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[PMID]:28583767
[Au] Autor:Errico TL; Méndez-Lara KA; Santos D; Cabrerizo N; Baila-Rueda L; Metso J; Cenarro A; Pardina E; Lecube A; Jauhiainen M; Peinado-Onsurbe J; Escolà-Gil JC; Blanco-Vaca F; Julve J
[Ad] Endereço:Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau - Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
[Ti] Título:LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity.
[So] Source:Transl Res;186:19-35.e5, 2017 Aug.
[Is] ISSN:1878-1810
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Diabetes Mellitus/genética
Diabetes Mellitus/metabolismo
Receptores X do Fígado/metabolismo
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Transporte Biológico
Lipoproteínas/genética
Lipoproteínas/metabolismo
Receptores X do Fígado/genética
Masculino
Camundongos
Obesidade
Transdução de Sinais
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, mouse); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Lipoproteins); 0 (Liver X Receptors); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE


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[PMID]:28298475
[Au] Autor:Toussaint F; Pierman B; Bertin A; Lévy D; Boutry M
[Ad] Endereço:Institut des Sciences de la Vie, Université catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium.
[Ti] Título:Purification and biochemical characterization of NpABCG5/NpPDR5, a plant pleiotropic drug resistance transporter expressed in BY-2 suspension cells.
[So] Source:Biochem J;474(10):1689-1703, 2017 May 04.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pleiotropic drug resistance (PDR) transporters belong to the ABCG subfamily of ATP-binding cassette (ABC) transporters and are involved in the transport of various molecules across plasma membranes. During evolution, genes appeared independently in fungi and in plants from a duplication of a half-size ABC gene. The enzymatic properties of purified PDR transporters from yeast have been characterized. This is not the case for any plant PDR transporter, or, incidentally, for any purified plant ABC transporter. Yet, plant PDR transporters play important roles in plant physiology such as hormone signaling or resistance to pathogens or herbivores. Here, we describe the expression, purification, enzymatic characterization and 2D analysis by electron microscopy of NpABCG5/NpPDR5 from , which has been shown to be involved in the plant defense against herbivores. We constitutively expressed NpABCG5/NpPDR5, provided with a His-tag in a homologous system: suspension cells from (Bright Yellow 2 line). NpABCG5/NpPDR5 was targeted to the plasma membrane and was solubilized by dodecyl maltoside and purified by Ni-affinity chromatography. The ATP-hydrolyzing specific activity (27 nmol min mg ) was stimulated seven-fold in the presence of 0.1% asolectin. Electron microscopy analysis indicated that NpABCG5/NpPDR5 is monomeric and with dimensions shorter than those of known ABC transporters. Enzymatic data (optimal pH and sensitivity to inhibitors) confirmed that plant and fungal PDR transporters have different properties. These data also show that suspension cells are a convenient host for the purification and biochemical characterization of ABC transporters.
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Proteínas de Plantas/metabolismo
Tabaco/metabolismo
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/isolamento & purificação
Adenosina Trifosfatases/química
Adenosina Trifosfatases/genética
Adenosina Trifosfatases/isolamento & purificação
Adenosina Trifosfatases/metabolismo
Trifosfato de Adenosina/metabolismo
Técnicas de Cultura Celular por Lotes
Reatores Biológicos
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Membrana Celular/ultraestrutura
Células Cultivadas
Cromatografia de Afinidade
Detergentes/química
Glucosídeos/química
Concentração de Íons de Hidrogênio
Processamento de Imagem Assistida por Computador
Moduladores de Transporte de Membrana/farmacologia
Microscopia Eletrônica
Peso Molecular
Fosfatidilcolinas/química
Proteínas de Plantas/química
Proteínas de Plantas/genética
Proteínas de Plantas/isolamento & purificação
Conformação Proteica
Transporte Proteico/efeitos dos fármacos
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/metabolismo
Solubilidade
Tabaco/citologia
Tabaco/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (Detergents); 0 (Glucosides); 0 (Membrane Transport Modulators); 0 (Phosphatidylcholines); 0 (Plant Proteins); 0 (Recombinant Fusion Proteins); 69227-93-6 (dodecyl maltoside); 69279-91-0 (asolectin); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.1.- (Adenosine Triphosphatases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170108


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[PMID]:27981300
[Au] Autor:Zimmermann A; Popp RA; Al-Khzouz C; Bucerzan S; Nascu I; Leucuta D; Galle PR; Grigorescu-Sido P
[Ad] Endereço:1st Clinic and Polyclinic of Internal Medicine, Dept. Endocrinology and Metabolic Diseases, University of Mainz, Mainz, Germany. zimmeran@uni-mainz.de.
[Ti] Título:Cholelithiasis in Patients with Gaucher Disease type 1: Risk Factors and the Role of ABCG5/ABCG8 Gene Variants.
[So] Source:J Gastrointestin Liver Dis;25(4):447-455, 2016 12.
[Is] ISSN:1842-1121
[Cp] País de publicação:Romania
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIM: Patients with Gaucher disease type 1 (GD1) show an altered lipid profile and a certain degree of insulin resistance, which might contribute to cholelithiasis (CL) and could possibly be associated with ABCG5/ABCG8 gene variants. We aimed to investigate the prevalence of CL in Caucasian adult patients with GD1 and the possible risk factors, including gene variants of the ABCG5/ABCG8 genes. METHODS: 61 Caucasian patients with GD1 (38 female/23male), aged 18-62 years and 61 healthy subjects matched for age, gender and BMI, without CL, for comparison of lipid profiles. Data before start of enzyme replacement therapy (ERT) were recorded: clinical, haematological, severity parameters, splenectomy, genotype. Fasting lipid profiles before ERT, glycemia, insulinaemia, HOMA-IR at the last visit were documented. Genotyping for the gene variants D19H, Y54C, T400K, A632V (ABCG8); Q604E (ABCG5) was performed. RESULTS: CL occurred in 45.9% of patients. Risk factors were: age, family history of CL, higher BMI values, LDL-cholesterol (LDL-C), disease severity, splenectomy. A specific dyslipidemia was found in patients vs. controls. Total serum cholesterol (TC) and LDL-C were higher in patients with CL than in those without; no obvious influence of insulin-resistance to lithogenesis was found. Patients with the GG genotype of D19H and the CC genotype of T400K (ABCG8 gene) had significantly higher levels of TC and LDL-C. CONCLUSION: Patients with GD1 showed an increased prevalence of CL, which was associated with common and disease-specific risk factors. Starting ERT soon after clinical onset and avoiding splenectomy might reduce the risk of CL in GD1.
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Colelitíase/genética
Doença de Gaucher/genética
Variação Genética
Lipoproteínas/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Casos e Controles
Colelitíase/diagnóstico
Colelitíase/epidemiologia
Estudos Transversais
Terapia de Reposição de Enzimas
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Doença de Gaucher/diagnóstico
Doença de Gaucher/tratamento farmacológico
Doença de Gaucher/epidemiologia
Frequência do Gene
Estudos de Associação Genética
Predisposição Genética para Doença
Glucosilceramidase/uso terapêutico
Heterozigoto
Homozigoto
Seres Humanos
Masculino
Meia-Idade
Fenótipo
Prevalência
Fatores de Risco
Romênia/epidemiologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ABCG8 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Lipoproteins); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170823
[Lr] Data última revisão:
170823
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE
[do] DOI:10.15403/jgld.2014.1121.254.zim


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[PMID]:27701660
[Au] Autor:Lotta LA; Sharp SJ; Burgess S; Perry JRB; Stewart ID; Willems SM; Luan J; Ardanaz E; Arriola L; Balkau B; Boeing H; Deloukas P; Forouhi NG; Franks PW; Grioni S; Kaaks R; Key TJ; Navarro C; Nilsson PM; Overvad K; Palli D; Panico S; Quirós JR; Riboli E; Rolandsson O; Sacerdote C; Salamanca EC; Slimani N; Spijkerman AM; Tjonneland A; Tumino R; van der A DL; van der Schouw YT; McCarthy MI; Barroso I; O'Rahilly S; Savage DB; Sattar N; Langenberg C; Scott RA; Wareham NJ
[Ad] Endereço:MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
[Ti] Título:Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes: A Meta-analysis.
[So] Source:JAMA;316(13):1383-1391, 2016 Oct 04.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. Objective: To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting, and Participants: The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. Exposures: Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. Main Outcomes and Measures: Odds ratios (ORs) for type 2 diabetes and coronary artery disease. Results: Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. Conclusions and Relevance: In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.
[Mh] Termos MeSH primário: LDL-Colesterol/genética
Doença da Artéria Coronariana/genética
Diabetes Mellitus Tipo 2/genética
Variação Genética
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos
Proteínas de Membrana/genética
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Adulto
Idoso
LDL-Colesterol/sangue
Estudos de Coortes
Diabetes Mellitus Tipo 2/sangue
Quimioterapia Combinada/efeitos adversos
Ezetimiba/administração & dosagem
Ezetimiba/efeitos adversos
Estudos de Associação Genética
Seres Humanos
Hidroximetilglutaril-CoA Redutases/genética
Lipoproteínas/genética
Meia-Idade
Razão de Chances
Polimorfismo Genético
Pró-Proteína Convertase 9/genética
Receptores de LDL/genética
Risco
Sinvastatina/administração & dosagem
Sinvastatina/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (Cholesterol, LDL); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (LDLR protein, human); 0 (Lipoproteins); 0 (Membrane Proteins); 0 (NPC1L1 protein, human); 0 (Receptors, LDL); AGG2FN16EV (Simvastatin); EC 1.1.1.- (HMGCR protein, human); EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9); EOR26LQQ24 (Ezetimibe)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2016.14568


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[PMID]:27383786
[Au] Autor:Hsieh J; Koseki M; Molusky MM; Yakushiji E; Ichi I; Westerterp M; Iqbal J; Chan RB; Abramowicz S; Tascau L; Takiguchi S; Yamashita S; Welch CL; Di Paolo G; Hussain MM; Lefkowitch JH; Rader DJ; Tall AR
[Ad] Endereço:Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
[Ti] Título:TTC39B deficiency stabilizes LXR reducing both atherosclerosis and steatohepatitis.
[So] Source:Nature;535(7611):303-7, 2016 07 14.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies, promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.
[Mh] Termos MeSH primário: Aterosclerose/genética
Fígado Gorduroso/genética
Lipoproteínas HDL/deficiência
Lipoproteínas HDL/genética
Receptores Nucleares Órfãos/metabolismo
[Mh] Termos MeSH secundário: Transportador 1 de Cassete de Ligação de ATP/metabolismo
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/metabolismo
Animais
Aterosclerose/prevenção & controle
Aterosclerose/terapia
Ácidos e Sais Biliares/metabolismo
Colesterol na Dieta/metabolismo
HDL-Colesterol/metabolismo
Dieta Hiperlipídica
Ácidos Graxos Insaturados/metabolismo
Fígado Gorduroso/prevenção & controle
Fígado Gorduroso/terapia
Feminino
Regulação da Expressão Gênica
Hepatócitos/metabolismo
Ligantes
Lipogênese/genética
Lipoproteínas/metabolismo
Lipoproteínas HDL/metabolismo
Lipoproteínas LDL/metabolismo
Receptores X do Fígado
Masculino
Camundongos
Receptores Nucleares Órfãos/genética
Fosfatidilcolinas/biossíntese
Fosfatidilcolinas/metabolismo
Estabilidade Proteica
Proteólise
Receptores de LDL/deficiência
Receptores de LDL/genética
Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ABCA1 protein, mouse); 0 (ABCG5 protein, mouse); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter 1); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Bile Acids and Salts); 0 (Cholesterol, Dietary); 0 (Cholesterol, HDL); 0 (Fatty Acids, Unsaturated); 0 (Ligands); 0 (Lipoproteins); 0 (Lipoproteins, HDL); 0 (Lipoproteins, LDL); 0 (Liver X Receptors); 0 (NR1H3 protein, human); 0 (Nr1h3 protein, mouse); 0 (Orphan Nuclear Receptors); 0 (Phosphatidylcholines); 0 (Receptors, LDL); 0 (Srebf1 protein, mouse); 0 (Sterol Regulatory Element Binding Protein 1); 0 (TTC39B protein, mouse)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170324
[Lr] Data última revisão:
170324
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160708
[St] Status:MEDLINE
[do] DOI:10.1038/nature18628


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[PMID]:27291889
[Au] Autor:Ali S; Ghosh K; Daly ME; Hampshire DJ; Makris M; Ghosh M; Mukherjee L; Bhattacharya M; Shetty S
[Ad] Endereço:Department of Haemostasis and Thrombosis, National Institute of Immunohaematology, Parel, Mumbai.
[Ti] Título:Congenital macrothrombocytopenia is a heterogeneous disorder in India.
[So] Source:Haemophilia;22(4):570-82, 2016 Jul.
[Is] ISSN:1365-2516
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Inherited macrothrombocytopenia represents a heterogeneous group of disorders which are characterized by the presence of a reduced number of abnormally large platelets in the circulation, which may or may not be associated with a bleeding tendency. In spite of several causative genes having been identified, the underlying genetic defects remain to be identified in approximately half of the cases. AIMS: To understand the molecular pathology of isolated giant platelet disorder from India. MATERIALS AND METHODS: We studied 112 cases that were referred for investigation of macrothrombocytopenia. Agonist induced platelet aggregation and platelet GP1b/IX/V receptor expression were investigated to assess GP1b/IX/V receptor expression and the GP1BA, GP1BB, GP9, ABCG5, ABCG8, TUBB1 and MYH9 genes were analysed to identify candidate gene defects. RESULTS: Twenty-three candidate gene defects were identified in 48 of 112 cases, 20 of which were novel. Of the candidate defects identified, 91% were missense and 9% were nonsense variations. The missense variations were in GP9 (9), ABCG5 (4), GP1BB (3), GP1BA (3) and MYH9 (2), while the nonsense defects occurred in MYH9 (1) and GP1BA (1). CONCLUSIONS: This study increases the understanding of the molecular basis of an isolated giant platelet disorder, a common heterogeneous condition prevalent in north and eastern India.
[Mh] Termos MeSH primário: Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico
Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo
Trombocitopenia/diagnóstico
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Adolescente
Adulto
Idoso
Testes de Coagulação Sanguínea
Plaquetas/citologia
Plaquetas/metabolismo
Criança
Códon sem Sentido
Feminino
Estudos de Associação Genética
Doenças Genéticas Ligadas ao Cromossomo X/genética
Genótipo
Hemorragia/etiologia
Heterozigoto
Seres Humanos
Índia
Lipoproteínas/genética
Masculino
Meia-Idade
Proteínas Motores Moleculares/genética
Mutação de Sentido Incorreto
Cadeias Pesadas de Miosina/genética
Fenótipo
Complexo Glicoproteico GPIb-IX de Plaquetas/genética
Polimorfismo de Nucleotídeo Único
Trombocitopenia/congênito
Trombocitopenia/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (Codon, Nonsense); 0 (Lipoproteins); 0 (MYH9 protein, human); 0 (Molecular Motor Proteins); 0 (Platelet Glycoprotein GPIb-IX Complex); 0 (adhesion receptor); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170223
[Lr] Data última revisão:
170223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160614
[St] Status:MEDLINE
[do] DOI:10.1111/hae.12917


  7 / 284 MEDLINE  
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[PMID]:27170062
[Au] Autor:Tada H; Kawashiri MA; Okada H; Endo S; Toyoshima Y; Konno T; Nohara A; Inazu A; Takao A; Mabuchi H; Yamagishi M; Hayashi K
[Ad] Endereço:Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine.
[Ti] Título:A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing.
[So] Source:J Atheroscler Thromb;23(7):884-90, 2016 Jul 01.
[Is] ISSN:1880-3873
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Whole exome sequencing (WES) technologies have accelerated genetic studies of Mendelian disorders, yielding approximately 30% diagnostic success. We encountered a 13-year-old Japanese female initially diagnosed with familial hypercholesterolemia on the basis of clinical manifestations of severe hypercholesterolemia (initial LDL cholesterol=609 mg/dl at the age of one) and systemic intertriginous xanthomas with histories of recurrent self-limiting episodes of fever and arthritis. Both her phenotypes seemed to co-segregate in a recessive manner. We performed WES on this patient, who was considered a proband. Among 206,430 variants found in this individual, we found 18,220 nonsense, missense, or splice site variants, of which 3,087 were rare (minor allele frequency ≤ 0.01 or not reported) in 1000 Genome (Asian population). Filtering by assuming a recessive pattern of inheritance with the use of an in silico annotation prediction tool, we successfully narrowed down the candidates to the compound heterozygous mutations in the ABCG5 gene (c.1256G>A or p.Arg419His/c.1763-1G>A [splice acceptor site]) and to the double-compound heterozygous mutations in the MEFV gene (c.329T>C/C or p.Leu110Pro/c.442G>C/C or p.Glu148Val). The patient was genetically diagnosed with sitosterolemia and familial Mediterranean fever using WES for the first time. Such a comprehensive approach is useful for identifying causative mutations for multiple unrelated inheritable diseases.
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Exoma/genética
Febre Familiar do Mediterrâneo/genética
Hipercolesterolemia/genética
Enteropatias/genética
Erros Inatos do Metabolismo Lipídico/genética
Lipoproteínas/genética
Fitosteróis/efeitos adversos
Polimorfismo de Nucleotídeo Único/genética
[Mh] Termos MeSH secundário: Adolescente
LDL-Colesterol/metabolismo
Biologia Computacional
Febre Familiar do Mediterrâneo/patologia
Feminino
Genoma Humano
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Hipercolesterolemia/patologia
Enteropatias/patologia
Erros Inatos do Metabolismo Lipídico/patologia
Fitosteróis/genética
Reação em Cadeia da Polimerase
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (Cholesterol, LDL); 0 (Lipoproteins); 0 (Phytosterols)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160513
[St] Status:MEDLINE
[do] DOI:10.5551/jat.34827


  8 / 284 MEDLINE  
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[PMID]:27144356
[Au] Autor:Lee JY; Kinch LN; Borek DM; Wang J; Wang J; Urbatsch IL; Xie XS; Grishin NV; Cohen JC; Otwinowski Z; Hobbs HH; Rosenbaum DM
[Ad] Endereço:Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
[Ti] Título:Crystal structure of the human sterol transporter ABCG5/ABCG8.
[So] Source:Nature;533(7604):561-4, 2016 05 26.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ATP binding cassette (ABC) transporters play critical roles in maintaining sterol balance in higher eukaryotes. The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and intestines. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Here we use crystallization in lipid bilayers to determine the X-ray structure of human G5G8 in a nucleotide-free state at 3.9 Å resolution, generating the first atomic model of an ABC sterol transporter. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter. The G5G8 structure provides a mechanistic framework for understanding sterol transport and the disruptive effects of mutations causing sitosterolaemia.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/química
Lipoproteínas/química
Esteróis/metabolismo
[Mh] Termos MeSH secundário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
Transportadores de Cassetes de Ligação de ATP/genética
Transportadores de Cassetes de Ligação de ATP/metabolismo
Adenosina Trifosfatases/metabolismo
Sequência de Aminoácidos
Sítios de Ligação
Biocatálise
Cristalografia por Raios X
Seres Humanos
Hipercolesterolemia/genética
Enteropatias/genética
Bicamadas Lipídicas/química
Bicamadas Lipídicas/metabolismo
Erros Inatos do Metabolismo Lipídico/genética
Lipoproteínas/genética
Lipoproteínas/metabolismo
Modelos Moleculares
Dados de Sequência Molecular
Nucleotídeos
Fitosteróis/efeitos adversos
Fitosteróis/genética
Dobramento de Proteína
Multimerização Proteica
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ABCG8 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Lipid Bilayers); 0 (Lipoproteins); 0 (Nucleotides); 0 (Phytosterols); 0 (Sterols); EC 3.6.1.- (Adenosine Triphosphatases)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160505
[St] Status:MEDLINE
[do] DOI:10.1038/nature17666


  9 / 284 MEDLINE  
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[PMID]:27052530
[Au] Autor:Abdullah MM; Cyr A; Lépine MC; Eck PK; Couture P; Lamarche B; Jones PJ
[Ad] Endereço:Department of Human Nutritional Sciences and Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, Manitoba, Canada; and.
[Ti] Título:Common Variants in Cholesterol Synthesis- and Transport-Related Genes Associate with Circulating Cholesterol Responses to Intakes of Conventional Dairy Products in Healthy Individuals.
[So] Source:J Nutr;146(5):1008-16, 2016 May.
[Is] ISSN:1541-6100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Dairy intake has been associated with varying impacts on circulating cholesterol concentrations across nutritional epidemiology and intervention studies, with findings attributed mainly to differences in the nature of dairy products consumed or study designs. The contribution of the genomic architecture to such observations has yet to be revealed. OBJECTIVE: We assessed the impact of multiple common genetic variations in cholesterol-related genes on responses of serum cholesterol to the recommended amount of dairy product intake in Canada. METHODS: In a multicenter, randomized crossover design, 101 normolipidemic adults (n = 29 men and 72 women), with a mean ± SD age of 41.7 ± 16.7 y and a body mass index (BMI, in kg/m(2)) of 25.9 ± 4.3 consumed 3 servings/d of dairy [375 mL 1% milk-fat (MF) milk, 175 g 1.5% MF yogurt, and 30 g of 34% MF cheese] or energy-matched control products (juice, cashews, and cookies) provided within a prudent background diet for 4 wk each, separated by a 4- to 8-wk washout period. Serum lipid variables were determined by standard enzymatic methods by using an autoanalyzer. Candidate single nucleotide polymorphisms were assessed by TaqMan genotyping assay. RESULTS: The responsiveness of serum total cholesterol (TC) and LDL cholesterol to the dairy compared with the control diet was associated with individuals' genotypes. The cholesterol transport gene ATP-binding cassette subfamily G, member 5 (ABCG5) rs6720173-GG homozygotes had higher concentrations of TC (+0.18 mmol/L; P = 0.0118) and LDL cholesterol (+0.17 mmol/L; P = 0.0056) relative to C-allele carriers (-0.07 and -0.06 mmol/L, respectively). The bile acid synthesis gene cholesterol 7α-hydroxylase (CYP7A1) rs3808607-G-allele carriers had higher TC (+0.20 to +0.28 mmol/L; P = 0.0026) and LDL cholesterol (+0.19 mmol/L for GT genotype; P = 0.0260) relative to TT homozygotes (-0.11 and -0.03 mmol/L, respectively). In addition, the cholesterol synthesis gene 7-dehydrocholesterol reductase (DHCR7) rs760241-A-allele carriers had higher LDL cholesterol (+0.26 mmol/L; P = 0.0399) relative to GG homozygotes (+0.06 mmol/L). CONCLUSION: Genetic variations in ABCG5, CYP7A1, and DHCR7 may contribute to differing responses of serum cholesterol to dairy intake among healthy adults. This trial was registered at clinicaltrials.gov as NCT01444326.
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Colesterol 7-alfa-Hidroxilase/genética
Colesterol/sangue
Laticínios
Dieta
Genótipo
Lipoproteínas/genética
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
LDL-Colesterol/sangue
Feminino
Variação Genética
Seres Humanos
Lipogênese/genética
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (Cholesterol, LDL); 0 (Lipoproteins); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (CYP7A1 protein, human); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.1.21 (7-dehydrocholesterol reductase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160408
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.3945/jn.115.222208


  10 / 284 MEDLINE  
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[PMID]:27014967
[Au] Autor:Wang HH; Li X; Patel SB; Wang DQ
[Ad] Endereço:Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA.
[Ti] Título:Evidence that the adenosine triphosphate-binding cassette G5/G8-independent pathway plays a determinant role in cholesterol gallstone formation in mice.
[So] Source:Hepatology;64(3):853-64, 2016 Sep.
[Is] ISSN:1527-3350
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: The adenosine triphosphate-binding cassette (ABC) sterol transporter, Abcg5/g8, is Lith9 in mice, and two gallstone-associated variants in ABCG5/G8 have been identified in humans. Although ABCG5/G8 plays a critical role in determining hepatic sterol secretion, cholesterol is still secreted to bile in sitosterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-knockout mice. We hypothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential for regulating hepatic secretion of biliary sterols, which is independent of the lithogenic mechanism of the ABCG5/G8 pathway. To elucidate the effect of the ABCG5/G8-independent pathway on cholelithogenesis, we investigated the biliary and gallstone characteristics in male wild-type (WT), ABCG5(-/-)/G8(-/-), and ABCG8 (-/-) mice fed a lithogenic diet or varying amounts of cholesterol, treated with a liver X receptor (LXR) agonist, or injected intravenously with [(3) H]sitostanol- and [(14) C]cholesterol-labeled high-density lipoprotein (HDL). We found that ABCG5(-/-)/G8(-/-) and ABCG8 (-/-) mice displayed the same biliary and gallstone phenotypes. Although both groups of knockout mice showed a significant reduction in hepatic cholesterol output compared to WT mice, they still formed gallstones. The LXR agonist significantly increased biliary cholesterol secretion and gallstones in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. The 6-hour recovery of [(14) C]cholesterol in hepatic bile was significantly lower in both groups of knockout mice than in WT mice and [(3) H]sitostanol was detected in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. CONCLUSIONS: The ABCG5/G8-independent pathway plays an important role in regulating biliary cholesterol secretion, the transport of HDL-derived cholesterol from plasma to bile, and gallstone formation, which works independently of the ABCG5/G8 pathway. Further studies are needed to observe whether this pathway is also operational in humans. (Hepatology 2016;64:853-864).
[Mh] Termos MeSH primário: Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Colesterol/secreção
Cálculos Biliares/etiologia
Lipoproteínas/genética
[Mh] Termos MeSH secundário: Animais
Bile/metabolismo
Ácidos e Sais Biliares/metabolismo
Colesterol/metabolismo
Feminino
Vesícula Biliar/fisiologia
Cálculos Biliares/metabolismo
Hidrocarbonetos Fluorados
Metabolismo dos Lipídeos
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Sulfonamidas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCG5 protein, mouse); 0 (ABCG8 protein, mouse); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 5); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 8); 0 (Bile Acids and Salts); 0 (Hydrocarbons, Fluorinated); 0 (Lipoproteins); 0 (Sulfonamides); 0 (TO-901317); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160326
[St] Status:MEDLINE
[do] DOI:10.1002/hep.28570



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