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
; 36(4): 665-678, 2022 08.
Article
en En
| MEDLINE
| ID: mdl-33740174
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fosfatidilinositol 3-Quinasas
/
Proteínas Proto-Oncogénicas c-akt
Límite:
Humans
Idioma:
En
Revista:
Cardiovasc Drugs Ther
Asunto de la revista:
ANGIOLOGIA
/
CARDIOLOGIA
/
TERAPIA POR MEDICAMENTOS
Año:
2022
Tipo del documento:
Article
País de afiliación:
China