TY - JOUR
T1 - Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes
AU - Sun, Runlu
AU - Fang, Pu
AU - Jiang, Jieyu
AU - Huang, Canxia
AU - Wang, Junjie
AU - Guo, Qi
AU - Li, Hongwei
AU - Wu, Xiaoying
AU - Xie, Xiangkun
AU - Jiang, Yuan
AU - Chen, Qian
AU - Bao, Jinlan
AU - Wang, Jingfeng
AU - Wang, Hong
AU - Zhang, Yuling
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2022/8
Y1 - 2022/8
N2 - 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 [
3H]-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.
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 [
3H]-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.
KW - Adipocytes
KW - Cholesterol efflux; large HDL2 particles
KW - Insulin
KW - MCP-1
KW - Cholesterol/metabolism
KW - Humans
KW - Adipocytes/metabolism
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Scavenger Receptors, Class B/genetics
KW - Overweight/metabolism
KW - Cholesterol, HDL
KW - Chemokine CCL2/metabolism
KW - ATP-Binding Cassette Transporters/genetics
KW - ATP Binding Cassette Transporter 1/genetics
KW - Obesity/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85103086149&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000630705000001&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1007/s10557-021-07166-2
DO - 10.1007/s10557-021-07166-2
M3 - Article
C2 - 33740174
SN - 0920-3206
VL - 36
SP - 665
EP - 678
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
IS - 4
ER -