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Agarose gel electrophoreses of RT-PCR products: lane 1, ABCG1 products with 135 bp; lane 2, 18S RNA product with 151 bp; lane 3, molecular weight standards with 100–1000 bp; lane 4, negative control with <100 bp; lane 5, ABCA1 products with 180 bp.
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ABCA1 and ABCG1 genes encode the cholesterol transporter proteins that play a key role in cholesterol and phospholipids homeostasis. This study was aimed at evaluating and comparing ABCA1 and ABCG1 genes expression in metabolic syndrome patients and healthy individuals. This case-control study was performed on 36 patients with metabolic syndrome an...
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Background:
Metabolic syndrome (MetSx) is common among liver transplant recipients. It contributes to morbidity and mortality.
Objective:
To determine the prevalence of MetSx in patients undergoing liver transplantation (LTx) in Iran.
Methods:
202 liver transplant recipients of both sexes completed this study. Relevant information including ag...
Citations
... No changes in the expression of ABCG1 in M1 and M2 subsets were observed by Littlefield et al. [25] compared to Waldo et al. [34]. Additionally, ABCG1 expression in metabolic syndrome patients has been shown to be significantly lower [35]. ABCG1 has been reported to promote LPL-dependent triglyceride storage in adipocytes [36] and to modulate ATM cholesterol content in obesity and weight loss regimes, leading to an alteration in M1 to M2 ratio [37]. ...
Background and Objectives: Visceral obesity is associated with chronic low-grade inflammation that predisposes to metabolic syndrome. Indeed, infiltration of adipose tissue with immune–inflammatory cells, including ‘classical’ inflammatory M1 and anti-inflammatory ‘alternative’ M2 macrophages, causes the release of a variety of bioactive molecules, resulting in the metabolic complications of obesity. This study examined the relative expression of macrophage phenotypic surface markers, cholesterol efflux proteins, scavenger receptors, and adenosine receptors in human circulating peripheral blood mononuclear cells (PBMCs), isolated from patients with type 2 diabetes mellitus (T2DM), with the aim to phenotypically characterize and identify biomarkers for these ill-defined cells. Materials and Methodology: PBMCs were isolated from four groups of adults: Normal-weight non-diabetic, obese non-diabetic, newly diagnosed with T2DM, and T2DM on metformin. The mRNA expression levels of macrophage phenotypic surface markers (interleukin-12 (IL-12), C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 17 (CCL17), and C-C motif receptor 7 (CCR7)), cholesterol efflux proteins (ATP-binding cassette transporter-1 (ABCA1), ATP binding cassette subfamily G member 1 (ABCG1), and sterol 27-hydroxylase (CYP27A)), scavenger receptors (scavenger receptor-A (SR-A), C-X-C motif ligand 16 (CXCL16), and lectin-like oxidized LDL receptor-1 (LOX-1)), and adenosine receptors (adenosine A2A receptor (A2AR) and adenosine A3 receptor (A3R)) were measured using qRT-PCR. Results: In PBMCs from T2DM patients, the expression of IL-12, CCR7, ABCA1, and SR-A1 was increased, whereas the expression of CXCL10, CCL17, ABCG1,27-hydroxylase, LOX-1, A2AR and A3R was decreased. On the other hand, treatment with the antidiabetic drug, metformin, reduced the expression of IL-12 and increased the expression of 27-hydroxylase, LOX-1, CXCL16 and A2AR. Conclusion: PBMCs in the circulation of patients with T2DM express phenotypic markers that are different from those typically present in adipose tissue M1 and M2 macrophages and could be representative of metabolically activated macrophages (MMe)-like cells. Our findings suggest that metformin alters phenotypic markers of MMe-like cells in circulation.
... ABCG1 expression has been found enhance the cholesterol efflux interrelated with ABCA1 performance and other supportive agent 27 and found significantly lower in Met S case. 28 To explain this finding, future study should be undertaken to explore the expression of ABCG1-dependent agent and its pathway, with some SNPs, in variation of many age levels. ...
Asian countries now suffers from a double burden issue that involves metabolic syndrome (MetS) even in the adolescent age. Many factors have been considered to explain this situation including genetic variation contribution to the susceptibility of said metabolic syndrome. ATP-Binding Cassette G1 (ABCG1) is known in its role in cholesterol efflux that is strongly related in lipid accumulation and insulin performance. In addition to this gene modulation work in reverse cholesterol transport that is also connected with the occurrence of metabolic syndrome. However, the effect of polymorphism in rs1044317 remains unclear. A total of 434 subjects in adolescent age were genotyped for ABCG1 rs1044317 by restricted fragmented length polymorphism polymerase chain reaction method. All the anthropometric and laboratory date was extracted by an approved protocol. The correlation of each variables was detected using SPSS ver.21. Frequencies of alleles and genotypes of the ABCG1 polymorphism were similar in both sexes. A significant correlation detected between adjusted males’ group with an increased level of interleukin-6 in wide genotype and an increased fasting blood sugar level in adjusted females’ group in variant genotype. The existence of rs1044317 ABCG1 SNP affected the susceptibility of specific criteria of MetS in Thai adolescence population. Additionally, there is a gender difference in the incidence of MetS, indicating a possible gene–gender interaction of the ABCG1 polymorphism in MetS among Thai adolescents.
... The nascent, immature HDL particles are matured by taking up more cholesterol via ABCG1 (24). Although no genetic disease caused by ABCG1 mutations has been reported, decrease in ABCG1 expression levels was observed in metabolic disorders (25,26). The working mechanism of ABCG1-mediated cholesterol efflux has not been elucidated. ...
The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.
... A recent study has also shown that the correlation between BMI and ABCG1 gene expression in monocytes is partially mediated by DNA methylation [31]. Previous studies have demonstrated that methylation of ABCG1 CpG sites cg06500161 and cg27243685 in the blood is positively associated with plasma triglyceride concentration and could be linked to obesity and metabolic syndrome [28,33,[48][49][50][51][52]. One possible explanation is that ABCG1 could regulate the bioavailability and the subsequent activity of lipoprotein lipase (LPL), a ratelimiting enzyme that hydrolyzes circulating triglyceride-rich lipoproteins [53,54]. ...
Abstract Background Recent studies have focused on the potential role of epicardial adipose tissue (EAT) in the development of coronary artery disease (CAD). ABCA1 and ABCG1 transporters regulate cell cholesterol content and reverse cholesterol transport. We aimed to determine whether DNA methylation and mRNA levels of the ABCA1 and ABCG1 genes in EAT and subcutaneous adipose tissue (SAT) were associated with CAD. Methods Paired EAT and SAT samples were collected from 82 patients undergoing elective cardiac surgery either for coronary artery bypass grafting (CAD group, N = 66) or valve surgery (NCAD group, N = 16). ABCA1 and ABCG1 mRNA levels in EAT and SAT samples were analyzed using real time polymerase chain reaction, ABCA1 protein levels in EAT samples were assessed by western blotting. ABCA1 and ABCG1 DNA methylation analysis was performed in 24 samples from the CAD group and 9 samples from the NCAD group via pyrosequencing. Results DNA methylation levels in the ABCA1 promoter and ABCG1 cg27243685 and cg06500161 CpG sites were higher in EAT samples from patients with CAD compared with NCAD (21.92% vs 10.81%, p = 0.003; 71.51% vs 68.42%, p = 0.024; 46.11% vs 37.79%, p = 0.016, respectively). In patients with CAD, ABCA1 and ABCG1 DNA methylation levels were higher in EAT than in SAT samples (p
... Another important feature of foam cell formation is reduced expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) genes, and scavenger receptor class B type I (SR-BI) under activation of UPR pathways, which interferes with cholesterol efflux [37]. Cholesterol transfer from macrophages to high density lipoprotein-cholesterol (HDL) through the ABC transmembrane transporters can decrease cellular cholesterol concentration [38,39]. ABC transporters' expression is tightly regulated by genetic (transcription factors) and epigenetic factors (miRNAs and RNA-binding proteins) in macrophages under physiology conditions [40,41]. ...
The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells.
... In addition, we have confirmed using two separate datasets that statin use was indeed correlated with a reduction in ABCG1 expression in human blood samples. Other studies have reported a link between ABCG1 downregulation and diabetes incidence [39] and high fasting glycaemia [40]. Taken together, our human cellular data is consistent with human observational studies, in which the inhibition of ABCG1 expression was deleterious for metabolism in adipose tissue. ...
Background:
Adipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis. Cholesterol-lowering statins increase type 2 diabetes (T2D) risk possibly by affecting adipogenesis and insulin resistance but the (epi)genetic mechanisms involved are unknown. Here, we characterised the effects of statin treatment on adipocyte differentiation using in vitro human preadipocyte cell model to identify putative effective genes.
Results:
Statin treatment during adipocyte differentiation caused a reduction in key genes involved in adipogenesis, such as ADIPOQ, GLUT4 and ABCG1. Using Illumina's Infinium '850K' Methylation EPIC array, we found a significant hypomethylation of cg14566882, located in the promoter of the histone deacetylase 9 (HDAC9) gene, in response to two types of statins (atorvastatin and mevastatin), which correlates with an increased HDAC9 mRNA expression. We confirmed that HDAC9 is a transcriptional repressor of the cholesterol efflux ABCG1 gene expression, which is epigenetically modified in obesity and prediabetic states. Thus, we assessed the putative impact of ABCG1 knockdown in mimicking the effect of statin in adipogenesis. ABCG1 KD reduced the expression of key genes involved in adipocyte differentiation and decreased insulin signalling and glucose uptake. In human blood cells from two cohorts, ABCG1 expression was impaired in response to statins, confirming that ABCG1 is targeted in vivo by these drugs.
Conclusions:
We identified an epigenetic link between adipogenesis and adipose tissue insulin resistance in the context of T2D risk associated with statin use, which has important implications as HDAC9 and ABCG1 are considered potential therapeutic targets for obesity and metabolic diseases.
... The human ABCG1 gene has 23 exons [178]. Though there has been no genetic disorder resulting from ABCG1 mutations reported to date, ABCG1 expression was shown to be significantly decreased (by~75%) in patients suffering from metabolic syndrome, in comparison with healthy controls [178,179]. In addition, modulation of ABCG1 expression might be related to the pathogenesis of obesity and diabetes, both being critical risk factors for CVD [178]. ...
Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired β-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.
... Beyond a role in cellular lipid homeostasis, ABCG1 equally participates to glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase. Moreover, there is a growing body of evidence suggesting that modulation of ABCG1 expression might contribute to the development of diabetes and obesity [64], which are major risk factors of CVD. The ABCG1, GALNT2 and HMGCR genes have been previously associated with pathogenesis and progression of CHD through manipulating the various lipid pathways [65,66]. ...
Sex is a major determinant of cardiometabolic risk. DNA methylation (DNAm), an important epigenetic mechanism that differs between sexes, has been associated with cardiometabolic diseases. Therefore, we aimed to systematically review studies in adults investigating sex-specific associations of DNAm with intermediate cardiometabolic traits and incident cardiovascular disease including stroke, myocardial infarction (MI) and coronary heart disease (CHD). Five bibliographic databases were searched from inception to 15 July 2019. We selected 35 articles (based on 30 unique studies) from 17,023 references identified, with a total of 14,020 participants of European, North American or Asian ancestry. Four studies reported sex differences between global DNAm and blood lipid levels and stroke risk. In 25 studies that took a genome wide or candidate gene approach, DNAm at 31 gene sites was associated with sex differences in cardiometabolic diseases. The identified genes were PLA2G7, BCL11A, KDM6A, LIPC, ABCG1, PLTP, CETP, ADD1, CNN1B, HOOK2, GFBP-7,PTPN1, GCK, PTX3, ABCG1, GALNT2, CDKN2B, APOE, CTH, GNASAS, INS, PON1, TCN2, CBS, AMT, KDMA6A, FTO, MAP3K13, CCDC8, MMP-2 and ER-α. Prioritized pathway connectivity analysis associated these genes with biological pathways such as vitamin B12 metabolism, statin pathway, plasma lipoprotein, plasma lipoprotein assembly, remodeling and clearance and cholesterol metabolism. Our findings suggest that DNAm might be a promising molecular strategy for understanding sex differences in the pathophysiology of cardiometabolic diseases and that future studies should investigate the effects of sex on epigenetic mechanisms in cardiometabolic risk. In addition, we emphasize the gap between the translational potential and the clinical utilization of cardiometabolic epigenetics.
... Interestingly, treatment with a LXR agonist induced ABCG1 expression and attenuated cholesterol accumulation in macrophages from T2D patients [110]. A reduction of ABCG1 expression was also reported in peripheral blood mononuclear cells from Iranian patients with Metabolic Syndrome exhibiting high fasting glycemia in comparison to the control group [111]. Consistent with studies in murine cells, high glucose and PUFAs repressed ABCG1 expression in human macrophages [112,113] whereas a conjugated linoleic acid isomer (trans-9, trans-11-CLA) was reported to activate ABCG1 expression through sterol regulatory element-binding protein (SREBP)-1c [114]. ...
De faibles concentrations de cholestérol associé aux HDL (HDL-C) est un facteur de risque indépendant des maladies cardiovasculaires (MCV). Les HDL sont capables de réaliser de l’efflux de lipides des tissus périphériques pour assurer son retour vers le foie, et ont des rôles athéroprotecteurs. Le travail mené ici vise à identifier de nouveaux acteurs impliqués dans la détermination des fonctions des HDL. Le transporteur ABCG1 réalise de l’efflux de cholestérol, de phospholipides (PL), ou encore de vitamines à partir des macrophages périphériques vers les HDL. Nous avons montré que la stimulation de l’expression d’ABCG1 dans l’hépatocyte favorisait un réarrangement du contenu des HDL en PL. Ce remodelage est associé à une amélioration de la capacité d’efflux de cholestérol des HDL et de leur fonction anti-inflammatoire. En parallèle, des études épidémiologiques nous ont permis d’identifier ZNF471, nouveau facteur de transcription. Il semble capable de moduler l’expression et l’activité de protéines clés du métabolisme des lipides, via une régulation épigénétique impactant la méthylation de l’ADN : ZNF471 dans les hépatocytes augmente la méthylation de l’ADN sur la région promotrice du gène codant la CETP. En conséquence, l’expression du gène et l’activité protéique de la CETP sont réduits, ce qui favorise l’accumulation de HDL-C. De plus, les capacités d’efflux de cholestérol des HDL sont également stimulées par ZNF471. Ces travaux de recherche permettent l’identification de nouveaux acteurs du métabolisme des lipoprotéines HDL. Ils ouvrent ainsi la voie à de nouvelles explorations thérapeutique et mécanistique sur les rôles des HDL dans les MCV liées à l’athérosclérose.
... ABCA1 protein level is significantly reduced in human atherosclerotic lesions, 18 and ABCG1 mRNA is markedly reduced in monocytes of humans with metabolic syndrome. 19 These observations are consistent with our findings that miR-34a expression is induced, whereas ABCA1 and ABCG1 are repressed in atherosclerotic lesions, and that miR-34a inhibits ABCA1 and ABCG1 expression. Both LXR activation and miR-33 ...
Macrophages play a crucial role in the pathogenesis of atherosclerosis, but the molecular mechanisms remain poorly understood. Here we show that microRNA-34a (miR-34a) is a key regulator of macrophage cholesterol efflux and reverse cholesterol transport by modulating ATP-binding cassette transporters ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1). miR-34a also regulates M1 and M2 macrophage polarization via liver X receptor α. Furthermore, global loss of miR-34a reduces intestinal cholesterol or fat absorption by inhibiting cytochrome P450 enzymes CYP7A1 and sterol 12α-hydroxylase (CYP8B1). Consistent with these findings, macrophage-selective or global ablation of miR-34a markedly inhibits the development of atherosclerosis. Finally, therapeutic inhibition of miR-34a promotes atherosclerosis regression and reverses diet-induced metabolic disorders. Our studies outline a central role of miR-34a in regulating macrophage cholesterol efflux, inflammation, and atherosclerosis, suggesting that miR-34a is a promising target for treatment of cardiometabolic diseases.
