Abstract
Monocyte chemoattractant protein-1 (MCP-1) plays crucial roles at multiple stages of atherosclerosis. We hypothesized that MCP-1 might impair the reverse cholesterol transport (RCT) capacity of HepG2 cells by decreasing the cell-surface protein expression of ATP binding cassette A1 (ABCA1), ATP binding cassette G1 (ABCG1), and scavenger receptor class B type I (SR-BI). MCP-1 reduced the total protein and mRNA levels of ABCA1 and SR-BI, but not of ABCG1. MCP-1 decreased the cell-surface protein expression of ABCA1, ABCG1, and SR-BI in dose-dependent and time-dependent manners, as measured using cell-surface biotinylation. We further studied the phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase Akt pathway in regulating receptor trafficking. Both the translation and transcription of ABCA1, ABCG1, and SR-BI were not found to be regulated by the PI3K/Akt pathway. However, the cell-surface protein expression of ABCA1, ABCG1, and SR-BI could be regulated by PI3K activity, and PI3K activation corrected the MCP-1-induced decreases in the cell-surface protein expression of ABCA1, ABCG1, and SR-BI. Moreover, we found that MCP-1 decreased the lipid uptake by HepG2 cells and the ABCA1-mediated cholesterol efflux to apoA-I, which could be reversed by PI3K activation. Our data suggest that MCP-1 impairs RCT activity in HepG2 cells by a PI3K/Akt-mediated posttranslational regulation of ABCA1, ABCG1, and SR-BI cell-surface expression.
Highlights
Monocyte chemoattractant protein-1 (MCP-1) plays crucial roles at multiple stages of atherosclerosis
The phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase Akt (Akt) pathway participates in the MCP-1mediated posttranslational suppression of the cell-surface localization of ATP binding cassette A1 (ABCA1), ATP binding cassette G1 (ABCG1), and scavenger receptor class B type I (SR-BI), and the PI3K activator restores the impaired reverse cholesterol transport (RCT) activity caused by MCP-1
The experiments in which mouse primary hepatocytes were transfected with siRNA indicated that the knockdown of ABCA1 induced a significant reduction in cholesterol efflux to apoA-I, whereas the knockdown of ABCG1 did not affect the cholesterol efflux, and the knockdown of SR-BI resulted in a slight increase in the efflux
Summary
Monocyte chemoattractant protein-1 (MCP-1) plays crucial roles at multiple stages of atherosclerosis. We hypothesized that MCP-1 might impair the reverse cholesterol transport (RCT) capacity of HepG2 cells by decreasing the cell-surface protein expression of ATP binding cassette A1 (ABCA1), ATP binding cassette G1 (ABCG1), and scavenger receptor class B type I (SR-BI). We further studied the phosphoinositide 3-kinase (PI3K)/ serine/threonine protein kinase Akt pathway in regulating receptor trafficking. We found that MCP-1 decreased the lipid uptake by HepG2 cells and the ABCA1-mediated cholesterol efflux to apoA-I, which could be reversed by PI3K activation. Our data suggest that MCP-1 impairs RCT activity in HepG2 cells by a PI3K/Akt-mediated posttranslational regulation of ABCA1, ABCG1, and SR-BI cell-surface expression.— Huang, C-X., Y-L. Bao. MCP-1 impacts RCT by repressing ABCA1, ABCG1, and SR-BI through PI3K/Akt posttranslational regulation in HepG2 cells. Many pro-inflammatory factors, including IFN-␥, lipopolysaccharide, tumor necrosis factor, interleukin-1, and interleukin-6, have been found to modulate the expression of HDL receptors and, in turn, alter RCT activity [24,25,26]
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