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1.
Mol Biol (Mosk) ; 55(1): 64-74, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33566026

RESUMO

The study aimed to investigate tissue-specific gene expression of ABCA1 and ABCG1, encoding cholesterol transporters, as well as PPARG, LXRß (NR1H2), and RORA, encoding the most important transcriptional regulators of lipid metabolism, in subcutaneous and visceral adipose tissue (SAT and VAT) in women with metabolic syndrome. It was shown that the ABCG1 mRNA SAT/VAT ratio decreases with age and correlates with the development of metabolic syndrome. After age adjustment, women have reduced chances of metabolic syndrome development when ABCG1 gene expression in SAT is higher relative to VAT than women with VAT ABCG1 gene expression higher or comparable to SAT: OR = 0.15 (95% CI 0.03-0.76), p = 0.023. The ABCA1 mRNA SAT/VAT ratio positively correlated with HDL cholesterol levels (after age adjustment ß = 0.350, p = 0.046), therefore individuals with higher ABCA1 mRNA level in SAT relative to VAT had elevated HDL levels. The ABCA1 mRNA level in SAT was decreased in smokers (p = 0.001). There was a negative correlation between the PPARG mRNA level in SAT with body mass index and waist circumference in the general sample (ß = -0.602, p = 0.003 and ß = -0.642, p = 0.001, respectively, after age adjustment). A decrease of the PPARG mRNA SAT/VAT ratio was associated with elevated plasma insulin level and the insulin resistance index HOMA-IR ß = -0.819, p = 0.004 and ß = -1.053, p = 0.008, respectively, after age adjustment). Thus, the study has shown that the ratio of ABCA1, ABCG1, and PPARG genes expression in different types of adipose tissue (SAT/VAT) could be a significant factor that predicts the development of atherogenic dyslipidemia, metabolic syndrome, and insulin resistance in obesity.


Assuntos
Síndrome Metabólica , PPAR gama , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Tecido Adiposo , Índice de Massa Corporal , Feminino , Humanos , Gordura Intra-Abdominal , Síndrome Metabólica/genética , PPAR gama/genética , Fatores de Transcrição , Circunferência da Cintura
2.
J Postgrad Med ; 67(1): 29-32, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33380594

RESUMO

Coronary heart disease (CHD) is the most important cause of cardiovascular death and when premature, it affects the most productive population of the community. Premature CHD usually has a specific etiology, which on diagnosis, might help in the secondary prevention in that individual. We report a case of young adult with recurrent myocardial infarction, who on evaluation had mildly reduced HDL and Protein C levels with elevated serum homocysteine. Clinical exome identified a possibly pathogenic variant of ABCA1 gene, associated with Tangier disease.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Infarto do Miocárdio/diagnóstico , Doença de Tangier/complicações , Adulto , Predisposição Genética para Doença , Humanos , Masculino , Infarto do Miocárdio/genética , Doença de Tangier/sangue , Doença de Tangier/genética
3.
BMC Public Health ; 20(1): 1024, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600448

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a metabolic disorder which accounts for high morbidity and mortality due to complications like renal failure, amputations, cardiovascular disease, and cerebrovascular events. METHODS: We collected medical reports, lifestyle details, and blood samples of individuals and used the polymerase chain reaction-ligase detection reaction method to genotype the SNPs, and a visit was conducted in August 2016 to obtain the incidence of Type 2 diabetes in the 2113 eligible people. To explore which genes and environmental factors are associated with type 2 diabetes mellitus in a Chinese Han population, we used elastic net to build a model, which is to explain which variables are strongly associated with T2DM, rather than predict the occurrence of T2DM. RESULT: The genotype of the additive of rs964184, together with the history of hypertension, regular intake of meat and waist circumference, increased the risk of T2DM (adjusted OR = 2.38, p = 0.042; adjusted OR = 3.31, p < 0.001; adjusted OR = 1.05, p < 0.001). The TT genotype of the additive and recessive models of rs12654264, the CC genotype of the additive and dominant models of rs2065412, the TT genotype of the additive and dominant models of rs4149336, together with the degree of education, regular exercise, reduced the risk of T2DM (adjusted OR = 0.46, p = 0.017; adjusted OR = 0.53, p = 0.021; adjusted OR = 0.59, p = 0.021; adjusted OR = 0.57, p = 0.01; adjusted OR = 0.59, p = 0.021; adjusted OR = 0.57, p = 0.01; adjusted OR = 0.50, p = 0.007; adjusted OR = 0.80, p = 0.032) . CONCLUSION: Eventually we identified a set of SNPs and environmental factors: rs5805 in the SLC12A3, rs12654264 in the HMGCR, rs2065412 and rs414936 in the ABCA1, rs96418 in the ZPR1 gene, waistline, degree of education, exercise frequency, hypertension, and the intake of meat. Although there was no interaction between these variables, people with two risk factors had a higher risk of T2DM than those only having one factor. These results provide the theoretical basis for gene and other risk factors screening to prevent T2DM.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Grupo com Ancestrais do Continente Asiático/genética , Diabetes Mellitus Tipo 2/genética , Hidroximetilglutaril-CoA Redutases/genética , Proteínas de Membrana Transportadoras/genética , Idoso , Carbolinas , China/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etnologia , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Circunferência da Cintura/etnologia , Circunferência da Cintura/genética
4.
PLoS Pathog ; 16(6): e1008621, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544188

RESUMO

During tuberculosis, lung myeloid cells have two opposing roles: they are an intracellular niche occupied by Mycobacterium tuberculosis, and they restrict bacterial replication. Lung myeloid cells from mice infected with yellow-fluorescent protein expressing M. tuberculosis were analyzed by flow cytometry and transcriptional profiling to identify the cell types infected and their response to infection. CD14, CD38, and Abca1 were expressed more highly by infected alveolar macrophages and CD11cHi monocyte-derived cells compared to uninfected cells. CD14, CD38, and Abca1 "triple positive" (TP) cells had not only the highest infection rates and bacterial loads, but also a strong interferon-γ signature and nitric oxide synthetase-2 production indicating recognition by T cells. Despite evidence of T cell recognition and appropriate activation, these TP macrophages are a cellular compartment occupied by M. tuberculosis long-term. Defining the niche where M. tuberculosis resists elimination promises to provide insight into why inducing sterilizing immunity is a formidable challenge.


Assuntos
Antígenos CD11/imunologia , Macrófagos Alveolares , Monócitos , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Animais , Antígenos CD11/genética , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Mycobacterium tuberculosis/genética , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Tuberculose/genética , Tuberculose/patologia
5.
Mol Cell Biol ; 40(16)2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32482798

RESUMO

Genome-wide association studies (GWAS) have linked IGF2BP2 single-nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D). Mice overexpressing mIGF2BP2 have elevated cholesterol levels when fed a diet that induces hepatic steatosis. These and other studies suggest an important role for insulin growth factor 2 mRNA binding protein 2 (IGF2BP2) in the initiation and progression of several metabolic disorders. The ATPase binding cassette protein ABCA1 initiates nascent high-density apolipoprotein (HDL) biogenesis by transferring phospholipid and cholesterol to delipidated apolipoprotein AI (ApoAI). Individuals with mutational ablation of ABCA1 have Tangier disease, which is characterized by a complete loss of HDL. MicroRNA 33a and 33b (miR-33a/b) bind to the 3' untranslated region (UTR) of ABCA1 and repress its posttranscriptional gene expression. Here, we show that IGF2BP2 works together with miR-33a/b in repressing ABCA1 expression. Our data suggest that IGF2BP2 is an accessory protein of the argonaute (AGO2)-miR-33a/b-RISC complex, as it directly binds to miR-33a/b, AGO2, and the 3' UTR of ABCA1 Finally, we show that mice overexpressing human IGF2BP2 have decreased ABCA1 expression, increased low-density lipoprotein-cholesterol (LDL-C) and cholesterol blood levels, and elevated SREBP-dependent signaling. Our data support the hypothesis that IGF2BP2 has an important role in maintaining lipid homeostasis through its modulation of ABCA1 expression, as its overexpression or loss leads to dyslipidemia.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Fator de Crescimento Insulin-Like II/genética , Fígado/metabolismo , MicroRNAs/genética , Animais , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica/genética , Humanos , Insulina/metabolismo , Camundongos , Camundongos Transgênicos
6.
Vascul Pharmacol ; 128-129: 106675, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32200116

RESUMO

The transformation of macrophages to foam cells is a critical component in atherosclerotic lesion formation. Maslinic acid (MA), a novel natural pentacyclic triterpene, has cardioprotective and anti-inflammatory properties. It is hypothesized that MA can suppress monocyte recruitment to endothelial cells and inhibit macrophage foam cells formation. Previous study shows that MA inhibits inflammatory effects induced by sPLA2-IIA, including foam cells formation. This study elucidates the regulatory effect of MA in monocyte recruitment, macrophage lipid accumulation and cholesterol efflux. Our findings demonstrate that MA inhibits THP-1 monocyte adhesion to HUVEC cells in a TNFα-dependent and independent manner, but it induces trans-endothelial migration marginally at low concentration. MA down-regulates both gene and protein expression on VCAM-1 and MCP-1 in HUVECs. We further showed that MA suppresses macrophage foam cells formation, as indicated from the Oil-Red-O staining and flow cytometric analysis of intracellular lipids accumulation. The effects observed may be attributed to the antioxidant properties of MA where it was shown to suppress CuSO4-induced lipid peroxidation. MA inhibits scavenger receptors SR-A and CD36 expression while enhancing cholesterol efflux. MA enhances cholesterol efflux transporters ABCA1 and ABCG1 genes expression marginally without inducing its protein expression. In this study, MA was shown to target important steps that contribute to foam cell formation, including its ability in reducing monocytes adhesion to endothelial cells and LDL peroxidation, down-regulating scavenger receptors expression as well as enhancing cholesterol efflux, which might be of great importance in the context of atherosclerosis prevention and treatment.


Assuntos
Antioxidantes/farmacologia , Aterosclerose/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Triterpenos/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Células Espumosas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Monócitos/metabolismo , Células THP-1 , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
7.
Arterioscler Thromb Vasc Biol ; 40(5): 1182-1194, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32131613

RESUMO

OBJECTIVE: To characterize the fate of protein and lipid in nascent HDL (high-density lipoprotein) in plasma and explore the role of interaction between nascent HDL and mature HDL in promoting ABCA1 (ATP-binding cassette transporter 1)-dependent cholesterol efflux. Approach and Results: Two discoidal species, nascent HDL produced by RAW264.7 cells expressing ABCA1 (LpA-I [apo AI containing particles formed by incubating ABCA1-expressing cells with apo AI]), and CSL112, human apo AI (apolipoprotein AI) reconstituted with phospholipids, were used for in vitro incubations with human plasma or purified spherical plasma HDL. Fluorescent labeling and biotinylation of HDL were employed to follow the redistribution of cholesterol and apo AI, cholesterol efflux was measured using cholesterol-loaded cells. We show that both nascent LpA-I and CSL112 can rapidly fuse with spherical HDL. Redistribution of the apo AI molecules and cholesterol after particle fusion leads to the formation of (1) enlarged, remodeled, lipid-rich HDL particles carrying lipid and apo AI from LpA-I and (2) lipid-poor apo AI particles carrying apo AI from both discs and spheres. The interaction of discs and spheres led to a greater than additive elevation of ABCA1-dependent cholesterol efflux. CONCLUSIONS: These data demonstrate that although newly formed discs are relatively poor substrates for ABCA1, they can interact with spheres to produce lipid-poor apo AI, a much better substrate for ABCA1. Because the lipid-poor apo AI generated in this interaction can itself become discoid by the action of ABCA1, cycles of cholesterol efflux and disc-sphere fusion may result in net ABCA1-dependent transfer of cholesterol from cells to HDL spheres. This process may be of particular importance in atherosclerotic plaque where cholesterol acceptors may be limiting.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , HDL-Colesterol/sangue , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteína A-I/sangue , Transporte Biológico , HDL-Colesterol/química , Humanos , Cinética , Lipoproteínas HDL/sangue , Camundongos , Tamanho da Partícula , Células RAW 264.7
8.
PLoS One ; 15(3): e0229322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176696

RESUMO

Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the ß-position. This modification renders TTA unable to undergo complete ß-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.


Assuntos
HDL-Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Lipoproteínas/metabolismo , PPAR alfa/agonistas , Sulfetos/administração & dosagem , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Sulfetos/farmacologia , Triglicerídeos/sangue
9.
Am J Physiol Renal Physiol ; 318(4): F911-F921, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068459

RESUMO

The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.


Assuntos
Tecido Adiposo/metabolismo , Hemodinâmica , Hipertensão/metabolismo , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Metabolismo dos Lipídeos , Mutação , Obesidade/metabolismo , Receptores para Leptina/genética , Circulação Renal , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Adiposidade , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Quimiocina CXCL16/genética , Quimiocina CXCL16/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Metabolismo dos Lipídeos/genética , Obesidade/genética , Obesidade/patologia , Obesidade/fisiopatologia , Fenótipo , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/fisiopatologia , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta
10.
Circ J ; 84(2): 217-225, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31915322

RESUMO

BACKGROUND: Midkine (MK), a heparin-binding protein, participates in multiple cellular processes, such as immunity, cellular growth and apoptosis. Overwhelming evidence indicates that MK plays an important role in various pathological processes, including chronic inflammation, autoimmunity, cancer, and infection. Recent studies demonstrated that MK may be involved in the development of atherosclerosis, yet the mechanism has not been fully explored. Therefore, this study aims to investigate the effect and mechanism of MK on macrophage cholesterol efflux.Methods and Results:Using Oil Red O staining, NBD-cholesterol fluorescence labeling and enzymatic methods, it observed that MK markedly promoted macrophage lipid accumulation. Liquid scintillation counting (LSC) showed that MK decreased cholesterol efflux. Moreover, cell immunofluorescence, western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) showed that MK downregulated ATP-binding membrane cassette transport protein A1 (ABCA1) expression. Functional promotion of ABCA1 expression attenuated the inhibitory effects of MK on cholesterol efflux, which reduced lipid accumulation. Additionally, intervention of adenosine monophosphate activated protein (AMPK)-mammalian target of rapamycin (mTOR) signaling molecule by the AMPK activator, AICAR, increased p-AMPK and ABCA1 expression, decreased p-mTOR expression and promoted cholesterol efflux, resulting in an obvious reduction in intracellular lipid content. CONCLUSIONS: These data suggest that MK reduces the expression of ABCA1, inhibits the efflux of cholesterol and promotes the accumulation of lipids in RAW264.7 macrophages, and AMPK-mTOR signaling is involved in MK-mediated regulation of cholesterol metabolism in RAW264.7 macrophages.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Macrófagos/efeitos dos fármacos , Midkina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Regulação para Baixo , Ativação Enzimática , Macrófagos/enzimologia , Camundongos , Fosforilação , Células RAW 264.7 , Transdução de Sinais
11.
Medicine (Baltimore) ; 99(4): e18662, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977856

RESUMO

BACKGROUND: As a key gene in the reverse transport pathway of cholesterol, ABCA1 (ATP-binding cassette transporter A1) plays an important role in the pathogenesis of coronary artery disease (CAD). In the ABCA1, rs2230806 is the most widely studied polymorphism and its role has been controversial. METHODS: We performed an updated meta-analysis by searching online electronic databases using the PubMed, Web of Science, Embase, Cochrane Library, EMBASE, Google Scholar, China National Knowledge Infrastructure, and Wan Fang databases before June 28, 2019. STATA12.0 software was used to perform a series of analyses on the data, including genetic effect model, heterogeneity, sensitivity, and publication bias analysis. RESULTS: Based on our inclusion and exclusion criteria, finally 43 articles including a total of 34,348 subjects (14,085 CAD cases and 20,263 healthy controls) were investigated. Results showed that carrying the K allele in rs223086 in the overall population significantly reduced the risk of CAD (OR = 0.745, 95% CI = 0.687-0.809, P < .001). After the ethnicity stratification analysis, the above phenomenon was found to be significant in Asian populations (OR = 0.686, 95% CI = 0.633-0.744, P < .001), marginally significant in Caucasians (OR = 0.887, 95% CI = 0.786-1.001, P = .051), and not significant in other populations (OR = 0.851, 95% CI = 0.558-1.297, P = .452). Further stratified according to the sample size in the Asian and Caucasian populations, in the Asian the K allele is more protective in small samples than large samples; however, in the Caucasian small samples carrying the K allele play a protective role while large samples are negative. In addition, according to the source of the control population and the geographical location in China, the results showed that rs2230806 was significantly associated with CAD in any group. Five genetic models (allelic, recessive, dominant, homozygote, and heterozygote) were analyzed in the above analysis. CONCLUSION: The K allele of rs2230806 was significantly associated with decreased risk of CAD, especially in Asian populations and small sample Caucasians.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Doença da Artéria Coronariana/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Doença da Artéria Coronariana/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único
12.
Biochem Biophys Res Commun ; 524(1): 77-82, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31980179

RESUMO

OBJECTIVES: Protein arginine methyltransferase 2 (PRMT2) is closely related to the occurrence and development of atherosclerosis. However, its underlying mechanisms remain to be elucidated. The purpose of this study is to observe the effect of overexpression of PRMT2 on the formation of foam cells and to explore its possible mechanism in RAW 264.7 macrophage. METHODS: Lentivirus vector of overexpression PRMT2 (LV-PRMT2) was constructed. LV-PRMT2 and lentivirus vector GV492 were transfected into RAW 264.7 macrophages, positive clone cells were screened by treatment with 4.0 µg/mL puromycin for 4 weeks. The macrophages were treated with ox-LDL (50 µg/mL) for 48 h to induce foaming. The lipid accumulation of macrophages was observed by oil red O staining. The levels of cellular total cholesterol (TC), free cholesterol (FC) and cholesteryl ester (CE) were measured by high performance liquid chromatography (HPLC) assays. The cholesterol efflux of macrophages was tested by the [3H] labeled cholesterol. The expressions of ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1), CD36 and scavenger receptor A1 (SR-A1) in macrophages were measured by Western Blot. RESULTS: The results showed that LV-PRMT2 and lentivirus vector has been successfully transfected into RAW 264.7 macrophage. Compared with the Vector group, the mRNA and protein expressions of PRMT2 were significantly up-regulated (P < 0.05). Compared with Control group, the expression of PRMT2 was significantly down-regulated in ox-LDL group (P < 0.05). A large number of red lipid droplets appeared in the cells in Vector group. Compared with Vector group, lipid droplets, the levels of TC, FC and CE and CE/TC, cholesterol efflux rate and expression of ABCA1 in RAW 264.7 macrophage was significantly decreased in LV-PRMT2 group (all P < 0.05). There was no significant difference about the expressions of ABCG1, CD36 and SR-A1 between LV-PRMT2 group and Vector group (all P > 0.05). CONCLUSIONS: Overexpression of PRMT2 inhibits the formation of foam cell induced by ox-LDL in RAW 264.7 macrophage, and the mechanism may be related to the increase of ABCA1 expression and ABCA1 mediated cholesterol efflux.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Arginina/metabolismo , Aterosclerose/metabolismo , Transporte Biológico , Antígenos CD36/metabolismo , Regulação da Expressão Gênica , Lentivirus/genética , Metilação , Camundongos , Células RAW 264.7 , RNA Mensageiro/metabolismo , Receptores Depuradores/metabolismo , Transfecção
13.
PLoS One ; 15(1): e0221915, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945064

RESUMO

The crystal structure of a C-terminal deletion of apolipoprotein A-I (apoA1) shows a large helical bundle structure in the amino half of the protein, from residues 8 to 115. Using site directed mutagenesis, guanidine or thermal denaturation, cell free liposome clearance, and cellular ABCA1-mediated cholesterol efflux assays, we demonstrate that apoA1 lipidation can occur when the thermodynamic barrier to this bundle unfolding is lowered. The absence of the C-terminus renders the bundle harder to unfold resulting in loss of apoA1 lipidation that can be reversed by point mutations, such as Trp8Ala, and by truncations as short as 8 residues in the amino terminus, both of which facilitate helical bundle unfolding. Locking the bundle via a disulfide bond leads to loss of apoA1 lipidation. We propose a model in which the C-terminus acts on the N-terminus to destabilize this helical bundle. Upon lipid binding to the C-terminus, Trp8 is displaced from its interaction with Phe57, Arg61, Leu64, Val67, Phe71, and Trp72 to destabilize the bundle. However, when the C-terminus is deleted, Trp8 cannot be displaced, the bundle cannot unfold, and apoA1 cannot be lipidated.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteína A-I/genética , Metabolismo dos Lipídeos/genética , Lipídeos/química , Transportador 1 de Cassete de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apolipoproteína A-I/química , Transporte Biológico/genética , Dicroísmo Circular , Cristalografia por Raios X , Humanos , Cinética , Lipídeos/genética , Camundongos , Mutagênese Sítio-Dirigida , Ligação Proteica , Estrutura Secundária de Proteína , Desdobramento de Proteína , Células RAW 264.7 , Deleção de Sequência/genética
14.
Mol Biol Rep ; 47(2): 1321-1329, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853766

RESUMO

ATP-binding cassette membrane transporters (ABC), functions as an outflow facilitator of phospholipids and cellular cholesterol, playing an important role in the development of atherosclerosis and arterial hypertension. ABC's transporters could post-transcriptionally regulated by miRs. Evaluate the association in the transporters ABCA1 and ABCG1 with the expression of miR-33a and miR-144 and the carotid intima media thickness (cIMT) in patients with essential arterial hypertension. The miR-33a-5p, miR-144-3p and mRNA ABCA1 and ABCG1 expression in monocytes from Mexican hypertensive patients were examined by RT-PCR. The miR-33a and miR-144 expression in monocytes and mRNA ABCA1 and ABCG1 from Mexican hypertensive patients were examined by RT-PCR. This study involved 84 subjects (42 normotensive subjects and 42 patients with essential hypertension). Our study revealed that miR-33a expression (p = 0.001) and miR-144 (p = 0.985) were up-regulated, meanwhile, ABCA1 and ABCG1 transporters were down-regulated (p = 0.007 and p = 0.550 respectively) in hypertensive patients compared with the control group. The trend remains for miR33a/ABCA1 in presence of cIMT. Moreover, an inverse correlation was found with the expression levels of ABCA1 and ABCG1 as well as in HDL-C with miR-33a and miR-144. Our results showed an increase in the expression of miR-33a and miR-144 and an inverse correlation in their target ABCA1 and ABCG1; it may be associated with essential arterial hypertension in patients with cIMT and as consequence for atheromatous plaque.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Espessura Intima-Media Carotídea , Regulação da Expressão Gênica , Estudos de Associação Genética , Hipertensão/genética , MicroRNAs/genética , Angiotensinas/metabolismo , Índice de Massa Corporal , Dislipidemias/genética , Feminino , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade
15.
J Pharmacol Sci ; 142(1): 9-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771811

RESUMO

Varenicline is a widely used and effective drug for smoking cessation. We previously reported that varenicline aggravates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. However, it remains unknown whether varenicline affects cardiovascular events in patients with nicotine addiction. Here, we examined the effect of varenicline on atherosclerotic plaque formation in nicotine-pretreated ApoE KO mice and oxidized low-density lipoprotein (oxLDL) uptake in nicotine-treated peritoneal macrophages. Varenicline caused significant progression of plaque formation in the whole aorta and aortic root and further accelerated the increased formation of a macrophage-rich plaque area in the aortic root in nicotine-pretreated ApoE KO mice. Varenicline (10 µM) enhanced oxLDL uptake in peritoneal macrophages. Furthermore, this treatment significantly further lowered the decreased protein levels of ATP-binding cassette (ABC) transporter without affecting the expression of scavenger receptors LOX-1 and CD36 in RAW264.7 cells treated with 100 nM nicotine. Varenicline enhanced nicotine-induced oxLDL uptake in macrophages through decreased expression of cholesterol efflux transporters ABCA1 and ABCG1 and thereby progressed atherosclerotic plaque formation. Taken together, we tentatively conclude that nicotine exposure before and/or during varenicline treatment can aggravate varenicline-increased atherosclerotic plaque formation and progression. Therefore, this enhanced risk requires special consideration when prescribing varenicline to smoker patients.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Macrófagos/metabolismo , Nicotina/farmacologia , Placa Aterosclerótica/etiologia , Vareniclina/toxicidade , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Nicotina/agonistas , Células RAW 264.7 , Agentes de Cessação do Hábito de Fumar/toxicidade
16.
J Sci Food Agric ; 100(4): 1418-1425, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31667852

RESUMO

BACKGROUND: Silkworm pupa oil polyunsaturated fatty acid (SPO PUFA) has been confirmed to have a cholesterol-lowering function. METHODS AND RESULTS: The effect of SPO PUFA and its main component, α-linolenic acid (ALA), on the metabolism of cholesterol and its regulation was investigated. The model of lipid denatured cells were constructed to carry out lipid accumulation, cholesterol metabolism and transformation. Real-time PCR and western blots were also used to analyze the expression levels of related genes and proteins to investigate the cholesterol efflux regulation mechanism. The data indicated that SPO PUFA and ALA dose-dependently decreased intracellular total cholesterol (TC) and enhanced total bile acid (TBA). They could also promote cholesterol removal by enhancing bile acid secretion and by upregulating genes LXRα, PPARγ, ABCA1, ABCG1, and CYP7A1, which were regulated by LXRα/PPARγ-ABCA1/ABCG1-CYP7A1 nuclear receptor signal pathways. CONCLUSIONS: This study is of great significance in maintaining the balance of cholesterol and lipid metabolism, and in reducing the risk of steatohepatitis. © 2019 Society of Chemical Industry.


Assuntos
Bombyx/química , Colesterol/metabolismo , Ácidos Graxos Insaturados/farmacologia , Hepatócitos/metabolismo , Pupa/química , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
J Invest Dermatol ; 140(2): 445-454, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31425704

RESUMO

Calpains, intracellular proteases specifically inhibited by calpastatin, play a major role in neoangiogenesis involved in tumor invasiveness and metastasis. They are partly exteriorized via the ATP-binding cassette transporter A1(ABCA1) transporter, but the importance of this process in tumor growth is still unknown. The aim of our study was to investigate the role of extracellular calpains in a model of melanoma by blocking their extracellular activity or exteriorization. In the first approach, a B16-F10 model of melanoma was developed in transgenic mice expressing high extracellular levels of calpastatin. In these mice, tumor growth was inhibited by ∼ 3-fold compared with wild-type animals. In vitro cytotoxicity assays and in vivo tumor studies have demonstrated that this protection was associated with a defect in tumor neoangiogenesis. Similarly, in wild-type animals given probenecid to blunt ABCA1 activity, melanoma tumor growth was inhibited by ∼ 3-fold. Again, this response was associated with a defect in neoangiogenesis. In vitro studies confirmed that probenecid limited endothelial cell migration and capillary formation from vascular explants. The observed reduction in fibronectin cleavage under these conditions is potentially involved in the response. Collectively, these studies demonstrate that probenecid, by blunting ABCA1 activity and thereby calpain exteriorization, limits melanoma tumor neoangiogenesis and invasiveness.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/antagonistas & inibidores , Calpaína/metabolismo , Melanoma Experimental/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Probenecid/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/patologia , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/patologia , Probenecid/uso terapêutico , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/patologia
18.
Lab Med ; 51(2): 157-168, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31150543

RESUMO

BACKGROUND: Adenosine triphosphate (ATP)-binding-cassette-transporter-A1 (ABCA1) transports cholesterol from cells into apolipoprotein A1 to form high-density lipoprotein (HDL) cholesterol. METHODS: We investigated the frequencies of ABCA1 functional variants in 273 patients with coronary artery disease (CAD) and 261 age-matched, healthy blood donors in southwest Iran. Sequence-specific primer polymerase-chain reaction (SSP-PCR) and polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) were used for genotyping. RESULTS: Frequencies of the rs2422493-TT genotype and T-allele, rs1800976-GG genotype, and G-allele in the promoter and rs2230806-GG genotype and G allele in the exon of the ABCA1 gene were higher in the patients. Abnormal left ventricular size and left-artery disease correlated with rs2422493-T and rs1800976-G alleles, respectively. Wall-motion abnormalities correlated with the rs1883025-G allele and rs2230806-A allele. Regarding the rs2422493/rs1800976/rs2230806/rs1883025 haplotype, T-G-G-A and T-G-A-A were more frequent in case individuals, whereas C-C-G-G was more frequent in control individuals. CONCLUSIONS: The rs2422493-T allele and the rs1800976-G allele increase the risk of disease, as single polymorphisms and in the haplotype. The effect of the rs1883025-G allele is prominent in the haplotype, rather than individually. Considering that G allele of rs2230806 in the third place is present in both susceptible and protective haplotypes, the susceptibility haplotype can be defined as T-G-X-A.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Haplótipos , Técnicas de Genotipagem , Humanos , Irã (Geográfico) , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único
19.
Perfusion ; 35(1): 57-65, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170866

RESUMO

PURPOSE: The aim of this study was to investigate the role of miR-33-5p in abdominal aortic aneurysm progression, which regulated adenosine triphosphate-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux and lipid accumulation in THP-1 macrophage-derived foam cells through the PI3K/Akt pathway. METHODS: Quantitative reverse transcription polymerase chain reaction was used to evaluate the expression level of miR-33-5p and ABCA1 mRNA in abdominal aortic aneurysm patient and normal person tissues. The relationship between miR-33-5p and ABCA1 was examined by dual luciferase report assay. High-performance liquid chromatography was used to evaluate the levels of cholesterol contents. Cholesterol efflux detection was performed by liquid scintillator. The expression of inflammatory cytokines was detected by quantitative reverse transcription polymerase chain reaction. Western blot was applied to determine the expression levels of ABCA1, PI3K (p-PI3K), and Akt (p-Akt). RESULTS: The quantitative reverse transcription polymerase chain reaction analysis results revealed miR-33-5p overexpression in abdominal aortic aneurysm tissues, but the expression level of ABCA1 was lower in abdominal aortic aneurysm tissues than non-abdominal aortic aneurysm tissues. Subsequently, the dual luciferase report gene assay confirmed that ABCA1 was a target of miR-33-5p, and miR-33-5p-negative regulated ABCA1 expression. Moreover, the expression levels of p-PI3K, p-Akt, and ABCA1 were decreased in THP-1 cell transferred with ABCA1 siRNA, but knockdown of miR-33-5p had an opposite effect. Furthermore, knockdown of miR-33-5p decreased the expression of MMP-2, MMP-9, TNF-α, total cellular cholesterol, and promoted cholesterol efflux in THP-1-derived foam cells. Importantly, LY294002 (PI3K inhibitor) or si-ABCA1 completely inhibited the stimulatory effects of miR-33-5p inhibitor. CONCLUSION: This study has found that knockdown of miR-33-5p induced ABCA1 expression and promoted inflammatory cytokines and cholesterol efflux likely via activating the PI3K/Akt signaling pathway.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/prevenção & controle , Células Espumosas/enzimologia , Técnicas de Silenciamento de Genes , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Idoso , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Colesterol/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Células Espumosas/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Transdução de Sinais , Células THP-1 , Regulação para Cima
20.
Artigo em Inglês | MEDLINE | ID: mdl-31678514

RESUMO

Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE-/-) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE-/- mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by ß-cyclodextrin (ß-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Inflamação/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Proteína Wnt-5a/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Aterosclerose/sangue , Aterosclerose/imunologia , Estudos de Casos e Controles , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/sangue , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Transdução de Sinais/imunologia , Proteína Wnt-5a/sangue , Proteína Wnt-5a/genética
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