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1.
Lipids Health Dis ; 18(1): 132, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31164121

RESUMO

BACKGROUND: Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia, among other lipid-related traits. Our aim is to evaluate clinical/biochemical features of a Chilean family with a proband showing clinical signs of familial LCAT deficiency, as well as to identify and assess the functional effects of LCAT mutations. METHODS: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239 T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In-silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. RESULTS: LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband's plasma, but with undetectable enzyme activity compared to control relatives. HEK-293 T transfected cells with vector expression plasmids containing either p.M404 V or p.V333 M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Additionally, the proband carried the minor allele of the synonymous p.L363 L variant. However, this variant is unlikely to affect the clinical phenotype of the proband given its relatively high frequency in the Chilean population (4%) and its small putative effect on plasma HDL-cholesterol levels. CONCLUSION: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404 V and p.V333 M in LCAT gene lead to suppression of LCAT enzyme activity and cause clinical features of familial LCAT deficiency.


Assuntos
Hipoalfalipoproteinemias/genética , Deficiência da Lecitina Colesterol Aciltransferase/genética , Lipídeos/sangue , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Adulto , Idoso , Chile/epidemiologia , Colesterol/sangue , HDL-Colesterol/sangue , Opacidade da Córnea/genética , Opacidade da Córnea/patologia , Éxons/genética , Feminino , Células HEK293 , Humanos , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/epidemiologia , Hipoalfalipoproteinemias/patologia , Deficiência da Lecitina Colesterol Aciltransferase/sangue , Deficiência da Lecitina Colesterol Aciltransferase/epidemiologia , Deficiência da Lecitina Colesterol Aciltransferase/patologia , Lipoproteínas HDL/sangue , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto/genética , Linhagem , Fosfatidilcolina-Esterol O-Aciltransferase/química , Relação Estrutura-Atividade
2.
PLoS One ; 14(4): e0215620, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30998801

RESUMO

HIV infection is known to be associated with cardiometabolic abnormalities; here we investigated the progression and causes of these abnormalities. Three groups of participants were recruited: HIV-negative subjects and two groups of treatment-naïve HIV-positive subjects, one group initiating antiretroviral treatment, the other remaining untreated. Intima-media thickness (cIMT) increased in HIV-positive untreated group compared to HIV-negative group, but treatment mitigated the difference. We found no increase in diabetes-related metabolic markers or in the level of inflammation in any of the groups. Total cholesterol, low density lipoprotein cholesterol and apoB levels were lower in HIV-positive groups, while triglyceride and Lp(a) levels did not differ between the groups. We found a statistically significant negative association between viral load and plasma levels of total cholesterol, LDL cholesterol, HDL cholesterol, apoA-I and apoB. HIV-positive patients had hypoalphalipoproteinemia at baseline, and we found a redistribution of sub-populations of high density lipoprotein (HDL) particles with increased proportion of smaller HDL in HIV-positive untreated patients, which may result from increased levels of plasma cholesteryl ester transfer protein in this group. HDL functionality declined in the HIV-negative and HIV-positive untreated groups, but not in HIV-positive treated group. We also found differences between HIV-positive and negative groups in plasma abundance of several microRNAs involved in lipid metabolism. Our data support a hypothesis that cardiometabolic abnormalities in HIV infection are caused by HIV and that antiretroviral treatment itself does not influence key cardiometabolic parameters, but mitigates those affected by HIV.


Assuntos
Antirretrovirais/administração & dosagem , Aterosclerose/sangue , Infecções por HIV/sangue , HIV-1 , Hipoalfalipoproteinemias/sangue , Lipídeos/sangue , Adulto , Aterosclerose/prevenção & controle , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Hipoalfalipoproteinemias/prevenção & controle , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Biochem Biophys Res Commun ; 508(2): 487-493, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30503498

RESUMO

Tangier disease is a rare disorder of lipoprotein metabolism that presents with extremely low levels of HDL cholesterol and apoprotein A-I. It is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene. Clinical heterogeneity and mutational pattern of Tangier disease are poorly characterized. Moreover, also familial HDL deficiency may be caused by mutations in ABCA1 gene. ATP-binding cassette transporter A1 (ABCA1) gene mutations in a patient with Tangier disease, who presented an uncommon clinical history, and in his family were found and characterized. He was found to be compound heterozygous for two intronic mutations of ABCA1 gene, causing abnormal pre-mRNAs splicing. The novel c.1510-1G > A mutation was located in intron 12 and caused the activation of a cryptic splice site in exon 13, which determined the loss of 22 amino acids of exon 13 with the introduction of a premature stop codon. Five heterozygous carriers of this mutation were also found in proband's family, all presenting reduced HDL cholesterol and ApoAI (0.86 ±â€¯0.16 mmol/L and 92.2 ±â€¯10.9 mg/dL respectively), but not the typical features of Tangier disease, a phenotype compatible with the diagnosis of familial HDL deficiency. The other known mutation c.1195-27G > A was confirmed to cause aberrant retention of 25 nucleotides of intron 10 leading to the insertion of a stop codon after 20 amino acids of exon 11. Heterozygous carriers of this mutation also showed the clinical phenotype of familial HDL deficiency. Our study extends the catalog of pathogenic intronic mutations affecting ABCA1 pre-mRNA splicing. In a large family, a clear demonstration that the same mutations may cause Tangier disease (if in compound heterozygosis) or familial HDL deficiency (if in heterozygosis) is provided.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Hipoalfalipoproteinemias/genética , Mutação , Processamento de RNA/genética , Doença de Tangier/genética , Códon sem Sentido , Família , Feminino , Heterozigoto , Humanos , Íntrons/genética , Masculino , Linhagem , Sítios de Splice de RNA/genética
4.
Atherosclerosis ; 280: 51-57, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30471555

RESUMO

BACKGROUND AND AIMS: Despite hypercholesterolemia has been recognized to increase cardiovascular risk in human immunodeficiency virus (HIV)-infected patients, cholesterol-lowering therapy is underused in this population, due to fear of drug-drug interactions with antiretroviral therapy (ART). We investigated the effects of a nutraceutical combination (NC) on lipid profile, proprotein convertase subtilisin/kexin type 9 (PCSK9), subclinical inflammation and arterial stiffness in ART-treated HIV-infected patients. METHODS: This was a prospective randomized open-label trial with a cross-over design including 30 stable HIV-infected patients on ART with low-density lipoprotein cholesterol (LDL-C) >115 mg/dL, not taking lipid-lowering treatment. After a 3-week lipid stabilization period, the effects associated with 3 months of an oral NC containing red yeast rice and berberine vs. no active treatment (noNC) were assessed for plasma total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), lipoprotein(a), PCSK9, high-sensitivity C-reactive protein (hs-CRP) levels and aortic pulse wave velocity (aPWV). RESULTS: At baseline, significant correlations between PCSK9 levels, age (rho = -0.51, p=0.004), waist circumference (rho = 0.36, p=0.005) and CD4+ cell count (rho = -0.40, p=0.027) were observed. NC treatment effects corrected for noNC were significant for TC (-14%, p<0.001), LDL-C (-19%, p<0.001), PCSK9 (-12%, p=0.02), hs-CRP (-14%, p=0.03) and aPWV (-6%, p=0.005). No significant effects were observed for HDL-C, TG and lipoprotein(a). NC treatment was safe and no significant alterations in muscle, liver and immunovirological parameters were observed. No carry over effect was recorded. CONCLUSIONS: The tested NC significantly reduced plasma cholesterol and PCSK9 levels, attenuated subclinical inflammation and improved arterial stiffness in stable HIV-infected patients on ART.


Assuntos
Suplementos Nutricionais , Infecções por HIV/terapia , Hipercolesterolemia/tratamento farmacológico , Adulto , Proteína C-Reativa/análise , LDL-Colesterol/sangue , Estudos Cross-Over , Feminino , Taxa de Filtração Glomerular , Humanos , Hipercolesterolemia/complicações , Hipertensão/complicações , Hipertrigliceridemia/complicações , Hipoalfalipoproteinemias/complicações , Inflamação , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Pró-Proteína Convertase 9/sangue , Estudos Prospectivos , Análise de Onda de Pulso , Fumar/efeitos adversos , Rigidez Vascular
5.
J Lipid Res ; 59(12): 2421-2435, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30333156

RESUMO

We assessed secondary and genetic causes of severe HDL deficiency in 258,252 subjects, of whom 370 men (0.33%) and 144 women (0.099%) had HDL cholesterol levels <20 mg/dl. We excluded 206 subjects (40.1%) with significant elevations of triglycerides, C-reactive protein, glycosylated hemoglobin, myeloperoxidase, or liver enzymes and men receiving testosterone. We sequenced 23 lipid-related genes in 201 (65.3%) of 308 eligible subjects. Mutations (23 novel) and selected variants were found at the following gene loci: 1) ABCA1 (26.9%): 2 homozygotes, 7 compound or double heterozygotes, 30 heterozygotes, and 2 homozygotes and 13 heterozygotes with variants rs9282541/p.R230C or rs111292742/c.-279C>G; 2) LCAT (12.4%): 1 homozygote, 3 compound heterozygotes, 13 heterozygotes, and 8 heterozygotes with variant rs4986970/p.S232T; 3) APOA1 (5.0%): 1 homozygote and 9 heterozygotes; and 4) LPL (4.5%): 1 heterozygote and 8 heterozygotes with variant rs268/p.N318S. In addition, 4.5% had other mutations, and 46.8% had no mutations. Atherosclerotic cardiovascular disease (ASCVD) prevalence rates in the ABCA1, LCAT, APOA1, LPL, and mutation-negative groups were 37.0%, 4.0%, 40.0%, 11.1%, and 6.4%, respectively. Severe HDL deficiency is uncommon, with 40.1% having secondary causes and 48.8% of the subjects sequenced having ABCA1, LCAT, APOA1, or LPL mutations or variants, with the highest ASCVD prevalence rates being observed in the ABCA1 and APOA1 groups.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Hipoalfalipoproteinemias/etiologia , Hipoalfalipoproteinemias/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteína A-I/genética , Proteína C-Reativa/metabolismo , HDL-Colesterol/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Lipoproteínas HDL/genética , Masculino , Mutação/genética
6.
Arterioscler Thromb Vasc Biol ; 38(8): 1913-1925, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29930009

RESUMO

Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.


Assuntos
Aorta/metabolismo , Doenças da Aorta/genética , HDL-Colesterol/sangue , Doença de Erdheim-Chester/genética , Histiócitos/metabolismo , Hipoalfalipoproteinemias/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta/efeitos dos fármacos , Aorta/patologia , Doenças da Aorta/tratamento farmacológico , Doenças da Aorta/enzimologia , Biomarcadores/sangue , Estudos de Casos e Controles , Doença de Erdheim-Chester/sangue , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/tratamento farmacológico , Feminino , Predisposição Genética para Doença , Histiócitos/efeitos dos fármacos , Histiócitos/patologia , Humanos , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/diagnóstico , Hipoalfalipoproteinemias/tratamento farmacológico , Receptores de Lipopolissacarídeos/sangue , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Fatores de Risco , Fatores Sexuais , Células THP-1 , Vemurafenib/uso terapêutico , Adulto Jovem
7.
Arterioscler Thromb Vasc Biol ; 38(7): 1440-1453, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29853565

RESUMO

OBJECTIVE: Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels. APPROACH AND RESULTS: In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels. CONCLUSIONS: This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , HDL-Colesterol/metabolismo , Fibroblastos/metabolismo , Variação Genética , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Receptores Depuradores Classe B/metabolismo , Apolipoproteína A-I/sangue , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Predisposição Genética para Doença , Células HEK293 , Humanos , Hipoalfalipoproteinemias/diagnóstico , Fígado/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Fenótipo , Estudos Prospectivos , Estabilidade Proteica , Transporte Proteico , Triglicerídeos/sangue
8.
J Lipid Res ; 59(8): 1529-1535, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29866657

RESUMO

Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV® caller algorithm to screen for CNVs that disrupted the ABCA1, LCAT, or APOA1 genes. In four individuals, we found three unique deletions in ABCA1: a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire ABCA1 gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in ABCA1 may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Deleção de Genes , Hipoalfalipoproteinemias/genética , Adulto , Biologia Computacional , Variações do Número de Cópias de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
9.
Biochim Biophys Acta Mol Basis Dis ; 1863(12): 3038-3048, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28887204

RESUMO

Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloidosis do not show a higher risk of cardiovascular diseases (CVD). The structural features, the lipid binding properties and the functionality of four ApoA-I amyloidogenic variants were therefore inspected in order to clarify the paradox observed in the clinical phenotype of the affected subjects. Our results show that ApoA-I amyloidogenic variants are characterized by a different oligomerization pattern and that the position of the mutation in the ApoA-I sequence affects the molecular structure of the formed HDL particles. Although lipidation increases ApoA-I proteins stability, all the amyloidogenic variants analyzed show a lower affinity for lipids, both in vitro and in ex vivo mouse serum. Interestingly, the lower efficiency at forming HDL particles is compensated by a higher efficiency at catalysing cholesterol efflux from macrophages. The decreased affinity of ApoA-I amyloidogenic variants for lipids, together with the increased efficiency in the cholesterol efflux process, could explain why, despite the unfavourable lipid profile, patients affected by ApoA-I related amyloidosis do not show a higher CVD risk.


Assuntos
Apolipoproteína A-I/química , Apolipoproteína A-I/metabolismo , HDL-Colesterol/metabolismo , Colesterol/metabolismo , Dislipidemias/metabolismo , Amiloidose/metabolismo , Animais , Apolipoproteína A-I/genética , Sítios de Ligação , Colesterol/sangue , Humanos , Hipoalfalipoproteinemias/metabolismo , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Análise de Sequência de Proteína , Relação Estrutura-Atividade
10.
Rev Assoc Med Bras (1992) ; 63(4): 324-331, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28614534

RESUMO

Introduction:: The purpose of this study was to evaluate the prevalence of peripheral polyneuropathy (PPN) in subjects with grade II and III obesity (Ob-II,III) and metabolic syndrome (MetS) but without diabetes and to investigate possible associated factors. Method:: A cross-sectional study was performed in non-diabetic Ob-II,III,MetS patients using the Michigan Neuropathy Screening Instrument (MNSI) to assess the presence of PPN. Results:: A total of 24 of 218 non-diabetic Ob-II,III,MetS patients had PPN. Based on univariate analysis, serum levels of LDL-cholesterol (p=0.046) were significantly associated with PPN, while serum triglycerides (p=0.118) and low HDL-cholesterol (p=0.057) showed a tendency toward this association. On a Poisson regression analysis, when the three possible associations were included, low HDL-cholesterol (p=0.047) remained independently associated. Conclusion:: In non-diabetic Ob-II,III,MetS patients, PPN defined by the MNSI showed a high prevalence and was associated with low levels of HDL-cholesterol. In order to diagnose that complication, neurological evaluation should be performed in these patients.


Assuntos
Hipoalfalipoproteinemias/complicações , Síndrome Metabólica/complicações , Obesidade Mórbida/complicações , Polineuropatias/epidemiologia , Polineuropatias/etiologia , Adulto , Antropometria , Glicemia/análise , Brasil/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipoalfalipoproteinemias/metabolismo , Hipoalfalipoproteinemias/fisiopatologia , Masculino , Síndrome Metabólica/fisiopatologia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/fisiopatologia , Distribuição de Poisson , Polineuropatias/metabolismo , Polineuropatias/fisiopatologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Estatísticas não Paramétricas , Inquéritos e Questionários , Triglicerídeos/sangue
11.
Clin Sci (Lond) ; 131(16): 2095-2107, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28634189

RESUMO

Loss-of-function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol (HDL-C) and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1-/- murine models reported defects in platelet count, morphology, and function, but the issue is still controversial. We analyzed three subjects with low to very low HDL-C levels due to the loss-of-function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all the patients. No morphological platelet abnormalities were detected under optical or EM. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin αIIbß3 were observed in one FHD patient. While α-granule secretion (P-selectin), content, and secretion of platelet δ-granules (serotonin, ATP, and ADP) and thromboxane (TX) A2 synthesis were normal in all the patients, the expression of lysosomal CD63, in response to some agonists, was reduced in TD patients. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists or bleeding.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Plaquetas/fisiologia , Mutação , Trombocitopenia/genética , Idoso , Plaquetas/ultraestrutura , Coleta de Amostras Sanguíneas/métodos , Feminino , Humanos , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/genética , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Agregação Plaquetária/fisiologia , Contagem de Plaquetas , Testes de Função Plaquetária/métodos , Doença de Tangier/sangue , Doença de Tangier/genética , Trombocitopenia/sangue
13.
Obes Res Clin Pract ; 11(3): 324-334, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27397794

RESUMO

OBJECTIVE: Hypo-HDL cholesterolemia is a potent cardiovascular risk factor, and HDL cholesterol level is influenced by lifestyles including alcohol drinking, smoking and regular exercise. The aim of this study was to clarify the relationships between hypo-HDL cholesterolemia and cardiovascular risk factors and to determine whether or not these relationships depend on the above-mentioned lifestyles. METHODS: The subjects were 3456 men and 2510 women (35-60 years of age) showing low HDL cholesterol levels (<40mg/dl for men and <50mg/dl for women) and their age-matched control subjects showing normal HDL cholesterol levels. Each cardiometabolic risk factor was compared between the groups with and without hypo-HDL cholesterolemia. Data for hypo-HDL cholesterolemic subjects not having habits of alcohol drinking, smoking and regular exercise (men, n=333; women, n=1410) and their age-matched control subjects were also analysed. RESULTS: Both in men and in women of overall subjects and subjects without histories of alcohol drinking, smoking and regular exercise, odds ratios of subjects with hypo-HDL cholesterolemia vs. subjects with normo-HDL cholesterolemia for high body mass index, high waist-to-height ratio, high triglycerides, high lipid accumulation product and multiple risk factors (three or more out of obesity, hypertension, dyslipidaemia and diabetes) were significantly higher than the reference level of 1.00. These associations in overall subjects were found when the above habits were adjusted. CONCLUSIONS: Hypo-HDL cholesterolemic men and women have adverse cardiovascular profiles, such as obesity, hypertriglyceridemia and multiple risk factors, independently of age, alcohol drinking, smoking and regular exercise.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , Exercício Físico/fisiologia , Hipoalfalipoproteinemias/complicações , Fumar/efeitos adversos , Adulto , Doenças Cardiovasculares/sangue , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Hipoalfalipoproteinemias/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco
14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(2): 188-195, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27815221

RESUMO

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.


Assuntos
HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Antioxidantes/metabolismo , Glicemia/metabolismo , Dislipidemias/sangue , Dislipidemias/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Índice Glicêmico/fisiologia , Humanos , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/metabolismo , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo/fisiologia
15.
Lipids Health Dis ; 15(1): 141, 2016 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-27567897

RESUMO

BACKGROUND: To determine whether 12 months of intensive medical therapy (IMT) improves HDL functionality parameters in subjects with type II diabetes (T2D). METHODS: Retrospective, randomized, and controlled 12-month IMT intervention trial that enrolled 13-subjects with T2D (age 51- years, fasting glucose 147 mg/dL, body mass index [BMI] 36.5 kg/m(2)) and nine healthy control (46-years, fasting glucose 90 mg/dL, BMI 26.5 kg/m2). Subjects with T2D underwent IMT and HDL functionality measures (pro-inflammatory index of high-density lipoprotein (pHDL)), paraoxonase one (PON1), ceruloplasmin (Cp), and myeloperoxidase (MPO) activity were performed on samples at baseline and at 12-months following IMT. RESULTS: At baseline, pHDL index was significantly higher in subjects with T2D (p < 0.001) and apolipoprotein A-1 levels were significantly lower (p = 0.013) vs. CONTROLS: After 12-months, there was a trend for improved pHDL activity (p = 0.083), as indicated by intent-to-treat analysis, but when the non-adherent subject was omitted (per-protocol), significant attenuations in pHDL activity (p = 0.040) were noted; Δ pHDL activity at 12-months was associated with Δ weight (r = 0.62, p = 0.032) and Δ fasting glucose (r = 0.65, p = 0.022). Moreover, PON1 activity significantly improved (p < 0.001). The aforementioned occurred in association with improvements in inflammatory markers (i.e., C-reactive protein & tumor necrosis factor), hemoglobin A1C, fasting glucose, triglycerides, high-density lipoprotein levels and adipokines. CONCLUSION: IMT ameliorates pHDL index and significantly improves anti-oxidative function, as measured by PON1. Improvements in weight and fasting glucose mediated the decrease in pHDL index. Pharmacological aids and lifestyle modification are required to improve cardiovascular risk factors, subsequent mortality risk, and promote T2D remission. Application of either form of therapy alone may only have relatively miniscule effects on the aforementioned factors, in relation to the aggregate.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Terapia por Exercício , Hipoglicemiantes/farmacologia , Lipoproteínas HDL/efeitos dos fármacos , Adulto , Apolipoproteína A-I/sangue , Apolipoproteína A-I/efeitos dos fármacos , Biguanidas/farmacologia , Biguanidas/uso terapêutico , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hipoalfalipoproteinemias/complicações , Hipoalfalipoproteinemias/dietoterapia , Hipoalfalipoproteinemias/tratamento farmacológico , Hipoalfalipoproteinemias/terapia , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Insulina/farmacologia , Insulina/uso terapêutico , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
16.
Prog Cardiovasc Dis ; 59(2): 97-106, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27565770

RESUMO

Low serum high density lipoprotein cholesterol level (HDL-C) <40 mg/dL in men and <50 mg/dL in women is a significant independent risk factor for cardiovascular disease (CVD), and is often observed in patients with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Patients with marked deficiency of HDL-C (<20 mg/dL) in the absence of secondary causes are much less common (<1% of the population). These patients may have homozygous, compound heterozygous, or heterozygous defects involving the apolipoprotein (APO)AI, ABCA1, or lecithin:cholesterol acyl transferase genes, associated with apo A-I deficiency, apoA-I variants, Tangier disease , familial lecithin:cholesteryl ester acyltransferase deficiency, and fish eye disease. There is marked variability in laboratory and clinical presentation, and DNA analysis is necessary for diagnosis. These patients can develop premature CVD, neuropathy, kidney failure, neuropathy, hepatosplenomegaly and anemia. Treatment should be directed at optimizing all non-HDL risk factors.


Assuntos
Hipoalfalipoproteinemias , Gerenciamento Clínico , Humanos , Hipoalfalipoproteinemias/diagnóstico , Hipoalfalipoproteinemias/etiologia , Hipoalfalipoproteinemias/terapia
17.
Am J Epidemiol ; 184(5): 366-77, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27543092

RESUMO

To shed light on the etiology of metabolic syndrome development, it is important to understand whether its 5 component disorders follow certain onset sequences. To explore disease progression of the syndrome, we studied the ages at onset of 5 cardiometabolic diseases: abdominal obesity, diabetes, hypertension, hypertriglyceridemia, and hypo-α-lipoproteinemia. In analyzing longitudinal data from the Cardiovascular Disease Risk Factors Two-Township Study (1989-2002) in Taiwan, we adjusted for nonsusceptibility, utilizing the logistic-accelerated failure time location-scale mixture regression models for left-truncated and interval-censored data to simultaneously estimate the associations of township and sex with the susceptibility probability and the age-at-onset distribution of susceptible individuals for each disease. We then validated the onset sequences of 5 cardiometabolic diseases by comparing the overall probability density curves across township-sex strata. Visualization of these curves indicates that women tended to have onsets of abdominal obesity and hypo-α-lipoproteinemia in young adulthood, hypertension and hypertriglyceridemia in middle age, and diabetes later; men tended to have onsets of abdominal obesity, hypo-α-lipoproteinemia, and hypertriglyceridemia in young adulthood, hypertension in middle age, and diabetes later. Different onset patterns of abdominal obesity, hypo-α-lipoproteinemia, and male hypertension were identified between townships. Our proposed method provides a novel strategy for investigating both pathogenesis and preventive measures of complex syndromes.


Assuntos
Idade de Início , Progressão da Doença , Suscetibilidade a Doenças , Síndrome Metabólica/etiologia , Adulto , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/etiologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertrigliceridemia/complicações , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/etiologia , Hipoalfalipoproteinemias/complicações , Hipoalfalipoproteinemias/epidemiologia , Hipoalfalipoproteinemias/etiologia , Modelos Logísticos , Estudos Longitudinais , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/etiologia , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
19.
Int J Environ Res Public Health ; 13(2): 176, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26828509

RESUMO

OBJECTIVE: To detect the interactions between six functional polymorphisms in ABCA1 and obesity in Kazakhs with low HDL-C levels. METHODS: A total of 204 patients with low HDL-C and 207 health control subjects, which were randomly selected from among 5692 adult Kazakhs, were matched for age and sex. We genotyped ABCA1 single nucleotide polymorphisms of rs2515602, rs3890182, rs2275542, rs2230806, rs1800976, and rs4149313. RESULTS: (1) The genotypic and allelic frequencies of rs2515602, rs2230806 and rs4149313 were different between normal HDL-C and low HDL-C subjects, the genotypic frequency of rs2275542 was also different between normal HDL-C and low HDL-C subjects (p < 0.05); (2) the level of HDL-C (rs2515602 and rs2275542) in normal HDL-C subjects were different among the genotypes (p < 0.05); the levels of TC, LDL-C (rs2515602, rs4149313); TG (rs2515602, rs1800976, rs4149313) in low HDL-C patients were different among the genotypes (p < 0.05); (3) interactions between the rs3890182, rs2275542, rs180096, and rs4149313 polymorphisms in ABCA1 gene and obesity may be associated with low HDL-C disease; (4) the C-C-C-A-A-G, T-C-C-A-A-A, T-C-C-A-A-G, C-C-C-A-A-A, C-T-G-G-A-A, and T-T-C-G-A-A haplotypes were significant between the subjects with normal HDL-C and low HDL-C level (p < 0.05). CONCLUSIONS: The differences in serum lipid levels between normal HDL-C and low HDL-C subjects among Kazakhs might partly result from ABCA1 gene polymorphisms; ABCA1 gene polymorphisms may be associated with low HDL-C disease; the low HDL-C disease might partly result from interactions between ABCA1 gene polymorphisms and obesity; the C-C-C-A-A-G, T-C-C-A-A-A, and T-C-C-A-A-G haplotypes may serve as risk factors of low HDL-C disease among Kazakhs, the C-C-C-A-A-A, C-T-G-G-A-A, and T-T-C-G-A-A haplotypes may serve as protective factor of low HDL-C disease among Kazakhs.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Hipoalfalipoproteinemias/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , China , HDL-Colesterol/sangue , HDL-Colesterol/deficiência , Feminino , Marcadores Genéticos , Genótipo , Humanos , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/complicações , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Fatores de Risco
20.
Mol Cell Proteomics ; 15(3): 1083-93, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26667175

RESUMO

Low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels contribute to the excess rate of cardiovascular events seen in subjects with type 2 diabetes. Fenofibrate treatment partially reverses dyslipidemia in these subjects. However, a paradoxical marked reduction in HDL-C and HDL's major protein, apolipoprotein A-I, is a complication of fenofibrate in combination with rosiglitazone, an insulin-sensitizing agent. Risk factors for this condition, termed hypoalphalipoproteinemia, have yet to be identified. Using a case-control study design with subjects enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, we tested the hypothesis that alterations in HDL's protein cargo predispose diabetic subjects to fenofibrate/rosiglitazone-induced hypoalphalipoproteinemia. HDL was isolated from blood obtained from controls (no decreases or increase in HDL-C while receiving fenofibrate/rosiglitazone therapy) and cases (developed hypoalphalipoproteinemia after fenofibrate/rosiglitazone treatment) participating in the ACCORD study before they began fenofibrate/rosiglitazone treatment. HDL proteins were quantified by targeted parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) with isotope dilution. This approach demonstrated marked increases in the relative concentrations of paraoxonase/arylesterase 1 (PON1), apolipoprotein C-II (APOC2), apolipoprotein C-I, and apolipoprotein H in the HDL of subjects who developed hypoalphalipoproteinemia. The case and control subjects did not differ significantly in baseline HDL-C levels or other traditional lipid risk factors. We used orthogonal biochemical techniques to confirm increased levels of PON1 and APOC2. Our observations suggest that an imbalance in HDL proteins predisposes diabetic subjects to develop hypoalphalipoproteinemia on fenofibrate/rosiglitazone therapy.


Assuntos
Apolipoproteína C-II/metabolismo , Arildialquilfosfatase/metabolismo , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada/efeitos adversos , Hipoalfalipoproteinemias/induzido quimicamente , Proteômica/métodos , Idoso , Doenças Cardiovasculares/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Fenofibrato/administração & dosagem , Fenofibrato/efeitos adversos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/efeitos adversos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/efeitos adversos
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