Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes

Runlu Sun; Pu Fang; Jieyu Jiang; Canxia Huang; Junjie Wang; Qi Guo; Hongwei Li; Xiaoying Wu; Xiangkun Xie; Yuan Jiang; Qian Chen; Jinlan Bao; Jingfeng Wang; Hong Wang; Yuling Zhang

doi:10.1007/s10557-021-07166-2

Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes

Runlu Sun
, Pu Fang
, Jieyu Jiang
, Canxia Huang
, Junjie Wang
, Qi Guo
, Hongwei Li
, Xiaoying Wu
, Xiangkun Xie
, Yuan Jiang
, Qian Chen
, Jinlan Bao
, Jingfeng Wang
, Hong Wang
, Yuling Zhang

Nuclear Dynamics and Cancer (NDC)

Sun Yat-Sen University
Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology
Temple University

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	665-678
Number of pages	14
Journal	Cardiovascular Drugs and Therapy
Volume	36
Issue number	4
DOIs	https://doi.org/10.1007/s10557-021-07166-2
State	Published - Aug 2022

Keywords

Adipocytes
Cholesterol efflux; large HDL2 particles
Insulin
MCP-1
Cholesterol/metabolism
Humans
Adipocytes/metabolism
Phosphatidylinositol 3-Kinases/metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics
Proto-Oncogene Proteins c-akt/metabolism
Scavenger Receptors, Class B/genetics
Overweight/metabolism
Cholesterol, HDL
Chemokine CCL2/metabolism
ATP-Binding Cassette Transporters/genetics
ATP Binding Cassette Transporter 1/genetics
Obesity/drug therapy

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10.1007/s10557-021-07166-2

Cite this

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. (2022). Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes. Cardiovascular Drugs and Therapy, 36(4), 665-678. https://doi.org/10.1007/s10557-021-07166-2

@article{6da3ff3e88634b038a7e6e2d12b2d33b,

title = "Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes",

abstract = "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.",

keywords = "Adipocytes, Cholesterol efflux; large HDL2 particles, Insulin, MCP-1, Cholesterol/metabolism, Humans, Adipocytes/metabolism, Phosphatidylinositol 3-Kinases/metabolism, ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics, Proto-Oncogene Proteins c-akt/metabolism, Scavenger Receptors, Class B/genetics, Overweight/metabolism, Cholesterol, HDL, Chemokine CCL2/metabolism, ATP-Binding Cassette Transporters/genetics, ATP Binding Cassette Transporter 1/genetics, Obesity/drug therapy",

author = "Runlu Sun and Pu Fang and Jieyu Jiang and Canxia Huang and Junjie Wang and Qi Guo and Hongwei Li and Xiaoying Wu and Xiangkun Xie and Yuan Jiang and Qian Chen and Jinlan Bao and Jingfeng Wang and Hong Wang and Yuling Zhang",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = aug,

doi = "10.1007/s10557-021-07166-2",

language = "English",

volume = "36",

pages = "665--678",

journal = "Cardiovascular Drugs and Therapy",

issn = "0920-3206",

publisher = "Springer",

number = "4",

}

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 2022, 'Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes', Cardiovascular Drugs and Therapy, vol. 36, no. 4, pp. 665-678. https://doi.org/10.1007/s10557-021-07166-2

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

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 - https://www.scopus.com/pages/publications/85103086149

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 -

Insulin Rescued MCP-1-Suppressed Cholesterol Efflux to Large HDL2 Particles via ABCA1, ABCG1, SR-BI and PI3K/Akt Activation in Adipocytes

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