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[PMID]:28449094
[Au] Autor:Ehrhardt N; Doche ME; Chen S; Mao HZ; Walsh MT; Bedoya C; Guindi M; Xiong W; Ignatius Irudayam J; Iqbal J; Fuchs S; French SW; Mahmood Hussain M; Arditi M; Arumugaswami V; Péterfy M
[Ad] Endereço:Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
[Ti] Título:Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis.
[So] Source:Hum Mol Genet;26(14):2719-2731, 2017 07 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The human transmembrane 6 superfamily member 2 (TM6SF2) gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease and myocardial infarction in multiple genome-wide association studies. To investigate the role of Tm6sf2 in metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV)-mediated gene delivery. Hepatic overexpression of mouse Tm6sf2 resulted in phenotypes previously observed in Tm6sf2-deficient mice including reduced plasma lipid levels, diminished hepatic triglycerides secretion and increased hepatosteatosis. Furthermore, increased hepatic Tm6sf2 expression protected against the development of atherosclerosis in LDL-receptor/ApoB48-deficient mice. In cultured human hepatocytes, Tm6sf2 overexpression reduced apolipoprotein B secretion and resulted in its accumulation within the endoplasmic reticulum (ER) suggesting impaired ER-to-Golgi trafficking of pre-very low-density lipoprotein (VLDL) particles. Analysis of two metabolic trait-associated coding polymorphisms in the human TM6SF2 gene (rs58542926 and rs187429064) revealed that both variants impact TM6SF2 expression by affecting the rate of protein turnover. These data demonstrate that rs58542926 (E167K) and rs187429064 (L156P) are functional variants and suggest that they influence metabolic traits through altered TM6SF2 protein stability. Taken together, our results indicate that cellular Tm6sf2 level is an important determinant of VLDL metabolism and further implicate TM6SF2 as a causative gene underlying metabolic disease and trait associations at the 19p13.11 locus.
[Mh] Termos MeSH primário: Apolipoproteínas B/metabolismo
Aterosclerose/metabolismo
Fígado/metabolismo
Proteínas de Membrana/biossíntese
Hepatopatia Gordurosa não Alcoólica/metabolismo
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas B/genética
Aterosclerose/sangue
Aterosclerose/genética
Células Cultivadas
Retículo Endoplasmático/metabolismo
Feminino
Estudo de Associação Genômica Ampla
Complexo de Golgi/metabolismo
Células Hep G2
Hepatócitos/metabolismo
Seres Humanos
Lipoproteínas/sangue
Masculino
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Hepatopatia Gordurosa não Alcoólica/sangue
Hepatopatia Gordurosa não Alcoólica/genética
Polimorfismo de Nucleotídeo Único
Transporte Proteico
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (Lipoproteins); 0 (Membrane Proteins); 0 (TM6SF2 protein, human); 0 (Triglycerides)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx159


  2 / 9016 MEDLINE  
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[PMID]:28464894
[Au] Autor:Zhao MJ; Wang SS; Jiang Y; Wang Y; Shen H; Xu P; Xiang H; Xiao H
[Ad] Endereço:Nanjing Medical University, Affiliated Nanjing Brain Hospital, No. 264 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
[Ti] Título:Hypolipidemic effect of XH601 on hamsters of Hyperlipidemia and its potential mechanism.
[So] Source:Lipids Health Dis;16(1):85, 2017 May 02.
[Is] ISSN:1476-511X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The novel compound XH601 is a synthesized derivative of formononetin. The present study was to investigate the hypolipidemia effect and potential mechanism of XH601. METHODS: Male Golden Syrian hamsters were induced by high-fat diet (HFD) for eight weeks and the hyperlipidemic model was established successfully. After XH601 treatment, serum and hepatic biochemistry parameters of hamsters were detected and the effect of XH601 on adipose tissue was also analyzed. Furthermore, 3 T3-L1 cell differentiation by Oil-Red-O staining was observed and the mRNA and protein expression of peroxisome proliferator-activated receptors (PPARs) were measured by qRT-PCR and Western-blot in mature adipocytes. RESULTS: The in vivo results suggest that XH601 significantly decreased the adipose weight and levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), apolipoprotein B (Apo-B), apolipoprotein E (Apo-E), while increased serum high-density lipoprotein (HDL-C). The in vitro results implied that XH601 up-regulated the mRNA and protein expression of both PPARα and PPARß/δ in a dose-dependent manner. CONCLUSIONS: The study suggests that XH601 exhibited strong ability to improve the dyslipidemia in hamsters fed with high-fat diet. The potential mechanism of XH601 was associated with the up-regulation of PPARα and PPARß/δ mRNA and protein expression.
[Mh] Termos MeSH primário: Hiperlipidemias/tratamento farmacológico
Hipolipemiantes/farmacologia
Isoflavonas/farmacologia
PPAR alfa/agonistas
PPAR delta/agonistas
PPAR beta/agonistas
[Mh] Termos MeSH secundário: Células 3T3-L1
Tecido Adiposo/efeitos dos fármacos
Tecido Adiposo/metabolismo
Tecido Adiposo/patologia
Animais
Apolipoproteínas B/sangue
Apolipoproteínas E/sangue
Diferenciação Celular
HDL-Colesterol/sangue
LDL-Colesterol/sangue
Cricetinae
Dieta Hiperlipídica/efeitos adversos
Regulação da Expressão Gênica
Hiperlipidemias/etiologia
Hiperlipidemias/metabolismo
Hiperlipidemias/patologia
Masculino
Mesocricetus
Camundongos
PPAR alfa/genética
PPAR alfa/metabolismo
PPAR delta/genética
PPAR delta/metabolismo
PPAR beta/genética
PPAR beta/metabolismo
RNA Mensageiro/agonistas
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (Apolipoproteins E); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 0 (Hypolipidemic Agents); 0 (Isoflavones); 0 (PPAR alpha); 0 (PPAR delta); 0 (PPAR-beta); 0 (RNA, Messenger); 0 (Triglycerides); 295DQC67BJ (formononetin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12944-017-0472-z


  3 / 9016 MEDLINE  
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[PMID]:27777316
[Au] Autor:Mehta R; Zubirán R; Martagón AJ; Vazquez-Cárdenas A; Segura-Kato Y; Tusié-Luna MT; Aguilar-Salinas CA
[Ad] Endereço:Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico.
[Ti] Título:The panorama of familial hypercholesterolemia in Latin America: a systematic review.
[So] Source:J Lipid Res;57(12):2115-2129, 2016 12.
[Is] ISSN:1539-7262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.
[Mh] Termos MeSH primário: Hiperlipoproteinemia Tipo II/epidemiologia
[Mh] Termos MeSH secundário: Apolipoproteínas B/genética
Seres Humanos
Hiperlipoproteinemia Tipo II/genética
Hiperlipoproteinemia Tipo II/terapia
América Latina/epidemiologia
Mutação
Receptores de LDL/genética
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (LDLR protein, human); 0 (Receptors, LDL)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  4 / 9016 MEDLINE  
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[PMID]:29031774
[Au] Autor:Damsteegt EL; Davie A; Lokman PM
[Ad] Endereço:Department of Zoology, University of Otago, 340 Great King Street, PO Box 56, Dunedin 9054, New Zealand. Electronic address: erin.damsteegt@otago.ac.nz.
[Ti] Título:The evolution of apolipoprotein B and its mRNA editing complex. Does the lack of editing contribute to hypertriglyceridemia?
[So] Source:Gene;641:46-54, 2018 Jan 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The evolution of apolipoprotein B (Apob) has been intensely researched due to its importance during lipid transport. Mammalian full-length apob100 can be post-transcriptionally edited by the enzyme apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like complex-one (Apobec1) resulting in a truncated Apob, known as Apob48. Whilst both full-length and truncated forms of Apob are important for normal lipid homeostasis in mammals, there is no evidence for the presence of apob mRNA editing prior to the divergence of the mammals, yet, non-mammalian vertebrates appear to function normally with only Apob100. To date, the majority of the research carried out in non-mammalian vertebrates has focused on chickens with only a very limited number examining apob mRNA editing in fish. This study focused on the molecular evolution of Apobec1 and Apob in order to ascertain if apob mRNA editing occurs in eels, a basal teleost which represents an evolutionarily important animal group. No evidence for the presence of Apobec1 or the ability for eel apob to be edited was found. However, an important link between mutant mice and the evident hypertriglyceridemia in the plasma of non-mammalian vertebrates was made. This study has provided imperative evidence to help bridge the evolutionary gap between fish and mammals and provides further support for the lack of apob mRNA editing in non-mammalian vertebrates.
[Mh] Termos MeSH primário: Desaminases APOBEC/genética
Apolipoproteínas B/genética
Hipertrigliceridemia/genética
Edição de RNA/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Anguilla/genética
Animais
Mapeamento Cromossômico
Seres Humanos
Filogenia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins B); EC 3.5.4.5 (APOBEC Deaminases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


  5 / 9016 MEDLINE  
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[PMID]:28957410
[Au] Autor:Kim SH; Oh D; Jung KS; Lee JE; Kim H; Kim HJ; Kim BS; Park HC; Lee BK; Choi HY
[Ad] Endereço:Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
[Ti] Título:The association between the apolipoprotein B/A-I ratio and coronary calcification may differ depending on kidney function in a healthy population.
[So] Source:PLoS One;12(9):e0185522, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The apolipoprotein B/A-1 ratio has been reported to be one of the strongest risk predictors of cardiovascular events. However, its prognostic value for cardiovascular disease is still uncertain, especially in patients with chronic kidney disease. This study aimed to investigate whether the association between the apolipoprotein B/A-I ratio and coronary artery calcification differed according to kidney function in a healthy population. METHODS: Of the data from 7,780 participants from the medical records database in Gangnam Severance Hospital from 2005 through 2016, a cross-sectional analysis included participants with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 determined based on the Chronic Kidney Disease -Epidemiology Collaboration equation (n  =  1,800). Mild renal insufficiency was defined as an eGFR of 60-90 mL/min/1.73 m2. Coronary artery calcification measured with computed tomography was defined as an above-zero score. Logistic regression analyses were used to determine the association between coronary calcification and the apolipoprotein B/A-I ratio according to eGFR by adjusting for the influence of confounders. RESULTS: The mean apolipoprotein B/A-I level was significantly higher in the participants with coronary artery calcification than in the participants without coronary artery calcification. The apolipoprotein B/A-I ratio was significantly different according to coronary artery calcification in the participants with normal kidney function, but in the participants with mild renal insufficiency, it was not different. After adjusting for age, male sex, systolic blood pressure, body mass index, current smoking status, and fasting plasma glucose, the apolipoprotein B/A-I ratio was significantly associated with an increased risk of coronary artery calcification in participants with normal kidney function (odds ratio = 2.411, p = 0.011), while in the participants with mild renal insufficiency, the apolipoprotein B/A-I ratio was not associated with coronary artery calcification. CONCLUSION: Our study showed that the predictive value of apolipoprotein B/A-I ratio for coronary artery calcification may differ according to kidney function.
[Mh] Termos MeSH primário: Apolipoproteína A-I/metabolismo
Apolipoproteínas B/metabolismo
Vasos Coronários/patologia
Testes de Função Renal
Rim/fisiopatologia
Calcificação Vascular/metabolismo
Calcificação Vascular/patologia
[Mh] Termos MeSH secundário: Vasos Coronários/fisiopatologia
Feminino
Seres Humanos
Modelos Logísticos
Masculino
Meia-Idade
Análise Multivariada
Curva ROC
Calcificação Vascular/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APOA1 protein, human); 0 (Apolipoprotein A-I); 0 (Apolipoproteins B)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185522


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[PMID]:28941609
[Au] Autor:Zhu YM; Verma S; Fung M; McQueen MJ; Anderson TJ; Lonn EM
[Ad] Endereço:Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
[Ti] Título:Association of Apolipoproteins B and A-1 With Markers of Vascular Health or Cardiovascular Events.
[So] Source:Can J Cardiol;33(10):1305-1311, 2017 Oct.
[Is] ISSN:1916-7075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1) are markers of lipoprotein metabolism. Although their relationship to cardiovascular disease has been well documented, little is known regarding their correlation to measures of vascular structure and function. This study was conducted to investigate the relationship between apoA-1, apoB, and measures of vascular function, as well their relationship to adverse cardiovascular events. Moreover, we evaluated whether apoB or the apoB/apoA-1 ratio was more closely related to vascular markers than was low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C). METHODS: One thousand five hundred twenty-two healthy middle-aged men of the Firefighters and Their Endothelium (FATE) cohort were assessed for risk factors and flow-mediated dilatation (FMD), hyperemic velocity (VTI), and carotid intima-media thickness (CIMT). Participants were then followed for 7.2 ± 1.7 years. ApoA-1 and apoB levels were measured at baseline. RESULTS: ApoA-1 was not correlated with VTI, FMD, or CIMT, whereas apoB was significantly related to VTI and CIMT. Multiple regression analyses confirmed apoB as being related to both VTI (ß = -0.083; P = 0.001) and CIMT (ß = 0.055; P = 0.022) in models adjusted for age; blood pressure; high-density lipoprotein C (HDL-C), triglyceride and insulin levels; waist circumference; and C-reactive protein levels. In substituted models, LDL-C (ß = -0.092; P < 0.001) and non-HDL-C (ß = -0.089; P = 0.001) levels appeared to have the same degree of association as apoB for VTI but were not associated with CIMT. ApoB was found to be associated with cardiovascular events (hazard ratio, 1.349; 95% confidence interval, 1.073-1.695; P = 0.010). CONCLUSIONS: ApoB had an independent but weak relationship with indices of microvascular health. Nevertheless, it was associated with occurrence rates of adverse cardiovascular events.
[Mh] Termos MeSH primário: Apolipoproteína A-I/sangue
Apolipoproteínas B/sangue
Doenças Cardiovasculares/sangue
Artérias Carótidas/fisiopatologia
Vasodilatação/fisiologia
[Mh] Termos MeSH secundário: Biomarcadores/sangue
Doenças Cardiovasculares/diagnóstico
Doenças Cardiovasculares/fisiopatologia
Espessura Intima-Media Carotídea
Endotélio Vascular/fisiopatologia
Voluntários Saudáveis
Seres Humanos
Masculino
Meia-Idade
Estudos Retrospectivos
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Apolipoprotein A-I); 0 (Apolipoproteins B); 0 (Biomarkers)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170925
[St] Status:MEDLINE


  7 / 9016 MEDLINE  
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[PMID]:28902930
[Au] Autor:Gu QL; Han Y; Lan YM; Li Y; Kou W; Zhou YS; Hai XJ; Yan B; Ci CH
[Ad] Endereço:The Institute of Minority Physique and Health, Medical College of Northwest University for Nationalities, Lanzhou, China.
[Ti] Título:Association between polymorphisms in the APOB gene and hyperlipidemia in the Chinese Yugur population.
[So] Source:Braz J Med Biol Res;50(11):e6613, 2017 Sep 12.
[Is] ISSN:1414-431X
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:We investigated the influence of apolipoprotein B gene (APOB) variants on the risk of hyperlipidemia (HL) in 631 middle-aged and elderly members of the Chinese Yugur population (HL, n=336; normolipidemia, n=295). APOB polymorphisms were identified using mass spectrometry, and five single nucleotide polymorphisms (rs1042034, rs2163204, rs512535, rs676210, and rs679899) and serum lipids were further analyzed. rs1042034 and rs676210 were significantly associated with HL (P<0.05). Compared with the GG or AA genotype, individuals with AG and AG+AA in rs1042034 and with AG and AG+GG in rs676210 had a 1.67-fold (95%CI=1.20-2.33),1.63-fold (95%CI=1.19-2.24), 1.72-fold (95%CI=1.24-2.40), and 1.67-fold (95%CI=1.21-2.291) increased risk of high HL, respectively. rs2163204 was in strong linkage disequilibrium with rs1042034, rs676210, and rs679899, and strong disequilibrium was observed between rs1042034 and rs676210 (D'>0.9). Compared with the GTGAA haplotype, haplotypes ATGGA and ATAGG were more strongly associated with HL [odds ratio (OR)=1.46, 95%CI=0.02-2.11; OR=1.63, 95%CI=1.03-2.60, respectively]. The risk factors age (P=0.008), body mass index (P<0.0001), GA+GG genotype in rs676210 (P=0.009), and alcohol consumption (P=0.056) contributed strongly to HL development. The A allele of rs1042034 and the G allele of rs676210 may thus predispose middle-aged and elderly members of the Chinese Yugur population to HL in combination with other genetic or nutritional factors, and could be used as new genetic markers for HL screening.
[Mh] Termos MeSH primário: Apolipoproteínas B/genética
Hiperlipidemias/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Grupo com Ancestrais do Continente Asiático/genética
Estudos de Casos e Controles
China/etnologia
Feminino
Frequência do Gene
Estudos de Associação Genética
Haplótipos
Seres Humanos
Hiperlipidemias/etnologia
Modelos Lineares
Lipídeos/sangue
Masculino
Meia-Idade
Medição de Risco
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (Lipids)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE


  8 / 9016 MEDLINE  
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[PMID]:28846118
[Au] Autor:Ference BA; Kastelein JJP; Ginsberg HN; Chapman MJ; Nicholls SJ; Ray KK; Packard CJ; Laufs U; Brook RD; Oliver-Williams C; Butterworth AS; Danesh J; Smith GD; Catapano AL; Sabatine MS
[Ad] Endereço:Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, Michigan.
[Ti] Título:Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk.
[So] Source:JAMA;318(10):947-956, 2017 09 12.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.
[Mh] Termos MeSH primário: Apolipoproteínas B/sangue
Doenças Cardiovasculares/genética
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores
LDL-Colesterol/sangue
Variação Genética
Hidroximetilglutaril-CoA Redutases/genética
Hipercolesterolemia/genética
[Mh] Termos MeSH secundário: Anticolesterolemiantes/uso terapêutico
Doenças Cardiovasculares/prevenção & controle
Proteínas de Transferência de Ésteres de Colesterol/genética
HDL-Colesterol/sangue
Feminino
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Hipercolesterolemia/sangue
Hipercolesterolemia/tratamento farmacológico
Masculino
Análise da Randomização Mendeliana
Meia-Idade
Fatores de Risco
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anticholesteremic Agents); 0 (Apolipoproteins B); 0 (CETP protein, human); 0 (Cholesterol Ester Transfer Proteins); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); EC 1.1.1.- (HMGCR protein, human); EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.11467


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[PMID]:28825717
[Au] Autor:Khetarpal SA; Zeng X; Millar JS; Vitali C; Somasundara AVH; Zanoni P; Landro JA; Barucci N; Zavadoski WJ; Sun Z; de Haard H; Toth IV; Peloso GM; Natarajan P; Cuchel M; Lund-Katz S; Phillips MC; Tall AR; Kathiresan S; DaSilva-Jardine P; Yates NA; Rader DJ
[Ad] Endereço:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
[Ti] Título:A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels.
[So] Source:Nat Med;23(9):1086-1094, 2017 Sep.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.
[Mh] Termos MeSH primário: Apolipoproteína C-III/genética
Lipoproteínas/metabolismo
Mutação de Sentido Incorreto
Triglicerídeos/metabolismo
[Mh] Termos MeSH secundário: Idoso
Animais
Anticorpos Monoclonais/farmacologia
Apolipoproteína C-III/efeitos dos fármacos
Apolipoproteínas B/metabolismo
HDL-Colesterol/metabolismo
Cromatografia Líquida
Simulação por Computador
Doença das Coronárias/genética
Estudos Transversais
Feminino
Seres Humanos
Immunoblotting
Metabolismo dos Lipídeos/genética
Lipoproteínas/efeitos dos fármacos
Lipoproteínas VLDL/metabolismo
Masculino
Espectrometria de Massas
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Meia-Idade
Fatores de Proteção
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Apolipoprotein C-III); 0 (Apolipoproteins B); 0 (Cholesterol, HDL); 0 (Lipoproteins); 0 (Lipoproteins, VLDL); 0 (Triglycerides); 0 (lipoprotein triglyceride); 0 (very low density lipoprotein triglyceride)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171104
[Lr] Data última revisão:
171104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4390


  10 / 9016 MEDLINE  
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[PMID]:28673045
[Au] Autor:Ooi TC; Krysa JA; Chaker S; Abujrad H; Mayne J; Henry K; Cousins M; Raymond A; Favreau C; Taljaard M; Chrétien M; Mbikay M; Proctor SD; Vine DF
[Ad] Endereço:Clinical Research Laboratory, Division of Endocrinology and Metabolism, Department of Medicine, University of Ottawa, Ottawa, Ontario K1H 7W9, Canada.
[Ti] Título:The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response.
[So] Source:J Clin Endocrinol Metab;102(9):3452-3460, 2017 Sep 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Proprotein convertase subtilisin kexin 9 (PCSK9) mediates degradation of the low-density lipoprotein receptor (LDLR), thereby increasing plasma low-density lipoprotein cholesterol (LDL-C). Variations in the PCSK9 gene associated with loss of function (LOF) of PCSK9 result in greater expression of hepatic LDLR, lower concentrations of LDL-C, and protection from cardiovascular disease (CVD). Apolipoprotein-B (apoB) remnants also contribute to CVD risk and are similarly cleared by the LDLR. We hypothesized that PCSK9-LOF carriers would have lower fasting and postprandial remnant lipoproteins on top of lower LDL-C. Objective: To compare fasting and postprandial concentrations of triglycerides (TGs), total apoB, and apoB48 as indicators of remnant lipoprotein metabolism in PCSK9-LOF carriers with those with no PCSK9 variants. Design: Case-control, metabolic study. Setting: Clinical Research Center of The Ottawa Hospital. Participants: Persons with one or more copies of the L10ins/A53V and/or I474V and/or R46L PCSK9 variant and persons with no PCSK9 variants. Intervention: Oral fat tolerance test. Main Outcomes Measures: Fasting and postprandial plasma TG, apoB48, total apoB, total cholesterol, and PCSK9 were measured at 0, 2, 4, and 6 hours after an oral fat load. Results: Participants with PCSK9-LOF variants (n = 22) had reduced fasting LDL-C (-14%) as well as lower fasting TG (-21%) compared with noncarrier controls (n = 23). LOF variants also had reduced postprandial total apoB (-17%), apoB48 (-23%), and TG (-18%). Postprandial PCSK9 declined in both groups (-24% vs -16%, respectively). Conclusions: Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk.
[Mh] Termos MeSH primário: Apolipoproteínas B/sangue
Variação Genética
Lipoproteínas/metabolismo
Período Pós-Prandial/fisiologia
Pró-Proteína Convertase 9/genética
[Mh] Termos MeSH secundário: Adulto
Fatores Etários
Apolipoproteínas E/sangue
Área Sob a Curva
Estudos de Casos e Controles
Estudos de Coortes
Jejum/fisiologia
Feminino
Genótipo
Seres Humanos
Metabolismo dos Lipídeos/fisiologia
Lipoproteínas/sangue
Masculino
Meia-Idade
Ontário
Período Pós-Prandial/genética
Valores de Referência
Medição de Risco
Fatores Sexuais
Estatísticas não Paramétricas
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (Apolipoproteins E); 0 (Lipoproteins); EC 3.4.21.- (PCSK9 protein, human); EC 3.4.21.- (Proprotein Convertase 9)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2017-00684



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