RESUMEN
Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing 'biological oxidations' activate cholesterol efflux and the substances influencing 'Signaling by GPCR and PTK6' inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.
Asunto(s)
Anticolesterolemiantes/farmacología , Aterosclerosis/metabolismo , Colesterol/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Anticolesterolemiantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Biología Computacional/métodos , Diseño de Fármacos , Metabolismo Energético/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas HDL/deficiencia , Redes y Vías Metabólicas/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Peso Molecular , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Hypertriglyceridaemia (HTG) and reduction and dysfunction of high density lipoprotein (HDL) are common lipid disturbances in chronic kidney disease (CKD). HTG in CKD is caused mainly by the decreased efficiency of lipoprotein lipase (LPL)-mediated very low density lipoprotein triglyceride (VLDL-TG) lipolysis. It has not been clarified whether HDL dysfunction in CKD contributes directly to HTG development; thus, the aim of this study was to assess the impact of CKD progression on the ability of HDL to enhance LPL-mediated VLDL-TG lipolysis efficiency. METHODS: VLDL was isolated from non-dialysis patients in CKD stages 3 and 4 and from non-CKD patients. The VLDL was incubated with LPL at the constant LPL:VLDL-TG ratio, in the absence or presence of HDL. After incubation, the VLDL was separated and the percentage (%) of hydrolyzed TG was calculated. RESULTS: HDL presence increased the lipolysis efficiency of VLDL isolated from CKD and non-CKD patients, for the VLDL-TG> 50 mg/dl. Its effect was dependent on the VLDL-TG and HDL-cholesterol concentrations in the reaction mixtures: the higher the concentrations of VLDL-TG and HDL-cholesterol, the greater the effect. The positive impact of HDL on VLDL lipolysis was modified by CKD progression: the percentage of lipolyzed VLDL-TG in the presence of HDL decreased with a reduction in eGFR (r=0.43, p=0.009), and for patients with stage 4 CKD, no positive impact of HDL on lipolysis was observed. The percentage of lipolyzed TG correlated negatively with apoE and apoCs content in VLDL, and positively with HDL-apoCII, as well as with VLDL and HDL apoCII/ apoCIII ratios. The progression of CKD was associated with unfavourable changes in VLDL and HDL composition; apoE and apoCs levels increased in VLDL with a decrease in eGFR whereas the HDL-cholesterol level decreased. CONCLUSION: The progression of CKD affects lipoprotein composition and properties, and modulates the positive impact of HDL on VLDL lipolysis efficiency. In CKD patients, HDL deficiency and dysfunction can directly affect hypertriglyceridaemia development.
Asunto(s)
Hipertrigliceridemia/etiología , Lipólisis/efectos de los fármacos , Lipoproteína Lipasa/metabolismo , Lipoproteínas HDL/farmacología , Lipoproteínas VLDL/metabolismo , Insuficiencia Renal Crónica/patología , Triglicéridos/metabolismo , Anciano , HDL-Colesterol/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Lipoproteínas HDL/deficiencia , Masculino , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Aterosclerosis/genética , Hígado Graso/genética , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/genética , Receptores Nucleares Huérfanos/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Aterosclerosis/prevención & control , Aterosclerosis/terapia , Ácidos y Sales Biliares/metabolismo , Colesterol en la Dieta/metabolismo , HDL-Colesterol/metabolismo , Dieta Alta en Grasa , Ácidos Grasos Insaturados/metabolismo , Hígado Graso/prevención & control , Hígado Graso/terapia , Femenino , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Ligandos , Lipogénesis/genética , Lipoproteínas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Receptores X del Hígado , Masculino , Ratones , Receptores Nucleares Huérfanos/genética , Fosfatidilcolinas/biosíntesis , Fosfatidilcolinas/metabolismo , Estabilidad Proteica , Proteolisis , Receptores de LDL/deficiencia , Receptores de LDL/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , UbiquitinaciónRESUMEN
BACKGROUND: We aimed to examine the risk factors for renal function decline (RFD) in a community-based cohort of a rural Chinese population with normal kidney function (estimated glomerular filtration rate, eGFR ≥60â mL/min/1.73â m(2)), both for the population as a whole and stratified by sex. METHODS: 2518 participants were included in the current analysis. RFD was defined as follows: a drop in the eGFR category accompanied by a 25% or greater drop in eGFR from baseline; or a sustained decline in eGFR of more than 5â mL/min/1.73â m(2)/year. RESULTS: The incidence rate of RFD was 8.7% (women 7.4% and men 9.8%). In the multivariable logistic regression model, the ORs (95% CI) of developing RFD was 1.60 (1.01 to 2.54) for men versus women, and 1.51 (1.09 to 2.08) for participants with obesity or abdominal obesity versus none (1.35 (0.85 to 2.14) for men, and 1.65 (1.04 to 2.64) for women). However, prehypertension (OR=1.64; 95% CI 1.02 to 2.63) or hypertension (2.05; 1.21 to 3.47), higher mean blood pressure (≥90 vs <80â mmâ Hg, 2.63; 1.11 to 6.20), higher pulse pressure (≥50 vs <40â mmâ Hg, 2.00; 1.26 to 3.18), lower high-density lipoprotein cholesterol (<0.9 vs ≥0.9â mmol/L, 2.65; 1.08 to 6.50) and low physical activity levels (vs high, 3.11; 1.59 to 6.10) were major risk factors for RFD in men. Current smoking (3.22; 1.22 to 2.64) and worse self-reported health (vs better, 2.57; 1.20 to 5.50) were major risk factors for RFD in women. CONCLUSIONS: Our findings suggested that sex-specific risk factors should be considered in prevention of RFD in the Chinese rural population with normal kidney function.
Asunto(s)
Tasa de Filtración Glomerular/fisiología , Hipertensión/epidemiología , Insuficiencia Renal Crónica/fisiopatología , Adulto , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , China/epidemiología , Femenino , Humanos , Incidencia , Lipoproteínas HDL/sangre , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/fisiología , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Actividad Motora/fisiología , Obesidad Abdominal/complicaciones , Obesidad Abdominal/epidemiología , Prevalencia , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etiología , Factores de Riesgo , Salud Rural/estadística & datos numéricos , Distribución por Sexo , Fumar/efectos adversos , Fumar/epidemiologíaRESUMEN
By screening directed libraries of serine hydrolase inhibitors using the cell surface form of endothelial lipase (EL), we identified a series of carbamate-derived (EL) inhibitors. Compound 3 raised plasma HDL-C levels in the mouse, and a correlation was found between HDL-C and plasma compound levels. Spectroscopic and kinetic studies support a covalent mechanism of inhibition. Our findings represent the first report of EL inhibition as an effective means for increasing HDL-C in an in vivo model.
Asunto(s)
HDL-Colesterol/sangre , Endotelio Vascular/enzimología , Inhibidores Enzimáticos/química , Lipasa/antagonistas & inhibidores , Tiocarbamatos/química , Animales , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Concentración de Iones de Hidrógeno , Lipasa/metabolismo , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tiocarbamatos/síntesis química , Tiocarbamatos/farmacologíaRESUMEN
BACKGROUND: Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDL(Healthy)) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDL(CAD) and HDL(Healthy) on the activation of endothelial anti- and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes. METHODS AND RESULTS: HDL was isolated from patients with stable CAD (HDL(sCAD)), an acute coronary syndrome (HDL(ACS)), and healthy subjects. HDL(Healthy) induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E-deficient mice in vivo. In contrast, HDL(sCAD) and HDL(ACS) did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen-activated protein kinase-mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDL(Healthy) were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDL(sCAD) and HDL(ACS) as mechanisms leading to altered effects on endothelial apoptosis. CONCLUSIONS: The present study demonstrates for the first time that HDL(CAD) does not activate endothelial antiapoptotic pathways, but rather stimulates potential endothelial proapoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease.
Asunto(s)
Apoptosis/fisiología , Enfermedad de la Arteria Coronaria/metabolismo , Endotelio Vascular/metabolismo , Lipoproteínas HDL/antagonistas & inhibidores , Lipoproteínas HDL/fisiología , Proteoma/fisiología , Transducción de Señal/fisiología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Apoptosis/genética , Enfermedad de la Arteria Coronaria/patología , Endotelio Vascular/patología , Femenino , Citometría de Flujo/métodos , Humanos , Lipoproteínas HDL/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Proteoma/genética , Transducción de Señal/genéticaRESUMEN
The srbi gene encodes a lipoprotein receptor with high affinity for high density lipoprotein that is mainly expressed in the liver and in steroidogenic tissues. Disruption of this gene in mice and mutations in humans lead to alterations in lipoprotein metabolism and/or fertility. During murine development, scavenger receptor class B member I (SR-BI) is present in the yolk sac and the placenta and is only expressed in the embryo itself late in gestation. In humans, it has been detected in trophoblast cells and placenta. Although the proportion of mice carrying a null mutation in SR-BI obtained from heterozygous intercrosses is lower than the expected by the Mendelian ratio, suggesting the involvement of this receptor in intrauterine development, the cause of this demise has remained unknown. In this work, we show that embryos lacking SR-BI exhibit a high prevalence of exencephaly with a sex bias toward females. Immunolocalization studies confirmed that SR-BI is not expressed in the embryo at early stages of development and allowed a more detailed description of its localization in the cells that mediate maternal-fetal transport of nutrients. SR-BI-null embryos contain less cholesterol than their wild-type littermates, suggesting the involvement of SR-BI in materno-fetal cholesterol transport. Newborn SR-BI-deficient pups exhibit intrauterine growth restriction, suggesting that this receptor is also important for fetal growth. Altogether, the results of our work suggest that the presence of SR-BI in extraembryonic tissues is involved in the maternal-fetal transport of cholesterol and/or other lipids with a role during neural tube closure and fetal growth.
Asunto(s)
Lipoproteínas HDL/deficiencia , Receptores de Lipoproteína/deficiencia , Receptores Depuradores de Clase B/deficiencia , Síndrome de Smith-Lemli-Opitz/embriología , Síndrome de Smith-Lemli-Opitz/metabolismo , Animales , Colesterol/metabolismo , Modelos Animales de Enfermedad , Femenino , Feto/anomalías , Feto/embriología , Feto/metabolismo , Humanos , Metabolismo de los Lípidos , Lipoproteínas HDL/genética , Masculino , Intercambio Materno-Fetal , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Embarazo , Receptores de Lipoproteína/genética , Receptores Depuradores de Clase B/genética , Síndrome de Smith-Lemli-Opitz/genéticaRESUMEN
An antibody against the lecithin:cholesterol acyltransferase (LCAT) enzyme, which negates cholesterol esterification in plasma, causing severe high-density lipoprotein deficiency (HD), was identified in a woman with a large-cell non-Hodgkin lymphoma. Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of the defective cholesterol esterification and HD. To our knowledge, an acquired LCAT deficiency leading to severe HD has not been reported previously in association with a malignant disease, and this patient represents the first such documented case.
Asunto(s)
Autoanticuerpos/sangre , Lipoproteínas HDL/deficiencia , Linfoma no Hodgkin/diagnóstico , Fosfatidilcolina-Esterol O-Aciltransferasa/inmunología , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apolipoproteína A-I/sangre , Apolipoproteína A-II/sangre , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Inmunoglobulina G/inmunología , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Linfoma no Hodgkin/tratamiento farmacológico , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Prednisona/uso terapéutico , Rituximab , Índice de Severidad de la Enfermedad , Triglicéridos/sangre , Vincristina/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Our purpose is to review recent publications in the area of marked human HDL deficiency, HDL particles, coronary heart disease (CHD), amyloidosis, the immune response, and kidney disease. RECENT FINDINGS: Lack of detectable plasma apolipoprotein (apo) A-I can be due to DNA deletions, rearrangements, or nonsense or frameshift mutations within the APOA1 gene resulting in a lack of apoA-I secretion. Such patients have marked HDL deficiency, normal levels of triglycerides and LDL cholesterol, and can have xanthomas and premature CHD. ApoA-I variants with amino acid substitutions, especially in the region of amino acid residues 50-93 and 170-178, have been associated with amyloidosis. Patients with homozygous Tangier disease have defective cellular cholesterol efflux due to mutations in the adenosine triphosphate-binding cassette transporter A1, detectable plasma apoA-I levels and prebeta-1 HDL in their plasma. They have decreased LDL cholesterol levels and can develop neuropathy and premature CHD. Patients with lecithin: cholesterol acyltransferase deficiency have both prebeta-1 and alpha-4 HDL present in their plasma and develop corneal opacities, anemia, proteinuria, and kidney failure. SUMMARY: Patients with marked HDL deficiency can have great differences in their clinical phenotype depending on the underlying defect.
Asunto(s)
Enfermedad Coronaria/metabolismo , Lipoproteínas HDL/deficiencia , Transportadoras de Casetes de Unión a ATP/metabolismo , Amiloidosis/genética , Amiloidosis/metabolismo , Apolipoproteína A-I/deficiencia , Apolipoproteína A-I/genética , Secuencia de Bases , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/genética , Enfermedad Coronaria/inmunología , Humanos , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismoRESUMEN
High levels of high-density lipoprotein (HDL) have protective effects against atherosclerosis and cardiovascular diseases. The postulated mechanism of action for these benefits is an enhanced reverse cholesterol transport. Apolipoprotein A-I (ApoA-I) is the major protein of HDL. The clinical benefits of raising ApoA-I/HDL have been clearly established by clinical and epidemiological studies. Despite these observations, there are not very effective pharmacological means for raising HDL. ApoA-I gene delivery by viral vectors seems a promising strategy to raise ApoA-I/HDL levels. Sustained gene expression in animals and humans has been attained using adeno-associated viral (AAV) vectors. The aim of the present study was to determine the efficiency, safety, and biological activity of human ApoA-I intramuscularly delivered using an AAV vector in mice. AAV serotype 8 vectors encoding for human ApoA-I transgene were administered intraportally and intramuscularly in ApoA-I- deficient animals. ApoA-I levels were measured every 2 weeks post administration. The effectiveness of the generated HDL was tested in vitro in cholesterol-loaded macrophages. The administration of the vectors resulted in a significant and sustained increase in ApoA-I and HDL plasma levels for up to 16 weeks at similar extent by both routes of administration. Activity of the generated HDL in removal of cholesterol from cholesterol-loaded macrophages was similar in both groups. Our data suggest that intramuscular AAV8-mediated gene transfer of human ApoA-I results in a significant and maintained increase in ApoA-I and functional HDL.
Asunto(s)
Apolipoproteína A-I/genética , Dependovirus/genética , Expresión Génica , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Lipoproteínas HDL/genética , Animales , Apolipoproteína A-I/sangre , Apolipoproteína A-I/deficiencia , Western Blotting , Línea Celular , Creatina Quinasa/sangre , Dependovirus/clasificación , Vectores Genéticos/toxicidad , Humanos , Inyecciones Intramusculares , Lipoproteínas HDL/sangre , Lipoproteínas HDL/deficiencia , Lipoproteínas LDL/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Oxidación-Reducción , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
OBJECTIVE: Lipoproteins modulate vascular cell function in inflammation. In this study, we analyzed whether plasma concentrations of lipoproteins and apolipoproteins in human sepsis are related to patient survival and the activation of blood monocytes and platelets. DESIGN: Observational study. SETTING: Medical and surgical intensive care units (ICU) of a university hospital. PATIENTS: 151 consecutive patients after sepsis criteria had been met for the first time. INTERVENTIONS: None. MEASUREMENTS: Plasma lipoproteins, apolipoproteins, platelet CD62P-expression, monocyte HLA-DR-expression, SAPS II-scores (Simplified Acute Physiology Score) and 30-day-mortality were recorded. RESULTS: Total cholesterol, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, apolipoprotein (apo)-AI and apo-B were all found to be significantly lower in non-survivors than in survivors. In contrast to other (apo)lipoproteins, apo-AI and HDL cholesterol further decreased in non-survivors during the ICU stay. Logistic regression analysis revealed apo-AI to be an independent predictor of 30-day-mortality. A significant inverse correlation was found for apo-AI/HDL-cholesterol and platelet activation. Later in the course of the disease, HLA-DR expression on monocytes correlated positively to apo-AI and apo-CI concentrations and inversely to the apo-E concentration. CONCLUSION: Low apo-AI is independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlates to increased platelet activation. Moreover, changes in apolipoproteins supposed to modulate lipopolysaccharide effects, such as apo-CI and apo-E, correlate to monocyte activation.
Asunto(s)
Apolipoproteína A-I , Apolipoproteínas B , Lipoproteínas HDL , Monocitos/inmunología , Activación Plaquetaria/inmunología , Sepsis , APACHE , Adulto , Anciano , Apolipoproteína A-I/sangre , Apolipoproteína A-I/deficiencia , Apolipoproteínas/deficiencia , Apolipoproteínas/inmunología , Apolipoproteínas B/sangre , Apolipoproteínas B/deficiencia , Colesterol/sangre , Colesterol/deficiencia , HDL-Colesterol/sangre , HDL-Colesterol/deficiencia , LDL-Colesterol/sangre , Femenino , Alemania/epidemiología , Antígenos HLA-DR/sangre , Humanos , Hipolipoproteinemias/sangre , Hipolipoproteinemias/complicaciones , Hipolipoproteinemias/inmunología , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/inmunología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Selectina-P/sangre , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Curva ROC , Sepsis/sangre , Sepsis/inmunología , Sepsis/mortalidad , Estadísticas no Paramétricas , Tasa de SupervivenciaRESUMEN
OBJECTIVE To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors. RESULTS A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1-1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1-1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05-1.18], P = 0.00017). CONCLUSIONS Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.
Asunto(s)
Glucemia/metabolismo , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Edad de Inicio , Anciano , Colesterol/sangre , Estudios Transversales , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/mortalidad , Dislipidemias/complicaciones , Dislipidemias/epidemiología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Lipoproteínas HDL/sangre , Lipoproteínas HDL/deficiencia , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores de Riesgo , Triglicéridos/sangreRESUMEN
OBJECTIVES: The objective was the identification and functional characterization of mutations in the ABCA1 gene in four patients with severe HDL deficiency. SUBJECTS: Patients were referred to the clinic because of almost complete HDL deficiency. METHODS: The ABCA1 gene was sequenced directly. The analysis of the ABCA1 protein, ABCA1 mRNA and ABCA1-mediated cholesterol efflux was performed in cultured fibroblasts. Intracellular localization of ABCA1 mutants was investigated in transfected HEK293 cells. RESULTS: Two patients were homozygous for mutations in the coding region of the ABCA1 gene, resulting in an amino acid substitution (p.A1046D) and a truncated protein (p.I74YFsX76). The third patient was homozygous for a splice site mutation in intron 35 (c.4773 + 1g>a), resulting in an in-frame deletion of 25 amino acids (del p.D1567_K1591) in ABCA1. These patients had clinical manifestations of accumulation of cholesterol in the reticulo-endothelial system. The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. A reduced ABCA1 protein content was observed in these cells, suggesting an increased intracellular degradation. The mutant p.W1699C was largely retained in the endoplasmic reticulum, when expressed in HEK293 cells. CONCLUSIONS: The homozygotes for mutations which abolish ABCA1 function showed overt signs of involvement of the reticulo-endothelial system. This was not the case in the compound heterozygote for missense mutations, suggesting that this patient retains some residual ABCA1 function that reduces cholesterol accumulation in the reticulo-endothelial system.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colesterol/metabolismo , Lipoproteínas HDL/deficiencia , Mutación Missense/genética , Transportador 1 de Casete de Unión a ATP , Adulto , Anciano , Sustitución de Aminoácidos , Apolipoproteína A-I/genética , Niño , Preescolar , Análisis Mutacional de ADN , Exones/genética , Femenino , Fibroblastos/metabolismo , Mutación del Sistema de Lectura , Humanos , Masculino , Persona de Mediana EdadRESUMEN
High-density lipoprotein (HDL) particles exert a spectrum of atheroprotective activities that can be deficient in type 2 diabetes. Key mechanisms leading to the formation of functionally deficient HDL involve 1) HDL enrichment in triglycerides and depletion in cholesteryl esters with conformational alterations of apolipoprotein A-I; 2) glycation of apolipoproteins and/or HDL-associated enzymes; and 3) oxidative modification of HDL lipids, apolipoproteins, and/or enzymes. Available data identify hypertriglyceridemia, with concomitant compositional modification of the HDL lipid core and conformational change of apolipoprotein A-I, as a driving force in functional alteration of HDL particles in type 2 diabetes. Therapeutic options for correcting HDL functional deficiency should target hypertriglyceridemia by normalizing circulating levels of triglyceride-rich lipoproteins.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Lipoproteínas HDL/deficiencia , Diabetes Mellitus Tipo 2/enzimología , Humanos , Lipoproteínas HDL/metabolismoRESUMEN
To elucidate the separate contributions of the lipolytic versus ligand-binding functions of hepatic lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL-WT) with mice expressing inactive HL (HL-S145G) in a background lacking endogenous HL and the LDLr (LDLr-KOxHL-KO). HL-WT and HL-S145G reduced (P < 0.05 for all) cholesterol (55% vs. 20%), non-HDL-cholesterol (63% vs. 22%), and apolipoprotein B (apoB; 34% vs. 16%) by enhancing the catabolism of autologous (125)I-apoB-intermediate density lipoprotein (IDL)/LDL (fractional catabolic rate in day(-1): 6.07 +/- 0.25, LDLr-KOxHL-WT; 4.76 +/- 0.30, LDLr-KOxHL-S145G; 3.70 +/- 0.13, LDLr-KOxHL-KO); HL-WT had a greater impact on the concentration, composition, particle size, and catabolism of apoB-containing lipoproteins (apoB-Lps) and HDL. Importantly, consistent with the changes in apoB-Lps, atherosclerosis in LDLr-KOxHL-KO mice fed a regular chow diet (RCD) was reduced by both HL-WT and HL-S145G (by 71% and 51% in cross-sectional analysis, and by 85% and 67% in en face analysis; P < 0.05 for all). These data identify physiologically relevant but distinct roles for the lipolytic versus ligand-binding functions of HL in apoB-Lp metabolism and atherosclerosis and demonstrate that their differential effects on these processes are mediated by changes in catabolism via non-LDLr pathways. These changes, evident even in the presence of apoE, establish an antiatherogenic role of the ligand-binding function of HL in LDLr-deficient mice.
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Aterosclerosis/prevención & control , Lipasa/metabolismo , Lipólisis , Hígado/enzimología , Receptores de LDL/deficiencia , Animales , Femenino , Ligandos , Lipoproteínas/sangre , Lipoproteínas/química , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/genética , Masculino , Ratones , Ratones Noqueados , ARN/genética , ARN/aislamiento & purificación , Receptores de LDL/genética , Receptores de Lipoproteína/deficiencia , Receptores de Lipoproteína/genética , Caracteres SexualesRESUMEN
Humans have innate immunity against Trypanosoma brucei brucei that is known to involve apolipoprotein L-I (APOL1). Recently, a case of T. evansi infection in a human was identified in India. We investigated whether the APOL1 pathway was involved in this occurrence. The serum of the infected patient was found to have no trypanolytic activity, and the finding was linked to the lack of APOL1, which was due to frameshift mutations in both APOL1 alleles. Trypanolytic activity was restored by the addition of recombinant APOL1. The lack of APOL1 explained the patient's infection with T. evansi.
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Apolipoproteínas/deficiencia , Apolipoproteínas/genética , Mutación del Sistema de Lectura , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/genética , Trypanosoma , Tripanosomiasis/genética , Secuencia de Aminoácidos , Animales , Apolipoproteína L1 , Apolipoproteínas/uso terapéutico , Humanos , Lipoproteínas HDL/uso terapéutico , Masculino , Datos de Secuencia Molecular , Proteínas Recombinantes/uso terapéutico , Trypanosoma/aislamiento & purificación , Tripanosomiasis/tratamiento farmacológicoRESUMEN
The role of transmembrane lipidtransporter molecules in the atherosclerotic process. The protective effect of high-density lipoprotein in the atherosclerotic process has been mainly attributed to its role in reverse cholesterol transport. Identification of mutations in the ATP-bindig casette transporter-A1 (ABCA1) as the genetic defect in genetic high-density lipoprotein-deficiency (Tangier disease) and selected patients with familiar hypoalphalipoproteinemia has generated interest in discovering the role of this lipid transporter molecule in the reverse cholesterol transport. It is well established, that the ABCA1 mediates cellular cholesterol efflux through transfer of phospholipids and cholesterol from the inner to the outer layer of the cell membrane, thus enabling the bindig to apolipoproteins. Previous studies showed that the ABCA1 is critically involved in cellular trafficking of cholesterol and phospholipids in total body of lipid homeostasis. In Tangier disease, the loss of the function of ABCA1, leads to an impaired formation of nascent high-density lipoprotein particles by preventing the release of cellular phospholipids and cholesterol to the acceptor apolipoprotein A1. This rare genetic disorder is characterized by a severe high-density lipoprotein deficiency, cholesterol deposition in macrophages and premature atherosclerosis. These findings implicate the ABCA1 as an important therapeutic target for preventing diseases that are associated with accelerated atherogenesis. The present review summarizes the current knowledge of the ABCA1, its pivotal role in the cholesterol homeostasis and preventing atherosclerosis.
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Transportadoras de Casetes de Unión a ATP/genética , Aterosclerosis/metabolismo , Proteínas Portadoras/metabolismo , Lipoproteínas HDL/deficiencia , Enfermedad de Tangier/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Apolipoproteína A-I/metabolismo , Aterosclerosis/etiología , Humanos , Macrófagos/metabolismo , Mutación , Fosfolípidos/metabolismo , Enfermedad de Tangier/complicaciones , Enfermedad de Tangier/genéticaRESUMEN
BACKGROUND: The aim of this study is to report an adverse systemic response associated with topical bimatoprost therapy. CASE REPORT: An otherwise healthy 58-year-old woman with primary open-angle glaucoma was started on bimatoprost drops once a day. Bimatoprost is a structural analog of prostaglandin F2 alpha-ethanolamide (PGF2a), a class of compounds that in systemic form has been associated with alterations in serum lipid levels. The patient subsequently experienced a significant decrease in her high-density lipoprotein (HDL) serum levels, which subsequently returned to normal on discontinuation of bimatoprost. CONCLUSIONS: This is the first published report of a possible association between topical bimatoprost therapy and decreased serum HDL levels. Because of the significantly increased risk of cardiovascular disease and morbidity associated with low HDL levels, further study is strongly indicated.
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Glaucoma de Ángulo Abierto/tratamiento farmacológico , Lípidos/administración & dosificación , Lipoproteínas HDL/sangre , Amidas , Bimatoprost , Biomarcadores/sangre , Cloprostenol/análogos & derivados , Femenino , Estudios de Seguimiento , Glaucoma de Ángulo Abierto/sangre , Humanos , Presión Intraocular/efectos de los fármacos , Lípidos/uso terapéutico , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/efectos de los fármacos , Persona de Mediana EdadRESUMEN
BACKGROUND: Although dyslipoproteinemia is associated with arterial atherothrombosis, little is known about plasma lipoproteins in venous thrombosis patients. METHODS AND RESULTS: We determined plasma lipoprotein subclass concentrations using nuclear magnetic resonance spectroscopy and antigenic levels of apolipoproteins AI and B in blood samples from 49 male venous thrombosis patients and matched controls aged <55 years. Venous thrombosis patients had significantly lower levels of HDL particles, large HDL particles, HDL cholesterol, and apolipoprotein AI and significantly higher levels of LDL particles and small LDL particles. The quartile-based odds ratios for decreased HDL particle and apolipoprotein AI levels in patients compared with controls were 6.5 and 6.0 (95% CI, 2.3 to 19 and 2.1 to 17), respectively. Odds ratios for apolipoprotein B/apolipoprotein AI ratio and LDL cholesterol/HDL cholesterol ratio were 6.3 and 2.7 (95% CI, 1.9 to 21 and 1.1 to 6.5), respectively. When polymorphisms in genes for hepatic lipase, endothelial lipase, and cholesteryl ester transfer protein were analyzed, patients differed significantly from controls in the allelic frequency for the TaqI B1/B2 polymorphism in cholesteryl ester transfer protein, consistent with the observed pattern of lower HDL and higher LDL. CONCLUSIONS: Venous thrombosis in men aged <55 years old is associated with dyslipoproteinemia involving lower levels of HDL particles, elevated levels of small LDL particles, and an elevated ratio of apolipoprotein B/apolipoprotein AI. This dyslipoproteinemia seems associated with a related cholesteryl ester transfer protein genotype difference.