RESUMEN
The common genetic variant in the promoter region of the hepatic lipase gene [LIPC -250G/A(rs2070895)] has an ambiguous association with cardiovascular disease. In this context, our study was performed to identify the relationships between the rs2070895 with carotid atherosclerosis, plasma lipids, and parameters of reverse cholesterol transport. A total of 285 normolipidemic and asymptomatic participants from an initial sample of 598,288 individuals (inclusion criteria: LDL-C ≤130 mg/dL and triglycerides ≤150 mg/dL; age: 20-75 years, both genders; confirmation of clinical, anthropometric and laboratory data; attended all visits; DNA was achieved to perform genetic analysis) were enrolled and the rs2070895 variant was genotyped by TaqMan® OpenArray® Plataform. Carotid intima-media thickness and the screening of atherosclerotic plaques were determined by B-mode ultrasonography. The rs2070895 genotype frequencies were 0.44, 0.41, and 0.15 (GG, GA, and AA, respectively). Logistic regression analysis showed that the risk of having plaques was increased in participants carrying the AA or AG genotypes (OR = 3.90; 95% CI = 1.54-10.33), despite an increase in high-density lipoprotein cholesterol levels, HDL diameter and apolipoprotein A-I, as compared to the GG genotype. Hepatic lipase and endogenous lecithin cholesterol acyl transferase activities were reduced (38% and 19%, respectively) and lipoprotein lipase was increased by 30% (AA vs GG). Our results provide evidence that the AA or AG genotypes of the rs2070895 were associated with carotid atherosclerosis in apparently healthy participants, probably as a consequence of reduced reverse cholesterol transport and accumulation of HDL subfraction 2 rich in triglycerides and depleted in cholesteryl esters that could become dysfunctional.
Asunto(s)
Enfermedades de las Arterias Carótidas/genética , Lipasa/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Enfermedades Asintomáticas , Brasil , Enfermedades de las Arterias Carótidas/sangre , Colesterol/sangre , Femenino , Estudios de Asociación Genética , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: Recent data suggests that cholesteryl ester transfer protein (CETP) activity may interact with acute stress conditions via inflammatory-oxidative response and thrombogenesis. We investigated this assumption in patients with ST-elevation myocardial infarction (STEMI). METHODS: Consecutive patients with STEMI (n = 116) were enrolled <24-h of symptoms onset and were followed for 180 days. Plasma levels of C-reactive protein (CRP), interleukin-2 (IL-2), tumor necrosis factor (TNFα), 8-isoprostane, nitric oxide (NOx) and CETP activity were measured at enrollment (D1) and at fifth day (D5). Flow-mediated dilation (FMD) was assessed by ultrasound and coronary thrombus burden (CTB) was evaluated by angiography. RESULTS: Neither baseline nor the change of CETP activity from D1 to D5 was associated with CRP, IL-2, TNFα, 8-isoprostane levels or CTB. The rise in NOx from D1 to D5 was inferior [3.5(-1; 10) vs. 5.5(-1; 12); p < 0.001] and FMD was lower [5.9(5.5) vs. 9.6(6.6); p = 0.047] in patients with baseline CETP activity above the median value than in their counterparts. Oxidized HDL was measured by thiobarbituric acid reactive substances (TBARS) in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r = 0.72; p = 0.014) and FMD (r = -0.61; p = 0.046). High CETP activity at admission was associated with the incidence of sudden death and recurrent MI at 30 days (OR 12.8; 95% CI 1.25-132; p = 0.032) and 180 days (OR 3.3; 95% CI 1.03-10.7; p = 0.044). CONCLUSIONS: An enhanced CETP activity during acute phase of STEMI is independently associated with endothelial dysfunction and adverse clinical outcome.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/sangre , Endotelio Vascular/fisiopatología , Lipoproteínas HDL/sangre , Infarto del Miocardio/sangre , Oxígeno/química , Sustancias Reactivas al Ácido Tiobarbitúrico/química , Anciano , Angiografía , Proteína C-Reactiva/metabolismo , Dinoprost/análogos & derivados , Dinoprost/sangre , Endotelio Vascular/patología , Femenino , Humanos , Interleucina-2/sangre , Masculino , Persona de Mediana Edad , Óxido Nítrico/sangre , Estudios Prospectivos , Sistema de Registros , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangre , Enfermedades Vasculares/patologíaRESUMEN
OBJECTIVE: Acute phase response modifies high-density lipoprotein (HDL) into a dysfunctional particle that may favor oxidative/inflammatory stress and eNOS dysfunction. The present study investigated the impact of this phenomenon on patients presenting ST-elevation myocardial infarction (STEMI). METHODS: Plasma was obtained from 180 consecutive patients within the first 24-h of onset of STEMI symptoms (D1) and after 5 days (D5). Nitrate/nitrite (NOx) and lipoproteins were isolated by gradient ultracentrifugation. The oxidizability of low-density lipoprotein incubated with HDL (HDLaoxLDL) and the HDL self-oxidizability (HDLautox) were measured after CuSO4 co-incubation. Anti-inflammatory activity of HDL was estimated by VCAM-1 secretion by human umbilical vein endothelial cells after incubation with TNF-α. Flow-mediated dilation (FMD) was assessed at the 30(th) day (D30) after STEMI. RESULTS: Among patients in the first tertile of admission HDL-Cholesterol (<33 mg/dL), the increment of NOx from D1 to D5 [6.7(2; 13) vs. 3.2(-3; 10) vs. 3.5(-3; 12); p = 0.001] and the FMD adjusted for multiple covariates [8.4(5; 11) vs 6.1(3; 10) vs. 5.2(3; 10); p = 0.001] were higher than in those in the second (33-42 mg/dL) or third (>42 mg/dL) tertiles, respectively. From D1 to D5, there was a decrease in HDL size (-6.3 ± 0.3%; p < 0.001) and particle number (-22.0 ± 0.6%; p < 0.001) as well as an increase in both HDLaoxLDL (33%(23); p < 0.001) and HDLautox (65%(25); p < 0.001). VCAM-1 secretion after TNF-a stimulation was reduced after co-incubation with HDL from healthy volunteers (-24%(33); p = 0.009), from MI patients at D1 (-23%(37); p = 0.015) and at D30 (-22%(24); p = 0.042) but not at D5 (p = 0.28). CONCLUSION: During STEMI, high HDL-cholesterol is associated with a greater decline in endothelial function. In parallel, structural and functional changes in HDL occur reducing its anti-inflammatory and anti-oxidant properties.
Asunto(s)
Endotelio Vascular/patología , Lipoproteínas HDL/sangre , Infarto del Miocardio/sangre , Óxido Nítrico/química , Oxígeno/sangre , Vasodilatación , Anciano , Antioxidantes/química , Área Bajo la Curva , Glucemia/química , Estudios de Casos y Controles , Femenino , Humanos , Inflamación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Oxígeno/química , Fenotipo , Estudios Prospectivos , Sustancias Reactivas al Ácido Tiobarbitúrico , Resultado del TratamientoRESUMEN
BACKGROUND: Reduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation. OBJECTIVE: This study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C. METHODS: Asymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2. RESULTS: Eighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD. CONCLUSIONS: In these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291.
Asunto(s)
Dislipidemias/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Indoles/uso terapéutico , Niacina/farmacología , Vasodilatadores/farmacología , Anciano , HDL-Colesterol/sangre , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Niacina/administración & dosificación , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificaciónRESUMEN
BACKGROUND: HDL is considered the most important mechanism for the excretion of intracellular cholesterol. The liver is the only organ capable to metabolize cholesterol into bile acid. The enzymatic conversion of cholesterol to bile acid is dependent on the cytochrome P450 microsomal system which is also responsible for the generation of oxysterols. The latter's plasma concentrations may reflect the metabolic processes of specific tissues where they are generated. The objective of this study was to investigate in healthy individuals who differ according to their HDL levels the concentration of oxysterols and relate it to the HDL-dependent cell cholesterol efflux rate. METHODS: 24-Hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol were determined in plasma by GLC/mass spectrometry in 107 healthy subjects with low HDL (HDL-C<1.03mmol/l) and high HDL cholesterol (HDL-C>1.55mmol/l). HDL-dependent in vitro cell cholesterol efflux rate was measured in 29 cases. RESULTS: No differences were found in plasma oxysterol concentrations between the Low HDL and High HDL groups. There was a significant negative correlation between HDL-C and 27-hydroxycholesterol. Plasma oxysterol concentrations were significantly lower in female than in male subjects. The Low HDL male group had higher 27-hydroxycholesterol than the High HDL male group. Cell cholesterol efflux rate was lower in Low HDL than in High HDL and related inversely with 27-hydroxycholesterol. CONCLUSION: As compared to High HDL, Low HDL men have increased 27-hydroxycholesterol plasma level that may circumvent their reduced cell cholesterol efflux rate.
Asunto(s)
HDL-Colesterol/sangre , Hidroxicolesteroles/sangre , Hidroxicolesteroles/metabolismo , Adulto , Transporte Biológico , HDL-Colesterol/metabolismo , Femenino , Voluntarios Sanos , Humanos , Hígado/citología , Hígado/metabolismo , MasculinoRESUMEN
BACKGROUND: We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects. METHODS: We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-1HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption. RESULTS: In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-1HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities. CONCLUSIONS: These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.
Asunto(s)
HDL-Colesterol/sangre , Resistencia a la Insulina , Insulina/sangre , Adulto , Anciano , Biomarcadores/sangre , Brasil , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/deficiencia , VLDL-Colesterol/sangre , Femenino , Voluntarios Sanos , Humanos , Peso Corporal Ideal , Absorción Intestinal , Lipasa/sangre , Metabolismo de los Lípidos , Errores Innatos del Metabolismo Lipídico/sangre , Lipoproteína Lipasa/sangre , Masculino , Persona de Mediana Edad , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Proteínas de Transferencia de Fosfolípidos/sangre , Adulto JovenRESUMEN
UNLABELLED: Sterol 27-hydroxylase converts cholesterol to 27-hydroxycholesterol (27-OHC) which is widely distributed among tissues and is expressed at high levels in the vascular endothelium and macrophages. There is a continuous flow of this oxysterol from the tissues into the liver, where it is converted to bile acids. OBJECTIVE: Measure plasma concentrations of 27-OHC in subjects that differ according to their plasma HDL-C concentration. METHODS: Healthy men presenting low HDL-C (<1.03 mmol/L), n=18 or high HDL-C (>1.55 mmol/L), n=18, BMI<30 kg/m² were recruited after excluding secondary causes that might interfere with their plasma lipid concentrations such as smoking, heavy drinking and diabetes. Blood samples were drawn after a 12h fasting period for the measurement of 27-OHC by the combined GC/MS analysis utilizing deuterium-label internal standards. RESULTS: The plasma ratio 27-OHC/total cholesterol (median and range nmoL/mmoL) was 50.41 (27.47-116.00) in the High HDL-C subjects and 63.34 (36.46-91.18) in the Low HDL-C subjects (p=0.0258). CONCLUSION: Our data indicate that the production of 27-OHC by extrahepatic tissues and its transport to the liver may represent an alternative pathway for a deficient reverse cholesterol transport system when plasma HDL-C is low.
Asunto(s)
HDL-Colesterol/sangre , Hidroxicolesteroles/sangre , Hígado/metabolismo , Adulto , Anciano , Transporte Biológico , Ayuno , Cromatografía de Gases y Espectrometría de Masas , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Metabolic predictors and the atherogenicity of oxidized LDL (oxLDL) and the specific antibodies against oxLDL (oxLDL Ab) are unclear and controversial. METHODS: In 107 adults without atherosclerotic manifestations, we measured oxLDL and oxLDL Ab, and also the activities of CETP, PLTP, lipases and the carotid intima-media thickness (cIMT). Comparisons were performed for the studied parameters between the lowest and the highest tertile of oxLDL and oxLDL Ab, and the relationships between studied variables were evaluated. RESULTS: Subjects with higher oxLDL Ab present reduced hepatic lipase activity and borderline increased cIMT. In the highest oxLDL tertile, besides the higher levels of total cholesterol, LDL-C and apoB100, we found reduced CETP activity and higher cIMT. A significant correlation between oxLDL Ab and cIMT, independent of oxLDL, and a borderline correlation between oxLDL and cIMT independent of oxLDL Ab were found. In the multivariate analysis, apoAI was a significant predictor of oxLDL Ab, in contrast to regulation of oxLDL by apoB100, PLTP and inverse of CETP. CONCLUSIONS: In adults without atherosclerotic disease, the metabolic regulation and carotid atherosclerosis of oxLDL Ab and oxLDL groups, characterized a dual trait in oxLDL Ab, as a contributor to carotid atherosclerosis, much less so than oxidized LDL, and with a modest atheroprotective role.
Asunto(s)
Anticuerpos/sangre , Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/sangre , Colesterol/sangre , Lipoproteínas LDL/sangre , Adulto , Anciano , Análisis de Varianza , Apolipoproteína B-100/sangre , Transporte Biológico , Enfermedades de las Arterias Carótidas/fisiopatología , Grosor Intima-Media Carotídeo , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , LDL-Colesterol/sangre , Femenino , Humanos , Lipasa/metabolismo , Lipoproteínas LDL/inmunología , Hígado/metabolismo , Persona de Mediana Edad , Proteínas de Transferencia de Fosfolípidos/metabolismo , Factores de RiesgoRESUMEN
OBJECTIVE: Enhanced sodium intake increases volume overload, oxidative stress and production of proinflammatory cytokines. In animal models, increased sodium intake favours ventricular dysfunction after myocardial infarction (MI). The aim of this study was to investigate, in human subjects presenting with ST-segment elevation MI (STEMI), the impact of sodium intake prior the coronary event. METHODS: Consecutive patients (n=372) admitted within the first 24 h of STEMI were classified by a food intake questionnaire as having a chronic daily intake of sodium higher (HS) or lower (LS) than 1.2 g in the last 90 days before MI. Plasma levels of 8-isoprostane, interleucin-2 (IL-2), tumour necrosis factor type α (TNF-α), C-reactive protein (CRP) and brain natriuretic peptide (BNP) were measured at admission and at the fifth day. Magnetic resonance imaging was performed immediately after discharge. Total mortality and recurrence of acute coronary events were investigated over 4 years of follow-up. RESULTS: The decrease of 8-isoprostane was more prominent and the increase of IL-2, TNF-α and CRP less intense during the first 5 days in LS than in HS patients (p<0.05). Sodium intake correlated with change in plasma BNP between admission and fifth day (r=0.46; p<0.0001). End-diastolic volumes of left atrium and left ventricle were greater in HS than in LS patients (p<0.05). In the first 30 days after MI and up to 4 years afterwards, total mortality was higher in HS than in LS patients (p<0.05). CONCLUSION: Excessive sodium intake increases oxidative stress, inflammatory response, myocardial stretching and dilatation, and short and long-term mortality after STEMI.
Asunto(s)
Infarto del Miocardio/mortalidad , Sodio/administración & dosificación , Sodio/efectos adversos , Adulto , Proteína C-Reactiva/metabolismo , Forma MB de la Creatina-Quinasa/sangre , Dinoprost/análogos & derivados , Dinoprost/sangre , Femenino , Estudios de Seguimiento , Humanos , Interleucina-2/sangre , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/fisiopatología , Péptido Natriurético Encefálico/sangre , Estrés Oxidativo/fisiología , Factor de Necrosis Tumoral alfa/sangre , Remodelación Ventricular/fisiologíaRESUMEN
BACKGROUND: The relationship between CETP and postprandial hyperlipemia is still unclear. We verified the effects of varying activities of plasma CETP on postprandial lipemia and precocious atherosclerosis in asymptomatic adult women. METHODS: Twenty-eight women, selected from a healthy population sample (n = 148) were classified according to three CETP levels, all statistically different: CETP deficiency (CETPd ≤ 4.5%, n = 8), high activity (CETPi ≥ 23.8, n = 6) and controls (CTL, CETP ≥ 4.6% and ≤ 23.7%, n = 14). After a 12 h fast they underwent an oral fat tolerance test (40 g of fat/m² of body surface area) for 8 hours. TG, TG-rich-lipoproteins (TRL), cholesterol and TRL-TG measurements (AUC, AUIC, AR, RR and late peaks) and comparisons were performed on all time points. Lipases and phospholipids transfer protein (PLTP) were determined. Correlation between carotid atherosclerosis (c-IMT) and postprandial parameters was determined. CETP TaqIB and I405V and ApoE-ε3/ε2/ε4 polymorphisms were examined. To elucidate the regulation of increased lipemia in CETPd a multiple linear regression analysis was performed. RESULTS: In the CETPi and CTL groups, CETP activity was respectively 9 and 5.3 higher compared to the CETPd group. Concentrations of all HDL fractions and ApoA-I were higher in the CETPd group and clearance was delayed, as demonstrated by modified lipemia parameters (AUC, AUIC, RR, AR and late peaks and meal response patterns). LPL or HL deficiencies were not observed. No genetic determinants of CETP deficiency or of postprandial lipemia were found. Correlations with c-IMT in the CETPd group indicated postprandial pro-atherogenic associations. In CETPd the regression multivariate analysis (model A) showed that CETP was largely and negatively predicted by VLDL-C lipemia (R² = 92%) and much less by TG, LDL-C, ApoAI, phospholipids and non-HDL-C. CETP (model B) influenced mainly the increment in ApoB-100 containing lipoproteins (R² = 85% negatively) and phospholipids (R² = 13%), at the 6(th)h point. CONCLUSION: The moderate CETP deficiency phenotype included a paradoxically high HDL-C and its sub fractions (as earlier described), positive associations with c-IMT, a postprandial VLDL-C increment predicting negatively CETP activity and CETP activity regulating inversely the increment in ApoB100-containing lipoproteins. We hypothesize that the enrichment of TG content in triglyceride-rich ApoB-containing lipoproteins and in TG rich remnants increases lipoproteins' competition to active lipolysis sites,reducing their catabolism and resulting on postprandial lipemia with atherogenic consequences.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangre , Hiperlipidemias/complicaciones , Hiperlipidemias/fisiopatología , Periodo Posprandial/fisiología , Adulto , Área Bajo la Curva , Aterosclerosis/sangre , Aterosclerosis/complicaciones , Estudios de Casos y Controles , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , Ayuno/sangre , Femenino , Genotipo , Humanos , Hiperlipidemias/sangre , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple/genética , Túnica Íntima/patología , Túnica Media/patologíaRESUMEN
BACKGROUND: The rat has been a mainstay of physiological and metabolic research, and more recently mice. This study aimed at characterizing the postprandial triglyceride profile of two members of the Muridae family: the Wistar rats (Rattus norvegicus albinus) and C57BL/6 mice (Mus musculus) plus comparing them to the profile obtained in humans. METHODS: Thirty-one male and twelve female Wistar rats, ten C57BL/6 male and nine female mice received a liquid meal containing fat (17%), protein (4%) and carbohydrates (4%), providing 2 g fat/Kg. Thirty-one men and twenty-nine women received a standardized liquid meal containing fat (25%), dextromaltose (55%), protein (14%), and vitamins and minerals (6%), and providing 40 g of fat per square meter of body surface. Serial blood samples were collected at 2, 4, 6, 8 and 10 h after the ingestion in rats, at 1, 2, 3, 4, 5 and 6 h in mice and in humans at 2, 4, 6 and 8 h. Wilcoxon and Mann-Whitney tests were used. RESULTS/DISCUSSION: The triglyceride responses were evaluated after the oral fat loads. Fasting and postprandial triglyceridemia were determined sequentially in blood sample. AUC, AUIC, AR, RR and late peaks were determined. CONCLUSIONS: Rats are prone to respond in a pro-atherogenic manner. The responses in mice were closer to the ones in healthy men. This study presents striking differences in postprandial triglycerides patterns between rats and mice not correlated to baseline triglycerides, the animal baseline body weight or fat load in all animal groups.
Asunto(s)
Hiperlipidemias/fisiopatología , Periodo Posprandial/fisiología , Animales , Femenino , Humanos , Hiperlipidemias/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Wistar , Triglicéridos/sangreRESUMEN
Cholesteryl ester transfer protein (CETP) exerts a profound impact on high-density lipoprotein (HDL) metabolism and, consequently, on the risk of atherosclerosis development and cardiovascular mortality. Here, we review the complex relationship between CETP and atherosclerosis based upon the experimental, clinical, and epidemiological studies. In addition, we discuss the recent findings that expand the functions of CETP to new areas of interest such as Alzheimer's disease, inflammation, and obesity.
Asunto(s)
Aterosclerosis/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Adipogénesis , Enfermedad de Alzheimer/metabolismo , Animales , Aterosclerosis/tratamiento farmacológico , Colesterol/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/genética , Ensayos Clínicos como Asunto , Humanos , Inflamación/metabolismo , Lipoproteínas/metabolismo , Mutación , Obesidad/metabolismo , Oxidación-ReducciónRESUMEN
OBJECTIVES: Experimental and in vitro evidences have established that reactive oxygen species (ROS) generated by vascular wall cells play a key role in atherogenesis. Here, we evaluated the rate of ROS generation by resting peripheral monocytes in naive hyperlipidemic subjects. DESIGN AND METHODS: Primary hypercholesterolemic, combined hyperlipidemic, and normolipidemic individuals were studied. ROS generation and the mitochondrial electrical transmembrane potential were estimated by flow cytometry. Plasma oxidized (ox) LDL levels and lipid profile were measured by ELISA and enzymatic colorimetric methods. RESULTS: Both hyperlipidemic groups presented significantly higher rates of monocyte ROS generation and elevated plasma levels of ox-LDL. Combined hyperlipidemic subjects presented increased levels of small dense LDL and insulin. Significant positive correlations between monocyte ROS generation and ox-LDL concentrations were found in pooled data. CONCLUSIONS: These data provide evidence that ROS production by circulating monocytes from hyperlipidemic subjects may contribute to the systemic oxidative stress and possibly to atherogenesis.
Asunto(s)
Hiperlipidemias/sangre , Lipoproteínas LDL/sangre , Monocitos/metabolismo , Especies Reactivas de Oxígeno/sangre , Adulto , Femenino , Humanos , Lipoproteínas/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Few studies have evaluated seasonal variations of biochemical parameters routinely analyzed in clinical laboratories. Rhythmic patterns for lipids and lipoproteins have been demonstrated and have been the object of research, mainly because of their demonstrated association with coronary artery disease. This study evaluated the occurrence of biological rhythms on serum lipids and lipoproteins and the effects of sex and age on the rhythms in a Brazilian hospital outpatient population. METHODS: Retrospective laboratory study was carried out to evaluate the results of total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and triglycerides (TG), from individuals registered at a university referral hospital over 8 years. The studied population was composed of individuals of both sexes and all ages totaling 38,579 participants and 301,934 measurements. Statistical analyses were carried out using the SAS program and the temporal analysis used the Cosinor method. RESULTS: TG rhythm was present only in females. All other parameters were equally rhythmic in both sexes. Regarding age, HDL-C presented rhythms in all age groups, but TC and LDL-C showed seasonality only for those > 13 years, TG did not present rhythms in all age groups. CONCLUSION: Effects of sex and age on biological rhythms detected in TC, LDL-C and HDL-C should be considered a significant cause of pre-analytical variation in these laboratory tests.
Asunto(s)
Envejecimiento/sangre , Ritmo Circadiano , Lipoproteínas/sangre , Caracteres Sexuales , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pacientes AmbulatoriosRESUMEN
The purpose of this study was to assess metformin effects on high-density lipoprotein (HDL) composition of patients with HIV-associated lipodystrophy (LDHIV). Twenty-four adult outpatients were enrolled to receive metformin (1700 mg/d) during 6 months, but 2 were lost to follow-up and 6 stopped the drug due to adverse events (gastrointestinal in 5, and excessive weight loss in 1). From the 16 subjects who completed the study, 69% were female. At baseline, 3 and 6 months, we assessed: weight, waist and hip circumferences, blood pressure, fasting glucose and insulin, homeostasis model assessment of insulin resistance (HOMA2-IR), lipids, and HDL subfractions by microultracentrifugation. At 0 and 6 months, body fat distribution was assessed by computed tomography (CT) scan (L4 and middle femur). Metformin use was associated with reduction of mean weight (-2.4Kg at 6 months; p < 0.001), body mass index, waist, waist-to-hip ratio and a marked decrease in blood pressure (p < 0.001). Subcutaneous (p = 0.01) and total abdominal fat (p = 0.002) were reduced, but no change was found in visceral or thigh fat. No difference was detected on plasma glucose, insulin, HOMA2-IR, cholesterol or triglycerides, except for an increase in HDL3-cholesterol (from 21 mg/dL to 24 mg/dL, p = 0.002) and a reduction of nascent HDL (the fraction of plasma HDL-cholesterol not associated to subfractions HDL2 or HDL3) (p = 0.008). Adverse effects were very common, but most were gastrointestinal and mild. Thus, metformin use in LDHIV increases HDL3-cholesterol (probably due to improved maturation of HDL) and decreases blood pressure, weight, waist, and subcutaneous truncal fat, making this an attractive option for preventing cardiovascular disease in this population.
Asunto(s)
HDL-Colesterol/sangre , Síndrome de Lipodistrofia Asociada a VIH/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Adolescente , Adulto , Anciano , Distribución de la Grasa Corporal , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Metformina/efectos adversos , Persona de Mediana EdadRESUMEN
This study evaluated the serum concentrations of lipids, lipoproteins, apolipoproteins, and high-density lipoprotein (HDL) subfractions in Brazilian adults. We analyzed the distribution of lipids in HDL2 and HDL3 in a normolipidemic population without evidence of established cardiovascular disease (CVD). A total of 93 males and 92 females, healthy and normolipidemic, volunteered to be submitted to a clinical examination, a blood collection, and to answer a questionnaire aimed at determining signs and symptoms of atherosclerotic disease. Their fasting plasma lipid, lipoproteins, apolipoproteins, and the cholesterol and triglyceride concentrations in HDL2 and HDL3, isolated by microultracentrifugation, were determined by enzymatic-colorimetric methods. The interpercentile intervals (2.5-97.5) for the population were established as being 5-18 mg/dL in men and 4-28 mg/dL in women for HDL2 cholesterol (HDL2chol) and 1-57 mg/dL in men and 2-61 mg/dL in women for HDL3 cholesterol (HDL3chol). HDL2 triglyceride levels (HDL2Tg) in men were 1-26 mg/dL and in women 2-28 mg/dL; moreover, the HDL3 triglyceride (HDL3Tg) intervals were established as 4-46 mg/dL for both sexes. The determination of reference ranges for lipids in HDL subfractions in populations without clinical atherosclerosis, is an useful tool for metabolic, diagnostic, and therapeutic approaches. We determined the intervals for HDL2chol, HDL3chol, HDL2Tg, and HDL3Tg. There were variations with sex and/or age for HDL2chol, HDL3chol, and HDL2Tg in the studied population.
Asunto(s)
Lipoproteínas HDL/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Lipoproteínas HDL2 , Lipoproteínas HDL3 , Masculino , Persona de Mediana Edad , Valores de Referencia , Encuestas y Cuestionarios , Triglicéridos/sangreRESUMEN
BACKGROUND: Dyslipidemia is diagnosed through the determination of plasma lipid profiles. This study is aimed at establishing the prevalence of dyslipidemia in a Brazilian out-patient population by using a hospital laboratory cohort. METHODS: Lipid profiles of 22,542 individuals from both sexes, aged 20 to 124 years, and registered at the University Hospital of the State University of Campinas, a standard of reference for hospital treatment in the state of São Paulo, Brazil, were retrospectively analyzed from 2000 to 2003. The cut-off values for cholesterol (C), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were determined as recommended by the National Cholesterol Education Program. Statistical analyses were carried out using the SPSS program. RESULTS: Altered C, LDL-C and TG were found in 44%, 38% and 37% of adults and in 55%, 48% and 41% of the elderly, respectively; 35% of adults and 32% of the elderly presented undesirable low HDL-C. Combined dyslipidemia was very prevalent. CONCLUSION: Dyslipidemia was a serious public health problem in the studied population, especially among women and the elderly. The mixed phenotype of hypercholesterolemia and hypertriglyceridemia was the most prevalent. The results of this study were validated by their agreement with previously studied non-hospital Brazilian populations.
Asunto(s)
Dislipidemias/epidemiología , Laboratorios de Hospital , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Estudios de Cohortes , Dislipidemias/sangre , Femenino , Humanos , Metabolismo de los Lípidos , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Prevalencia , Caracteres SexualesRESUMEN
BACKGROUND: Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles. METHODS: In the present work, we evaluated the frequency and severity of dyslipidemia in 257 Brazilian HIV positive patients. Two hundred and thirty-eight (93%) were submitted to antiretroviral therapy (224 treated with protease inhibitors plus nucleoside reverse transcriptase inhibitors, 14 treated only with the latter, 12 naive and 7 had no records of treatment). The average time on drug treatment with antiretroviral therapy was 20 months. None of the patients was under lipid lowering drugs. Cholesterol, triglyceride, phospholipid and free fatty acids were determined by enzymatic colorimetric methods. Lipoprotein profile was estimated by the Friedewald formula and Fredrickson's phenotyping was obtained by serum electrophoresis on agarose. Apolipoprotein B and AI and lipoprotein "a" were measured by nephelometry. RESULTS: The Fredrickson phenotypes were: type IIb (51%), IV (41%), IIa (7%). In addition one patient was type III and another type V. Thirty-three percent of all HIV+ patients presented serum cholesterol levels >or= 200 mg/dL, 61% LDL-cholesterol >or= 100 mg/dL, 65% HDL-cholesterol below 40 mg/dL, 46% triglycerides >or= 150 mg/dL and 10% have all these parameters above the limits. Eighty-six percent of patients had cholesterol/HDL-cholesterol ratio >or= 3.5, 22% increased lipoprotein "a", 79% increased free fatty acids and 9% increased phospholipids. The treatment with protease inhibitors plus nucleoside reverse transcriptase inhibitors increased the levels of cholesterol and triglycerides in these patients when compared with naïve patients. The HDL-cholesterol (p = 0.01) and apolipoprotein A1 (p = 0.02) levels were inversely correlated with the time of protease inhibitor therapy while total cholesterol levels had a trend to correlate with antiretroviral therapy (p = 0.09). CONCLUSION: The highly varied and prevalent types of dyslipidemia found in Brazilian HIV positive patients on antiretroviral therapies indicate the urgent need for their early diagnosis, the identification of the risk factors for CHD and, when needed, the prompt intervention on their lifestyle and/or with drug treatment.
Asunto(s)
Infecciones por VIH/complicaciones , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo IV/complicaciones , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Brasil , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Hipercolesterolemia/inducido químicamente , Hiperlipoproteinemia Tipo III/complicaciones , Hiperlipoproteinemia Tipo V/complicaciones , Masculino , Fenotipo , Factores de Riesgo , Carga ViralRESUMEN
Atherosclerotic disease remains a leading cause of death in westernized societies, and reactive oxygen species (ROS) play a pivotal role in atherogenesis. Mitochondria are the main intracellular sites of ROS generation and are also targets for oxidative damage. Here, we show that mitochondria from atherosclerosis-prone, hypercholesterolemic low-density lipoprotein (LDL) receptor knockout mice have oxidative phosphorylation efficiency similar to that from control mice but have a higher net production of ROS and susceptibility to develop membrane permeability transition. Increased ROS production was observed in mitochondria isolated from several tissues, including liver, heart, and brain, and in intact mononuclear cells from spleen. In contrast to control mitochondria, knockout mouse mitochondria did not sustain a reduced state of matrix NADPH, the main source of antioxidant defense against ROS. Experiments in vivo showed faster liver secretion rates and de novo synthesis of triglycerides and cholesterol in knockout than in control mice, suggesting that increased lipogenesis depleted the reducing equivalents from NADPH and generated a state of oxidative stress in hypercholesterolemic knockout mice. These data provide the first evidence of how oxidative stress is generated in LDL receptor defective cells and could explain the increased LDL oxidation, cell death, and atherogenesis seen in familiar hypercholesterolemia.