10.1007/s10557-021-07166-2. Epub 2021 Mar 19.