scholarly journals The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1593
Author(s):  
Leonor Jacobo-Albavera ◽  
Mayra Domínguez-Pérez ◽  
Diana Jhoseline Medina-Leyte ◽  
Antonia González-Garrido ◽  
Teresa Villarreal-Molina
Keyword(s):  
Plasma Membrane ◽  
Cancer Progression ◽  
Transmembrane Protein ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Age Related Macular Degeneration ◽  
Phospholipid Content ◽  
Atp Binding ◽  
Age Related ◽  
Atp Binding Cassette

Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.

scholarly journals Bioinformatical Analysis of miRNA-mRNA Interaction Network Underlying Macrophage Aging and Cholesterol-Responsive Difference between Young and Aged Macrophages

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jianqing Li ◽  
Xue Yin ◽  
Bingyu Zhang ◽  
Chen Li ◽  
Peirong Lu
Keyword(s):  
Target Genes ◽  
Density Lipoprotein ◽  
Interaction Network ◽  
Metabolic Process ◽  
Cholesterol Homeostasis ◽  
Age Related Macular Degeneration ◽  
Differentially Expressed ◽  
Functional Annotations ◽  
Age Related ◽  
Bioinformatical Analysis

Purpose. Macrophage aging is involved with the occurrence and progression of age-related macular degeneration (AMD). The purpose of this study was to identify the specific microRNAs (miRNA), mRNAs, and their interactions underlying macrophage aging and response to cholesterol through bioinformatical analysis in order to get a better understanding of the mechanism of AMD. Methods. The microarray data were obtained from Gene Expression Omnibus (accession GSE111304 and GSE111382). The age-related differentially expressed genes in macrophages were identified using R software. Further miRNA-mRNA interactions were analyzed through miRWalk, mirTarBase, starBase, and then produced by Cytoscape. The functional annotations including Gene Ontology and KEGG pathways of the miRNA target genes were performed by the DAVID and the STRING database. In addition, protein-protein interaction network was constructed to identify the key genes in response to exogenous cholesterol. Results. When comparing aged and young macrophages, a total of 14 miRNAs and 101 mRNAs were detected as differentially expressed. Besides, 19 validated and 544 predicted miRNA-mRNA interactions were detected. Lipid metabolic process was found to be associated with macrophage aging through functional annotations of the miRNA targets. After being treated with oxidized and acetylated low-density lipoprotein, miR-714 and 16 mRNAs differentially expressed in response to both kinds of cholesterol between aged and young macrophages. Among them, 6 miRNA-mRNA predicted pairs were detected. The functional annotations were mainly related to lipid metabolism process and farnesyl diphosphate farnesyl transferase 1 (FDFT1) was identified to be the key gene in the difference of response to cholesterol between aged and young macrophages. Conclusions. Lipid metabolic process was critical in both macrophage aging and response to cholesterol thus was regarded to be associated with the occurrence and progression of AMD. Moreover, miR-714-FDFT1 may modulate cholesterol homeostasis in aged macrophages and have the potential to be a novel therapeutic target for AMD.

scholarly journals Liver X Receptor β (LXRβ) Interacts Directly with ATP-binding Cassette A1 (ABCA1) to Promote High Density Lipoprotein Formation during Acute Cholesterol Accumulation

2011 ◽  
Vol 286 (22) ◽  
pp. 20117-20124 ◽  
Author(s):  
Masako Hozoji-Inada ◽  
Youichi Munehira ◽  
Kohjiro Nagao ◽  
Noriyuki Kioka ◽  
Kazumitsu Ueda
Keyword(s):  
Translational Regulation ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Transcriptional Response ◽  
Liver X Receptor ◽  
Cholesterol Homeostasis ◽  
Atp Binding ◽  
Transcriptional Level ◽  
Cholesterol Accumulation ◽  
Atp Binding Cassette

Cells have evolved multiple mechanisms for maintaining cholesterol homeostasis, and, among these, ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux is highly regulated at the transcriptional level through the activity of the nuclear receptor liver X receptor (LXR). Here, we show that in addition to its well defined role in transcription, LXRβ directly binds to the C-terminal region (2247LTSFL2251) of ABCA1 to mediate its post-translational regulation. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXRβ complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur. Exogenously added LXR ligands, which mimic cholesterol accumulation, cause LXRβ to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux. Photoaffinity labeling experiments with 8-azido-[α-32P]ATP showed that the interaction of LXRβ with ABCA1 inhibits ATP binding by ABCA1. This is the first study to show that a protein-protein interaction with the endogenous protein suppresses the function of ABC proteins by inhibiting ATP binding. LXRβ can cause a post-translational response by binding directly to ABCA1, as well as a transcriptional response, to maintain cholesterol homeostasis.

scholarly journals Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Akash Das ◽  
Michael S Brown ◽  
Donald D Anderson ◽  
Joseph L Goldstein ◽  
Arun Radhakrishnan
Keyword(s):  
Plasma Membrane ◽  
Regulatory Mechanism ◽  
Low Density Lipoprotein ◽  
Human Fibroblasts ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Mutant Form ◽  
Perfringolysin O ◽  
Cholesterol Levels ◽  
Plasma Membrane Cholesterol

When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.

scholarly journals Two B-type ATP-binding cassette (ABC) transporters localize to the plasma membrane in Thalictrum minus

2015 ◽  
Vol 32 (3) ◽  
pp. 243-247 ◽  
Author(s):  
Nobukazu Shitan ◽  
Kazuyoshi Terasaka ◽  
Hirobumi Yamamoto ◽  
Fumihiko Sato ◽  
Kazufumi Yazaki
Keyword(s):  
Plasma Membrane ◽  
Abc Transporters ◽  
Atp Binding ◽  
Thalictrum Minus ◽  
Atp Binding Cassette

scholarly journals MicroRNA-33-5p inhibits cholesterol efflux in vascular endothelial cells by regulating citrate synthase and ATP-binding cassette transporter A1

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qiong Xie ◽  
Jianqiang Peng ◽  
Ying Guo ◽  
Feng Li
Keyword(s):  
Endothelial Cells ◽  
Lipid Metabolism ◽  
Cholesterol Efflux ◽  
Citrate Synthase ◽  
Vascular Endothelial Cells ◽  
Density Lipoprotein ◽  
Atp Binding ◽  
Vascular Endothelial ◽  
Lipid Metabolism Disorders ◽  
Atp Binding Cassette

Abstract Background A high level of total cholesterol is associated with several lipid metabolism disorders, including atherosclerosis and cardiovascular diseases. ATP-binding cassette (ABC) transporter A1 (ABCA1) and miR-33-5p play crucial roles in atherosclerosis by controlling cholesterol efflux. While citrate is a precursor metabolite for lipid and cholesterol synthesis, little is known about the association between citrate synthase (CS) and cholesterol efflux. This study investigated the role of the miR-33-5p/ABCA1/CS axis in regulating cholesterol efflux in vascular endothelial cells (VECs). Materials and methods VECs were treated with oxidized low-density lipoprotein cholesterol (ox-LDL), or pretreated with plasmids overexpressing CS, ABCA1, siRNAs against CS and ABCA1, and an miR-33-5p inhibitor. Cell apoptosis, cellular senescence-associated β-galactosidase activity, inflammation, and cholesterol efflux were detected. Results Treatment with ox-LDL decreased ABCA1 and CS levels and increased miR-33-5p expression and apoptosis in dose-dependent manners. In contrast, treatment with the miR-33-5p inhibitor and ABCA1 and CS overexpression plasmids inhibited the above-mentioned ox-LDL-induced changes. In addition, treatment with ox-LDL decreased cholesterol efflux, induced aging, and promoted the production of inflammatory cytokines (i.e., IL-6 and tumor necrosis factor TNF-α), as well as the expression of Bax and Caspase 3 proteins in VECs. All these changes were rescued by miR-33-5p inhibition and ABCA1 and CS overexpression. The inhibition of ABCA1 and CS by siRNAs eliminated the effects mediated by the miR-33-5p inhibitor, and knockdown of CS eliminated the effects of ABCA1 on VECs. Conclusions This study demonstrated the crucial roles played by the miR-33-5p/ABCA1/CS axis in regulating cholesterol efflux, inflammation, apoptosis, and aging in VECs, and also suggested the axis as a target for managing lipid metabolism disorders.

Elevated apolipoprotein A1 and HDL cholesterol associated with age-related macular degeneration: two population cohorts

2021 ◽  
Author(s):  
Liv Tybjærg Nordestgaard ◽  
Anne Tybjærg-Hansen ◽  
Ruth Frikke-Schmidt ◽  
Børge Grønne Nordestgaard
Keyword(s):  
Macular Degeneration ◽  
Ldl Cholesterol ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Age Related Macular Degeneration ◽  
Apolipoprotein A1 ◽  
Age Related ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Plasma Apolipoprotein

Abstract Context To enable prevention and treatment of age-related macular degeneration(AMD), understanding risk factors for AMD is important. Objective We tested the hypotheses that elevated plasma apolipoprotein A1 and high-density lipoprotein(HDL) cholesterol, and low levels of low-density lipoprotein(LDL) cholesterol, are associated with increased risk of AMD. Design and Setting From the Danish general population, we studied 106,703 and 16,032 individuals in the Copenhagen General Population Study(CGPS) and the Copenhagen City Heart Study(CCHS) with median follow-up of respectively 9 and 32 years. Main Outcome Measures 1,787 AMD in CGPS and 206 in CCHS. Results Higher concentrations of plasma apolipoprotein A1 and HDL cholesterol, and lower concentrations of LDL cholesterol, were associated with higher risk of AMD in CGPS. After multifactorial adjustment, individuals in the highest versus lowest quartile of plasma apolipoprotein A1 and HDL cholesterol had hazard ratios for AMD of 1.40(95%CI:1.20-1.63) and 1.22(1.03-1.45). Corresponding hazard ratios for individuals in the lowest versus highest quartile of LDL cholesterol were 1.18(1.02-1.37). Per 100 mg/dL higher plasma apolipoprotein A1, 1 mmol/L(39 mg/dL) higher HDL, and 1 mmol/L(39mmol/L) lower LDL cholesterol, the hazard ratios for AMD were 1.53(1.31-1.80), 1.19(1.07-1.32), and 1.05(1.00-1.11), respectively, with similar results across strata of different risk factors. Higher concentrations of HDL cholesterol were also associated with higher risk of AMD in the CCHS. Conclusion Elevated plasma apolipoprotein A1 and HDL cholesterol, and lower LDL cholesterol, are associated with increased risk of age-related macular degeneration.

The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study

2020 ◽  
Author(s):  
Xikun Han ◽  
Jue-Sheng Ong ◽  
Alex W Hewitt ◽  
Puya Gharahkhani ◽  
Stuart MacGregor
Keyword(s):  
Macular Degeneration ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipid Biomarkers ◽  
Age Related Macular Degeneration ◽  
Apolipoprotein A1 ◽  
Lipoprotein Cholesterol ◽  
European Descent ◽  
Age Related

Abstract Background Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear. Methods Two-sample Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64–407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium. Results Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. Conclusion These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.

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