scholarly journals ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease

2005 ◽  
Vol 85 (4) ◽  
pp. 1343-1372 ◽  
Author(s):  
John F. Oram ◽  
Jay W. Heinecke
Keyword(s):  
Cardiovascular Disease ◽  
Density Lipoprotein ◽  
Deficiency Syndrome ◽  
Atp Binding ◽  
The Metabolic Syndrome ◽  
Atp Binding Cassette Transporter ◽  
A Cell ◽  
Cell Membrane Protein ◽  
Abca1 Protein ◽  
Atp Binding Cassette

Blood high-density lipoprotein (HDL) levels are inversely related to risk for cardiovascular disease, implying that factors associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins. ABCA1 transcription is highly induced by sterols, a major substrate for cellular export, and its expression and activity are regulated posttranscriptionally by diverse processes. Liver ABCA1 initiates formation of HDL particles, and macrophage ABCA1 protects arteries from developing atherosclerotic lesions. ABCA1 mutations can cause a severe HDL deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels and atherogenesis. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages. Moreover, oxidative modifications of HDL found in patients with cardiovascular disease reduce the ability of apolipoproteins to remove cellular cholesterol by the ABCA1 pathway. These observations raise the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become an important new therapeutic target for treating cardiovascular disease.

scholarly journals Sortilin promotes macrophage cholesterol accumulation and aortic atherosclerosis through lysosomal degradation of ATP-binding cassette transporter A1 protein

2019 ◽  
Vol 51 (5) ◽  
pp. 471-483 ◽  
Author(s):  
Yuncheng Lv ◽  
Jing Yang ◽  
Anbo Gao ◽  
Sha Sun ◽  
Xilong Zheng ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Atp Binding ◽  
Low Density ◽  
Lysosomal Degradation ◽  
Atp Binding Cassette Transporter ◽  
Abca1 Expression ◽  
Abca1 Protein ◽  
Atp Binding Cassette

Abstract Sortilin is closely associated with hyperlipidemia and the risk of atherosclerosis (AS). The role of sortilin and the underlying mechanism in peripheral macrophage are not fully understood. In this study, we investigated the effect of macrophage sortilin on ATP-binding cassette transporter A1 (ABCA1) expression, ABCA1-mediated cholesterol efflux, and aortic AS. Macrophage sortilin expression was upregulated by oxidized low-density lipoproteins (ox-LDLs) in both concentration- and time-dependent manners. Its expression reached the peak level when cells were incubated with 50 μg/ml ox-LDL for 24 h. Overexpression of sortilin in macrophage reduced cholesterol efflux, leading to an increase in intracellular total cholesterol, free cholesterol, and cholesterol ester. Sortilin was found to bind with ABCA1 protein and suppress macrophage ABCA1 expression, resulting in a decrease in cholesterol efflux from macrophages. The inhibitory effect of sortilin in cholesterol efflux was partially reversed by treatment with chloroquine, a lysosomal inhibitor. On the contrary, the ABCA1 protein level and ABCA1-mediated cholesterol efflux is increased by sortilin short hairpin RNA transfection. The fecal and biliary cholesterol 3H-sterol from cholesterol-laden mouse peritoneal macrophage was reduced by sortilin overexpression through lentivirus vector (LV)-sortilin in low-density lipoprotein receptor knockout mice, which was prevented by co-treatment with chloroquine. Treatment with LV-sortilin reduced plasma high-density lipoprotein and increased plasma ox-LDL levels. Accordingly, aortic lipid deposition and plaque area were exacerbated, and ABCA1 expression was reduced in mice in response to infection with LV-sortilin alone. These effects of LV-sortilin were partially reversed by chloroquine. Sortilin enhances lysosomal degradation of ABCA1 protein and suppresses ABCA1-mediated cholesterol efflux from macrophages, leading to foam cell formation and AS development.

Effect of Apolipoprotein A-I on ATP Binding Cassette Transporter A1 Degradation and Cholesterol Efflux in THP-1 Macrophage-derived Foam Cells

2004 ◽  
Vol 36 (3) ◽  
pp. 218-226 ◽  
Author(s):  
Chao-Ke Tang ◽  
Guo-Hua Tang ◽  
Guang-Hui Yi ◽  
Zuo Wang ◽  
Lu-Shan Liu ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Cholesterol Efflux ◽  
Foam Cells ◽  
Atp Binding ◽  
Thiol Protease ◽  
Atp Binding Cassette Transporter ◽  
Apolipoprotein A ◽  
Abca1 Protein ◽  
Abca1 Mrna ◽  
Atp Binding Cassette

Abstract Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ATP binding cassette transporter A1 (ABCA1), the defective molecule in Tangier disease, mediates the efflux of phospholipid and cholesterol from cells to apolipoprotein A-I (apoA-I), reversing foam cell formation. This study investigated the effect of apoA-I on ABCA1 degradation and cholesterol efflux in THP-1 macrophage-derived foam cells. After exposure of the cultured THP-1 macrophage-derived foam cells to apoA-I for different time, cholesterol efflux, ABCA1 mRNA and protein levels were determined by FJ-2107P type liquid scintillator, RT-PCR and Western blot, respectively. The mean ABCA1 fluorescence intensity on THP-1 macrophage-derived foam cells was detected by flow cytometry. Results showed that apoA-I markedly increased ABCA1-mediated cholesterol efflux from THP-1 macrophage-derived foam cells. This was accompanied by an increase in the content of ABCA1. ApoA-I did not alter ABCA1 mRNA abundance. Significantly, thiol protease inhibitors increased the level of ABCA1 protein and slowed its decay in THP-1 macrophage-derived foam cells, whereas none of the proteosome-specific inhibitor lactacystin, other protease inhibitors, or the lysosomal inhibitor NH4Cl showed such effects. The apoA-I-mediated cellular cholesterol efflux was enhanced by thiol protease inhibitors. Our results suggested that thiol protease inhibitors might provide an alternative way to upregulate ABCA1 protein. This strategy is especially appealing since it may mimic the stabilizing effect of the natural ligands apoA-I.

scholarly journals Berberine Improves High-Fat Diet Induced Atherosclerosis and Hepatic Steatosis in Apoe-/-Mice by Down-Regulating PCSK9 via ERK1/2 Pathway

2020 ◽  
Author(s):  
Chun-Yan Ma ◽  
Xiao-Yun Shi ◽  
Ya-Ru Wu ◽  
Yue Zhang ◽  
Hui-Lin Qu ◽  
...  
Keyword(s):  
Western Blotting ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Density Lipoprotein ◽  
Atp Binding ◽  
Type I ◽  
High Fat ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

Abstract Background:Berberine (BBR) is a kind of alkaloid derived from Chinese herbal medicine, which has multiple pharmacological activities including anti-atherosclerosis (AS). However, the mechanism underlying the role of BBR in modulating lipid metabolic disorders is not fully clear. The aim of the present study was to investigate the beneficial effects of BBR on AS in ApoE-/- mice and its potential mechanisms.Methods: Eight-week old ApoE-/- mice with high-fat diet (HFD) and wild type mice were administered eitherBBR (50mg/kg/d and 100mg/kg/d, respectively) or equivoluminal saline. After the 16-week treatment, the blood was collected for lipid evaluation, and aorta and liver were obtained from the mice for hematoxylin-eosin (HE) staining, oil red O staining and Western blotting. HepG2 Cells were treated by BBR (0, 5, 25, and 50 μg/ml) for 24 hours. Real-time PCR or Western blotting was used to examine the expression levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor (LDLR), ATP-binding cassette transporter A1(ABCA1), ATP-binding cassette transporter G1(ABCG1) and scavenger receptor class B type I(SR-BI).Results: BBR significantly decreased serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) level in ApoE-/- mice fed with HFD. Moreover, BBR markedly reduced aorta atheroscleroticplaque, ameliorated lipid deposition in the liver in vivo. BBR could also promote intracellular cholesterol efflux and regulate LDLR and PCSK9 expression via the ERK1/2 pathway in HepG2 cells.Conclusions: BBR could improve lipid metabolism, decrease aorta AS and hepatic lipid accumulation in ApoE-/- mice fed with HFD, which was associated with down-regulation of PCSK9 through ERK1/2 pathway.

Abstract 462: Activation of Akt2 by Apolipoprotein E Protects ATP-binding Cassette A1 From Degradation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Hong Yang ◽  
Emmanuel U Okoro ◽  
Zhongmao Guo
Keyword(s):  
Apolipoprotein E ◽  
Protein Level ◽  
Low Density Lipoprotein ◽  
Mrna Level ◽  
Density Lipoprotein ◽  
Atp Binding ◽  
Mrna Levels ◽  
Akt Phosphorylation ◽  
Abca1 Protein ◽  
Atp Binding Cassette

We previously reported that lipid-free apolipoprotein E (apoE) is able to increase ATP-binding cassette transporter A1 (ABCA1) transcription by activation of a signaling cascade involving very low-density lipoprotein receptor, apoE receptor 2, disabled-1, phosphatidylinositol 3-kinase (PI3K), protein kinase Cζ, and specificity protein 1 (Sp1). Here we demonstrated that treatment of RAW 264.7 murine macrophages with human apoE3 enhanced Akt phosphorylation, and upregulated ABCA1 protein and mRNA expression. Inhibition of PI3K weakened apoE3-induced Akt phosphorylation, and reduced ABCA1 protein and mRNA levels. In contrast, inhibition of Akt only diminished apoE-induced ABCA1 protein but not significantly alter ABCA1 mRNA level. Inhibition of protein synthesis did not erase the ability of apoE3 to increase ABCA1 protein level. Further, apoE3 increased the resistance of ABCA1 protein to calpain-mediated degradation without affecting calpain activity. Treatment of 264.7 cells with apoE3 selectively enhanced the phosphorylation of Akt1 and Akt2 but not Akt3. Knockdown of Akt1 enhanced the phosphorylation of Akt2. Vice versa, knockdown of Akt2 enhanced Akt1 phosphorylation. Underexpression of Akt1 or Akt2, respectively, increased and decreased ABCA1 protein level; while overexpression of these Akt isoenzymes caused changes in ABCA1 protein level opposite to those induced by knockdown of the corresponding Akt. These data imply that apoE3 guards against calpain-mediated ABCA1 degradation through Akt2. PI3K might be a step in the signaling pathway for apoE3 to trigger Akt2. [This study was supported by NIH grants SC1HL101431].

scholarly journals Acrolein Impairs ATP Binding Cassette Transporter A1-dependent Cholesterol Export from Cells through Site-specific Modification of Apolipoprotein A-I

2005 ◽  
Vol 280 (43) ◽  
pp. 36386-36396 ◽  
Author(s):  
Baohai Shao ◽  
Xiaoyun Fu ◽  
Thomas O. McDonald ◽  
Pattie S. Green ◽  
Koji Uchida ◽  
...  
Keyword(s):  
Critical Role ◽  
Density Lipoprotein ◽  
Spectrometric Analysis ◽  
Atp Binding ◽  
Major Protein ◽  
Cellular Interactions ◽  
Atp Binding Cassette Transporter ◽  
Apolipoprotein A ◽  
Tandem Mass Spectrometric ◽  
Atp Binding Cassette

Acrolein is a highly reactive α,β-unsaturated aldehyde, but the factors that control its reactions with nucleophilic groups on proteins remain poorly understood. Lipid peroxidation and threonine oxidation by myeloperoxidase are potential sources of acrolein during inflammation. Because both pathways are implicated in atherogenesis and high density lipoprotein (HDL) is anti-atherogenic, we investigated the possibility that acrolein might target the major protein of HDL, apolipoprotein A-I (apoA-I), for modification. Tandem mass spectrometric analysis demonstrated that lysine 226, located near the center of helix 10 in apoA-I, was the major site modified by acrolein. Importantly, this region plays a critical role in the cellular interactions and ability of apoA-I to transport lipid. Indeed, we found that conversion of Lys-226 to Nϵ-(3-methylpyridinium)lysine by acrolein associated quantitatively with decreased cholesterol efflux from cells via the ATP-binding cassette transporter A1 pathway. In the crystal structure of truncated apoA-I, Glu-234 lies adjacent to Lys-226, suggesting that negatively charged residues might direct the modification of specific lysine residues in proteins. Finally, immunohistochemical studies with a monoclonal antibody revealed co-localization of apoA-I with acrolein adducts in human atherosclerotic lesions. Our observations suggest that acrolein might interfere with normal reverse cholesterol transport by HDL by modifying specific sites in apoA-I. Thus, acrolein might contribute to atherogenesis by impairing cholesterol removal from the artery wall.

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