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1.
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
2.
Adv Exp Med Biol ; 1185: 51-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884588

RESUMO

The importance of cholesterol as a structural component of photoreceptors and the association between impaired cholesterol homeostasis and age-related macular degeneration (AMD) prompted in the last years a deep investigation of its metabolism in the retina. Here, we focus on the export of cholesterol from intracellular membranes to extracellular acceptors, an active mechanism mediated by the ATP-binding cassette transporters A1 and G1 (ABCA1 and G1) also known as "active cholesterol efflux." Expression of genes involved in this pathway was shown for most retinal cells, while functional in vitro assays focused on the retinal pigment epithelium (RPE) due to availability of cell models. Cell-specific knockout (KO) mice were generated in the past years, and their characterization unveils an important role of the ABCA1/G1 pathway in RPE, rods, and retinal inflammatory cells. The actual involvement of cholesterol efflux in the pathogenesis of AMD still needs to be demonstrated and will help in establishing the scientific rationale for targeting the ABCA1/G1 pathway in retinal diseases.


Assuntos
Colesterol/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Degeneração Macular/metabolismo , Camundongos , Camundongos Knockout
3.
Internist (Berl) ; 60(12): 1311-1318, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31686116

RESUMO

Both low and very high levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of atherosclerotic cardiovascular disease (ASCVD) and shorten life expectancy. Low and high levels of HDL­C are often caused by underlying diseases, lifestyle or medication, which should primarily be excluded. Much less frequently, monogenic diseases due to mutations in the APOA1, ABCA1 and LCAT genes are the cause of very low or unmeasurable HDL­C levels or in the CETP, LIPC and SCARB1 genes for very high HDL­C values. Genetic and detailed biochemical diagnostics should be considered, especially in cases of absolute HDL deficiency, early onset ASCVD or the presence of clinical symptoms or laboratory values characteristic for deficiencies of apolipoprotein A­I (ApoA-I), lecithin cholesterol acyltransferase (LCAT) or Tangier disease. These included corneal opacities, xanthomas, large tonsils, hepatomegaly, peripheral neuropathy, proteinuria, anemia or thrombocytopenia. Sequencing of the APOA1 gene should also be considered in familial amyloidosis. There is no specific treatment for monogenic HDL diseases. Cholesterol and blood pressure lowering are indicated for the prevention of cardiovascular and renal complications.


Assuntos
Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , HDL-Colesterol/genética , Mutação/genética , Fosfatidilcolina-Esterol O-Aciltransferase
4.
Fitoterapia ; 139: 104393, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31669721

RESUMO

The extract of Dioscorea zingiberensis C.H. Wright rhizomes is found to be effective in the therapy of cardiovascular disease. Steroidal saponins make substantial contribution. Previous study has proposed that methylprotodioscin (MP) may promote cholesterol efflux by increasing ABCA1 expression. But the other main saponins ingredients are not referred to. The aim of the present work was to reveal the effect and mechanism of protodioscin (PD), MP and pseudoprotodioscin (PPD) on the synthesis-related gene expression of cholesterol and triglycerides. MTT assay apoptosis assay with annexin AV-APC and 7-AAD double staining were performed. MicroRNA assay and qRT-PCR were used to analyze the gene expression which regulates synthesis of cholesterol and triglycerides. Western blot was to demonstrate the levels of target proteins. Cholesterol efflux assay was executed to study the stimulative effect of saponins on cholesterol efflux. In Hep G2 cells, PPD increased ABCA1 protein and mRNA levels, and promoted the effluxion of ApoA-1-mediated cholesterol. The underlying mechanisms involved that PPD inhibited SREBP1c and SREBP2 transcription by decreasing microRNA 33a/b levels. This procedure reciprocally led to the increase of ABCA1 levels. In THP-1 macrophages, PPD showed the similar effect, which reduced HMGCR, FAS and ACC mRNA levels and promoted low density lipoprotein receptor by decreasing the PCSK9 levels. These studies demonstrated that PPD is a potential agent for cholesterol efflux, SREBPs and microRNA 33a/b inhibition, which related to the gene expression for the synthesis of cholesterol and triglycerides.


Assuntos
Colesterol/biossíntese , Diosgenina/análogos & derivados , MicroRNAs/antagonistas & inibidores , Saponinas/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 2/antagonistas & inibidores , Triglicerídeos/biossíntese , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Dioscorea/química , Diosgenina/farmacologia , Células Hep G2 , Humanos , MicroRNAs/genética , Extratos Vegetais/farmacologia , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Rizoma/química , Células THP-1
5.
Vasc Health Risk Manag ; 15: 309-316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692533

RESUMO

Experimentally induced injury triggers up-regulation and mobilization of stem cells in Apoe -/- mice that causes accelerated atherosclerosis. Abca1 -/- Abcg1-/- mice have chronic activation of stem cell up-regulation/mobilization and accelerated atherosclerosis. In addition, the Abca1 -/- Abcg1-/- mice have elevation of serum cytokines G-CSF, IL-17 and IL-23, each necessary for stem cell mobilization. IL-17 and IL-23 are elevated in two human illnesses that have cardiovascular (CV) risk independent of traditional risk factors-SLE and psoriasis. Serum G-CSF, which can be elevated in liver disease, predicts major adverse cardiovascular events in humans. These serum cytokine elevations suggest activation of the stem cell mobilization mechanism in humans that results, as in mice, in accelerated atherosclerosis. Efforts to reduce CV disease in these patient populations should include mitigation of the diseases that trigger stem cell mobilization. Since activation of the stem cell up-regulation/mobilization mechanism appears to accelerate human atherosclerosis, use of stem cells as therapy for arterial occlusive disease should distinguish between direct administration of stem cells and activation of the stem cell up-regulation/mobilization mechanism.


Assuntos
Doenças Cardiovasculares/patologia , Movimento Celular , Hepatopatias/patologia , Psoríase/patologia , Células-Tronco/patologia , Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mediadores da Inflamação/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/terapia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos Knockout para ApoE , Fenótipo , Prognóstico , Psoríase/genética , Psoríase/metabolismo , Psoríase/terapia , Fatores de Risco , Células-Tronco/metabolismo
6.
DNA Cell Biol ; 38(11): 1323-1337, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536386

RESUMO

Our previous study has indicated that the parathyroid hormone type 1 receptor (PTHR1) may play important roles in development and progression of osteosarcoma (OS) by regulating Wnt, angiogenesis, and inflammation pathway genes. The goal of this study was to further illuminate the roles of PTHR1 in OS by investigating upstream regulation mechanisms (including microRNA [miRNA] and transcription factors [TFs]) of crucial genes. The microarray dataset GSE46861 was downloaded from the Gene Expression Omnibus database, in which six tumors with short hairpin RNA (shRNA) PTHR1 knockdown (PTHR1.358) and six tumors with shRNA control knockdown (Ren.1309) were collected from mice. Differentially expressed genes (DEGs) between PTHR1.358 and Ren.1309 were identified using the linear models for microarray data (LIMMA) method, and then the miRNA-TF-mRNA regulatory network was constructed using data from corresponding databases, followed by module analysis, to screen crucial regulatory relationships. OS-related human miRNAs were extracted from the curated Osteosarcoma Database. Gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. As a result, the miRNA-TF-mRNA regulatory network, including 1049 nodes (516 miRNA, 25 TFs, and 508 DEGs) and 15942 edges (interaction relationships, such as Pparg-Abca1 and miR-590-3p-AXIN2), was constructed, from which three significant modules were extracted and modules 2 and 3 contained interactions between miRNAs/TFs and DEGs such as miR-103-3p-AXIN2, miR-124-3p-AR-Tgfb1i1, and miR-27a-3p-PPARG-Abca1. miR-27a-3p was a known miRNA associated with OS. Abca1, AR, and miR-124-3p were hub genes in the miRNA-TF-mRNA network. Tgfb1i1 was involved in cell proliferation, Abca1 participated in the cholesterol metabolic process, and AXIN2 was associated with the canonical Wnt signaling pathway. Furthermore, we also confirmed upregulation of miR-590-3p and downregulation of AXIN2 in the mouse OS cell line K7M2-WT transfected with PTHR1 shRNA. In conclusion, PTHR1 may play important roles in progression of OS by activating miR-124-3p-AR-Tgfb1i1, miR-27a-3p-PPARG-Abca1, and miR-103/590-3p-AXIN2 axes.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Receptor Tipo 1 de Hormônio Paratireóideo/fisiologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Animais , Proteína Axina/genética , Proteína Axina/fisiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Progressão da Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/fisiologia , Osteossarcoma/genética , Osteossarcoma/patologia , PPAR gama/genética , PPAR gama/fisiologia , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Receptores Androgênicos/genética , Receptores Androgênicos/fisiologia , Transdução de Sinais/genética , Células Tumorais Cultivadas
7.
Mediators Inflamm ; 2019: 6710759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379468

RESUMO

Epidemiological studies have demonstrated that cardiovascular diseases (CVDs) are the leading cause of death in the world. Atherosclerosis, a kind of chronic vascular disorder related to multiple pathogenic processes, has been reported to be an underlying cause of CVDs. Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine formulation and has been broadly used for the treatment of CVDs in East Asia. However, whether SBP affects the development of atherosclerosis is poorly understood. The aim of this study was to investigate the antiatherosclerotic roles and relevant mechanisms of SBP in apolipoprotein E knockout mice. Our results showed that SBP treatment markedly decreased the size of atherosclerotic plaques of the entire aorta and the aortic sinus. Biochemical analyses indicated that SBP gavage improved oxidative stress in vivo, as seen by the level elevation of SOD, CAT, and GSH and the level reduction of MDA, H2O2, and MPO. Moreover, the concentration of MCP-1, IFN-γ, and IL-17A was reduced, and the content of IL-10 and TGF-ß1 was increased in the serum from SBP-treated mice. We discovered that the expression levels of inflammatory factors including VCAM-1, ICAM-1, IL-6, and IL-2 in the vascular wall of the SBP group were also decreased in comparison with those of the normal saline group. Moreover, we found that SBP alleviated the activation of inflammation-related pathways in the aorta tissue, as seen by the level elevation of Mfn2 and reduced phosphorylation of p38, JNK, and NF-κB. Furthermore, western blot showed that SBP administration reduced the level of SR-A and LOX-1 and elevated the content of LXRα, ABCA1, and ABCG1 in the arterial wall, indicating that SBP was capable of alleviating lipid influx and facilitating lipid efflux. In conclusion, our data suggested that SBP exerted antiatherosclerotic effects via improving inflammation response and inhibiting lipid accumulation.


Assuntos
Aorta/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Transportador 1 de Cassete de Ligação de ATP/sangue , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Animais , Aorta/efeitos dos fármacos , Apolipoproteínas E/sangue , Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Inflamação , Molécula 1 de Adesão Intercelular/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Camundongos , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/sangue
8.
Diabetes Metab Syndr ; 13(2): 1529-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336517

RESUMO

ATP-binding cassette transporter A1 (ABCA1) is an integral cell-membrane protein that mediates the rate-limiting step of high density lipoprotein (HDL) biogenesis and suppression of inflammation by triggering a number of signaling pathways via interacting with an apolipoprotein acceptor. The hepatic ABCA1 is involved in regulation of very low density lipoprotein (VLDL) production by affecting the apolipoprotein B trafficking and lipidation of VLDL particles. This protein is involved in protecting the function of pancreatic ß-cells and insulin secretion by cholesterol homeostasis. Adipose tissue lipolysis is associated with ABCA1 activity. This transporter is involved in controlling obesity and insulin sensitivity by regulating triglyceride (TG) lipolysis and influencing on adiponectin, visfatin, leptin, and GLUT4 genes expression. The ABCA1 of skeletal muscle cells play a role in increasing the glucose uptake by enhancing the Akt phosphorylation and transferring GLUT4 to the plasma membrane. Abnormal status of ABCA1-regulated phenotypes is observed in metabolic syndrome. This syndrome is associated with the occurrence of many diseases. This review is a summary of the role of ABCA1 in HDL and VLDL production, homeostasis of insulin and glucose, suppression of inflammation and obesity controlling to provide a better insight into the association of this protein with metabolic syndrome.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Glucose/metabolismo , Inflamação/fisiopatologia , Insulina/metabolismo , Lipoproteínas HDL/biossíntese , Lipoproteínas VLDL/biossíntese , Síndrome Metabólica/epidemiologia , Obesidade/fisiopatologia , Homeostase , Humanos , Irã (Geográfico)/epidemiologia
9.
J Food Sci ; 84(8): 2330-2336, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313321

RESUMO

It has been reported that genistein could improve metabolic syndromes. Our study aimed to investigate the effects and potential mechanisms of genistein on improving cholesterol metabolism in HepG2 cell. HepG2 cells were cultured with 0, 0.01, 1.00, 10.00, and 50.00 µM genistein for 24 hr. The current results showed a dose-dependent manner between genistein and intracellular contents of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and cellular apolipoprotein A1 (Apo-A1) secretion. TC was increased by 25.69%, meanwhile HDL-C and Apo-A1 were decreased by 56.00% and 25.93%, respectively, when the dosage of genistein was 1.00 µM. Genistein dose-dependently upregulated the protein and mRNA levels of sterol regulatory element binding proteins-2 (SREBP-2), as well as the mRNA levels of low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGCR), by 145.91%, 72.29%, 310.23%, and 123.08%, respectively, when we gave 1.00 µM genistein, indicating that intracellular cholesterol synthesis and absorption of exogenous cholesterol were increased. In addition, the mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ) and liver X receptor (LXRα), lowered by 58.23% and 34.86% at 0.01 µM genistein, were reduced in a dose-dependent manner. LXRα and ATP-binding cassette transporter A1 (ABCA1) protein levels were significantly (P < 0.05) decreased by 50.35% and 11.60% at 1.00 µM genistein, which indicated that cellular cholesterol efflux was inhibited. Taken together, our results suggested that genistein at dosage of more than 1.00 µM was able to increase the intracellular cholesterol levels by up regulating SREBP-2/LDLR/HMGCR pathway and suppressing PPARγ/LXRα/ABCA1 pathway. PRACTICAL APPLICATION: In this study, genistein appeared to be effective in reducing plasma cholesterol levels due to increase the intracellular cholesterol levels by upregulating cholesterol absorption through SREBP-2/LDLR/HMGCR pathway, and also downregulating cholesterol efflux via PPARγ/LXRα/ABCA1 pathway in vitro. In addition, plasma cholesterol is regarded as the key indicator of atherosclerosis; therefore, we believe that our findings could be used for further exploration on a possible therapeutic application of genistein for atherosclerosis.


Assuntos
Colesterol/metabolismo , Genisteína/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Expressão Gênica , Células Hep G2 , Humanos , Metabolismo dos Lipídeos , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
10.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261750

RESUMO

Acetylation of nuclear apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is associated with its extracellular secretion, despite the lack of an N-terminal protein secretion signal. In this study, we investigated plasma membrane targeting and translocation of APE1/Ref-1 in HEK293T cells with enhanced acetylation. While APE1/Ref-1 targeting was not affected by inhibition of the endoplasmic reticulum/Golgi-dependent secretion, its secretion was reduced by inhibitors of ATP-binding cassette (ABC) transporters, and siRNA-mediated down-regulation of ABC transporter A1. The association between APE1/Ref-1 and ABCA1 transporter was confirmed by proximal ligation assay and immunoprecipitation experiments. An APE1/Ref-1 construct with mutated acetylation sites (K6/K7R) showed reduced co-localization with ABC transporter A1. Exposure of trichostatin A (TSA) induced the acetylation of APE1/Ref-1, which translocated into membrane fraction. Taken together, acetylation of APE1/Ref-1 is considered to be necessary for its extracellular targeting via non-classical secretory pathway using the ABCA1 transporter.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Via Secretória , Acetilação , Motivos de Aminoácidos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/química , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Células HEK293 , Humanos , Ácidos Hidroxâmicos/farmacologia , Mutação , Ligação Proteica , Processamento de Proteína Pós-Traducional , Transporte Proteico/efeitos dos fármacos
11.
PLoS Pathog ; 15(7): e1007907, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31344124

RESUMO

HIV infection has a profound effect on "bystander" cells causing metabolic co-morbidities. This may be mediated by exosomes secreted by HIV-infected cells and containing viral factors. Here we show that exosomes containing HIV-1 protein Nef (exNef) are rapidly taken up by macrophages releasing Nef into the cell interior. This caused down-regulation of ABCA1, reduction of cholesterol efflux and sharp elevation of the abundance of lipid rafts through reduced activation of small GTPase Cdc42 and decreased actin polymerization. Changes in rafts led to re-localization of TLR4 and TREM-1 to rafts, phosphorylation of ERK1/2, activation of NLRP3 inflammasome, and increased secretion of pro-inflammatory cytokines. The effects of exNef on lipid rafts and on inflammation were reversed by overexpression of a constitutively active mutant of Cdc42. Similar effects were observed in macrophages treated with exosomes produced by HIV-infected cells or isolated from plasma of HIV-infected subjects, but not with exosomes from cells and subjects infected with ΔNef-HIV or uninfected subjects. Mice injected with exNef exhibited monocytosis, reduced ABCA1 in macrophages, increased raft abundance in monocytes and augmented inflammation. Thus, Nef-containing exosomes potentiated pro-inflammatory response by inducing changes in cholesterol metabolism and reorganizing lipid rafts. These mechanisms may contribute to HIV-associated metabolic co-morbidities.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/virologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Efeito Espectador , Colesterol/metabolismo , Exossomos/metabolismo , Exossomos/virologia , Células HEK293 , HIV-1 , Humanos , Inflamação/metabolismo , Inflamação/virologia , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/virologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Células RAW 264.7 , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
12.
Biol Pharm Bull ; 42(6): 1019-1024, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155576

RESUMO

Apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) biogenesis, function and structural dynamics. Peptides that mimic apoA-I have a short amphipathic α-helical structure that can functionally recapitulate many of the same biologic properties of full-length apoA-I in HDL. Hence, they might be expected to have clinical applications in the reduction of atherosclerosis. However, nonspecific cellular efflux of cholesterol induced by apoA-I mimetic peptides might cause side effects that are, as yet, unidentified. In this study, we developed a photo-activatable peptide, 2F*, which is an 18 amino acid peptide mimicking apoA-I bearing an internal photocleavable caging group that is designed to assume an α-helical structure in response to a light stimulus and trigger efflux of cholesterol from cells. Without light irradiation, 2F* peptide showed a low tendency for the formation of α-helices, and therefore did not associate with lipids and failed to induce efflux of cholesterol. In addition, 2F* did not cause hemolysis under our experimental condition. Mass spectrometry indicated that, after light exposure, the caging group detached from 2F* and it assumed the α-helical structure in the presence of lipids, and enhanced cholesterol efflux from cells. Photo-activatable peptides such as 2F* that control cholesterol efflux following light stimulus may be useful for future atherosclerosis-reducing therapies.


Assuntos
Apolipoproteína A-I , Peptídeos/farmacologia , Peptídeos/efeitos da radiação , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Biomimética , Linhagem Celular , Colesterol/metabolismo , Cricetinae , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Luz , Ratos
13.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172973

RESUMO

Obesity is characterised by imbalance in lipid metabolism manifested by high concentrations of circulating triacylglycerols and total cholesterol as well as low high-density lipoprotein (HDL) levels. Abnormalities related to these lipids lead to metabolic complications such as type 2 diabetes, arterial hypertension and cardiovascular disease. Despite extensive research, it is still unclear why a subset of obese subjects develop metabolic syndrome, while others do not. The aim of our work was to assess total and plasma membrane expressions of cholesterol transport proteins: adipocyte ATP-binding cassette A1 (ABCA1), adipocyte ATP-binding cassette G1 (ABCG1), class B scavenger receptor (SR-BI) in visceral and subcutaneous adipose tissue of obese subjects with and without metabolic syndrome. To keep our preliminary study group uniform, we focused on women, who constitute the majority of bariatric patients. The study was performed on 34 patients: 24 morbidly obese women subjected to bariatric surgery, half of whom had metabolic syndrome; and 10 lean subjects undergoing elective laparoscopic cholecystectomy. Total and plasma membrane expressions of cholesterol transport proteins (SR-BI, ABCA1 and ABCG1) were assessed in samples of both visceral and subcutaneous adipose and analysed in relation to other clinical and laboratory parameters. We demonstrated lower plasma membrane expressions of ABCG1 in visceral adipose tissue of obese patients with metabolic syndrome as compared to lean ones. In addition, total ABCG1 expressions in both types of adipose tissue were lower in morbidly obese patients with metabolic syndrome compared to those without metabolic syndrome. Plasma membrane ABCA1 expressions in visceral adipose tissue were lower in the group of morbidly obese patients without metabolic syndrome, compared to lean patients. We did not find any significant differences in SR-BI expressions. Because of ABCG1 is responsible for cholesterol efflux to HDL, reduced plasma membrane expression of ABCG1 in VAT of morbidly obese women with metabolic syndrome may leads to a significantly decreased concentration of HDL in serum. This may be also confirmed by high positive correlation between both parameters.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/metabolismo , Síndrome Metabólica/metabolismo , Obesidade Mórbida/metabolismo , Adulto , Idoso , Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Hipertensão/metabolismo , Pessoa de Meia-Idade , Receptores Depuradores Classe B/metabolismo , Adulto Jovem
14.
J Agric Food Chem ; 67(25): 7157-7166, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31146527

RESUMO

Lonicera caerulea berry polyphenols (LCBP) are known to reduce cholesterol accumulation. Currently, it is unknown whether LCBP can activate Sirtuin 1 (SIRT1) to regulate the formation of RAW264.7 macrophage foam cells. In this study, the effect of LCBP on lipid accumulation in macrophages was evaluated. Fluorescently labeled ox-LDL and 25-NBD cholesterol were used to detect the ox-LDL uptake and cholesterol outflow rate from macrophages. Gene silencing was performed using siRNA to detect changes in the expression of the ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 2 (SREBP2), and SIRT1 proteins using Western blotting, and changes in the expression of miR-33 were detected by real-time polymerase chain reaction. The results showed that treatment with 80 µg/mL LCBP significantly inhibited the accumulation of lipids in RAW264.7 macrophages induced by ox-LDL and reduced intracellular cholesterol levels by activating SIRT1 to enhance the expression of ABCA1, a cholesterol efflux gene, but not independent effect. Of the three key LCBP components investigated, chlorogenic acid was found to activate SIRT1 and regulate the expression of the cholesterol-related factors ABCA1, SREBP2, and miR-33; cyanidin-3-glucoside and catechins were effective to a lesser extent. Our results suggest a novel hypolipidemic mechanism of LCBP.


Assuntos
Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Lonicera/química , Macrófagos/efeitos dos fármacos , Polifenóis/farmacologia , Sirtuína 1/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Células Espumosas/metabolismo , Frutas/química , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Sirtuína 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
15.
Cells ; 8(6)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234415

RESUMO

Single nucleotide polymorphisms located in 5' untranslated regions (5'UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5'UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5'UTRs during gene evolution is scarce. Using the example of the ATP-binding cassette transporter A1 (ABCA1) gene (Tangier disease), we describe our algorithm for functionally significant sequence finding. 5'UTR features (upstream start and stop codons, open reading frames (ORFs), GC content, motifs, and secondary structures) were studied using freely available bioinformatics tools in 55 vertebrate orthologous genes obtained from Ensembl and UCSC. The most conserved sequences were suggested as hot spots. Exon and intron enhancers and silencers (sc35, ighg2 cgamma2, ctnt, gh-1, and fibronectin eda exon), transcription factors (TFIIA, TATA, NFAT1, NFAT4, and HOXA13), some of them cancer related, and microRNA (hsa-miR-4474-3p) were localized to these regions. An upstream ORF, overlapping with the main ORF in primates and possibly coding for a small bioactive peptide, was also detected. Moreover, we showed several features of 5'UTRs, such as GC content variation, hairpin structure conservation or 5'UTR segmentation, which are interesting from a phylogenetic point of view and can stimulate further evolutionary oriented research.


Assuntos
Regiões 5' não Traduzidas/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Vertebrados/genética , Transportador 1 de Cassete de Ligação de ATP/química , Sequência de Aminoácidos , Animais , Composição de Bases/genética , Sequência de Bases , Sequência Conservada/genética , Elementos Facilitadores Genéticos/genética , Humanos , Íntrons/genética , Mamíferos/genética , Anotação de Sequência Molecular , Conformação de Ácido Nucleico , Motivos de Nucleotídeos/genética , Fases de Leitura Aberta/genética , Filogenia , Processamento de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
Biochemistry (Mosc) ; 84(5): 529-539, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234767

RESUMO

Hypoxia plays a critical role in progression of atherosclerosis. Local oxygen deficiency in a plaque creates a specific microenvironment that alters the transcriptome of resident cells, particularly of macrophages. Reverse cholesterol transport from plaque to liver is considered a main mechanism for regression of atherosclerosis. Ubiquitously expressed ATP-binding cassette transporter A1 (ABCA1) and liver- and small intestine-derived apolipoprotein A-1 (ApoA-1) are two main actors in this process. We recently reported endogenous apoA-1 expression in human macrophages. While ABCA1 and ApoA-1 have antiatherogenic properties, the role of complement factor C3 is controversial. Plasma C3 level positively correlates with the risk of cardiovascular diseases. On the other hand, C3 gene knockout in a murine atherosclerosis model increases both plaque size and triglycerides level in blood. In the present study, we show for the first time that a hypoxia-mimicking agent, CoCl2, induces the upregulation of the apoA-1 and C3 genes and the accumulation of intracellular and membrane protein ApoA-1 in THP-1 macrophages. The MEK1/2-Erk1/2 and MKK4/7-JNK1/2/3 cascades are involved in upregulation of ABCA1 and C3 via activation of transcription factor NF-κB, which interacts with the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1). The three major MAP-kinase cascades (Erk1/2, JNK1/2/3, and p38) and the NF-κB transcription factor are involved in the hypoxia-induced expression of the apoA-1 gene in THP-1 macrophages.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteína A-I/metabolismo , Hipóxia Celular , Complemento C3/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteína A-I/genética , Linhagem Celular Tumoral , Cobalto/farmacologia , Complemento C3/análise , Complemento C3/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Prensa méd. argent ; 105(5): 284-292, jun 2019. tab, fig
Artigo em Inglês | LILACS, BINACIS | ID: biblio-1024554

RESUMO

Diabetes remains unique among the main non-communicable ailments (NCDs) recognized by the World Health Organization (WHO), apart from the circulatory diseases, tumours, and long-lasting respiratory ailments. The current study aimed to determine the correlation between ABCA1 gene polymorphismo and lipid profile in type 2 diabetes mellitus patients. Serum samples from 100 type 2 diabetes mellitus patients (46 males and 54 females) and 50 standard subjects (26 males and 24 females) were colected from Najaf province/Irak. Fasting blood sugar (FBS), and lipid profiles (total cholesterol (TC), triglycerides (TH), HDL, LDL, and VLDL) were meassured. Plymerase chain reaction (PCR) with the Taq1 enzye was used for the amplification of the ABCA1 gene, which contains 525bp of the AABCA1 gene in the locus V825I. The present study revaled a positive corrrelation between FBS and body mass index (BMI) (r= 0.2390, p= 0.0463), TG (r = 0.1836, p= .01743), and VLDL (r = 0.1836, p = 0.1839). The frequencies of the GG genotype and the G allele were higher in the normal groups compared to the patientes (58% vs. 56% and 70% vs. 67%, respectively); conversely, the frequencies of the AA genotype (18% vs. 22%) and the A allele (30% vs. 33%) were higher in the patients compared to the normal groups. The data also showed a significant relationship between ABCA1 gene polymorphim and both TG and VLDL (P=0.007 for cach). There is relationship between the ABCA1 gene and HDL level. Additiionally, the G allele could be a defensive factor against diabetes mellitus in Iraqi peole (AU)


Assuntos
Humanos , Polimorfismo Genético , Glicemia/análise , Diabetes Mellitus Tipo 2 , Transportador 1 de Cassete de Ligação de ATP/genética , Frequência do Gene , Hipercolesterolemia/sangue
18.
Biomed Pharmacother ; 115: 108840, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048189

RESUMO

BACKGROUND AND AIMS: Hirudo is an important Chinese medicine that has been widely used in patients with thrombosis-related diseases. We aimed to evaluate the protective effect and potential mechanism of Hirudo extract (HE) on the process of atherosclerosis (AS) as well as identify its active components in the lipopolysaccharide (LPS) - or oxidized low-density lipoprotein (ox-LDL)-induced cell models. METHODS: After treatment, adhesion molecules and pro-inflammatory cytokines induced by LPS were examined by qPCR and ELISA. ROS production, cell apoptosis, and lipid accumulation in ox-LDL-induced cells were analyzed by flow cytometry, qPCR, western blotting, and immunofluorescence staining. In addition, the main active components of HE were identified and analyzed for preventing the progression of AS. RESULTS: In this study, we found that HE pretreatment for 48 h significantly inhibited monocyte adhesion and reduced the levels of adhesion factors (ICAM-1 and VCAM-1) and pro-inflammatory factors (IL-6 and TNF-α) in LPS-induced endothelial cells. Moreover, HE attenuated ox-LDL-induced ROS accumulation and apoptosis in macrophage cells via mitochondrial apoptotic pathways. Additionally, HE pretreatment effectively inhibited cholesterol uptake and increased cholesterol efflux by regulating the LOX-1/LXR-α/ABCA1 pathway. Importantly, the polypeptides from HE (PP) with a molecular weight < 10,000 Da accounted for about 62.9% of the total amount of polypeptides, which in turn may be active components of HE that are responsible for inhibiting inflammation, foam cell formation and apoptosis. CONCLUSION: PP from HE potently inhibits endothelial cell inflammatory injury and macrophage foam cell formation and apoptosis by regulating the LOX-1/LXR-α/ABCA1 pathway, thereby providing additional support to the beneficial effects of HE in preventing AS.


Assuntos
Células Espumosas/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Sanguessugas/química , Macrófagos/efeitos dos fármacos , Peptídeos/farmacologia , Receptores Depuradores Classe E/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Lipoproteínas LDL/administração & dosagem , Lipoproteínas LDL/toxicidade , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Camundongos , Peptídeos/química , Células RAW 264.7 , Espécies Reativas de Oxigênio , Receptores Depuradores Classe E/genética , Células THP-1
19.
J Nutr Sci ; 8: e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037218

RESUMO

Coffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P < 0·01) and serum cholesterol (P < 0·001), alanine aminotransferase and glucose (P < 0·05). Accordingly, liver PPAR- α (P < 0·05) and acyl-CoA oxidase-1 (P < 0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P < 0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P < 0·05), duodenal claudin (P < 0·05) and duodenal peptide YY (P < 0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P < 0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.


Assuntos
Café/metabolismo , Dieta Hiperlipídica/efeitos adversos , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acil-CoA Oxidase/metabolismo , Alanina Transaminase/sangue , Alcaligenaceae , Animais , Glicemia , Colesterol/sangue , Claudinas/metabolismo , Suplementos Nutricionais , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Haptoglobinas/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , Polifenóis/farmacologia , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo
20.
PLoS One ; 14(4): e0215911, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31039173

RESUMO

For most complex traits, the majority of SNPs identified through genome-wide association studies (GWAS) reside within noncoding regions that have no known function. However, these regions are enriched for the regulatory enhancers specific to the cells relevant to the specific trait. Indeed, many of the GWAS loci that have been functionally characterized lie within enhancers that regulate expression levels of key genes. In order to identify polymorphisms with potential allele-specific regulatory effects, we developed a bioinformatics pipeline that harnesses epigenetic signatures as well as transcription factor (TF) binding motifs to identify putative enhancers containing a SNP with potential allele-specific TF binding in linkage disequilibrium (LD) with a GWAS-identified SNP. We applied the approach to GWAS findings for blood lipids, revealing 7 putative enhancers harboring associated SNPs, 3 of which lie within the introns of LCAT and ABCA1, genes that play crucial roles in cholesterol biogenesis and lipoprotein metabolism. All 3 enhancers demonstrated allele-specific in vitro regulatory activity in liver-derived cell lines. We demonstrated that these putative enhancers are in close physical proximity to the promoters of their respective genes, in situ, likely through chromatin looping. In addition, the associated alleles altered the likelihood of transcription activator STAT3 binding. Our results demonstrate that through our approach, the LD blocks that contain GWAS signals, often hundreds of kilobases in size with multiple SNPs serving as statistical proxies to the true functional site, can provide an experimentally testable hypothesis for the underlying regulatory mechanism linking genetic variants to complex traits.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Alelos , HDL-Colesterol/metabolismo , Elementos Facilitadores Genéticos , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Sequência de Bases , Linhagem Celular , Cromatina/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , Ligação Proteica , Elementos de Resposta/genética , Fator de Transcrição STAT3/metabolismo
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