Effects of SNVs in ABCA1, ABCG1, ABCG5, ABCG8, and SCARB1 Genes on Plasma Lipids, Lipoproteins, and Adiposity Markers in a Brazilian Population.

Several proteins are involved in cholesterol homeostasis, as scavenger receptor class B type I and ATP-binding cassette (ABC) transporters including ABCA1, ABCG1, ABCG5, and ABCG8. This study aimed to determine the effects of single nucleotide variants (SNVs) rs2275543 (ABCA1), rs1893590 (ABCG1), rs6720173 (ABCG5), rs6544718 (ABCG8), and rs5888 (SCARB1) on plasma lipids, lipoproteins, and adiposity markers in an asymptomatic population and its sex-specific effects. Volunteers (n = 590) were selected and plasma lipids, lipoproteins, and adiposity markers (waist-to-hip and waist-to-height ratios, lipid accumulation product and body adiposity index) were measured. Genomic DNA was isolated from peripheral blood cells according to the method adapted from Gross-Bellard. SNVs were detected in the TaqMan® OpenArray® Real-Time polymerase chain reaction platform and data analyses were performed using the TaqMan® Genotyper Software. The rs2275543*C point to an increase of high-density lipoprotein size in females while in males very-low-density lipoprotein, cholesterol, and triglycerides were statistically lower (P value < 0.05). The rs1893590*C was statistically associated with lower apolipoprotein A-I levels and higher activities of paraoxonase-1 and cholesteryl ester transfer protein (P value < 0.05). The rs6720173 was statistically associated with an increase in cholesterol and low-density lipoprotein cholesterol in males; moreover, rs6544718*T reduced adiposity markers in females (P value < 0.05). Regarding the rs5888, a decreased adiposity marker in the total population and in females occurred (P value < 0.05). Multivariate analysis of variance showed that SNVs could influence components of high-density lipoprotein metabolism, mainly through ABCG1 (P value < 0.05). The ABCA1 and ABCG5 variants showed sex-specific effects on lipids and lipoproteins, while SCARB1 and ABCG8 variants might influence adiposity markers in females. Our data indicate a possible role of ABCG1 on HDL metabolism.

Lipase C, Hepatic Type -250A/G (rs2070895) Variant Enhances Carotid Atherosclerosis in Normolipidemic and Asymptomatic Individuals from Brazil.

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.

p.Q192R SNP of PON1 seems not to be Associated with Carotid Atherosclerosis Risk Factors in an Asymptomatic and Normolipidemic Brazilian Population Sample / O SNP p.Q192R da PON1 não Parece Associar-se a Fatores de Risco para a Aterosclerose Carotídea em Amostra de População Brasileira Normolipidêmica e Assintomática

Evidences suggest that paraoxonase 1 (PON1) confers important antioxidant and anti-inflammatory properties when associated with high-density lipoprotein (HDL).

p.Q192R SNP of PON1 seems not to be Associated with Carotid Atherosclerosis Risk Factors in an Asymptomatic and Normolipidemic Brazilian Population Sample.

BACKGROUND: Evidences suggest that paraoxonase 1 (PON1) confers important antioxidant and anti-inflammatory properties when associated with high-density lipoprotein (HDL). OBJECTIVE: To investigate the relationships between p.Q192R SNP of PON1, biochemical parameters and carotid atherosclerosis in an asymptomatic, normolipidemic Brazilian population sample. METHODS: We studied 584 volunteers (females n = 326, males n = 258; 19-75 years of age). Total genomic DNA was extracted and SNP was detected in the TaqMan® SNP OpenArray® genotyping platform (Applied Biosystems, Foster City, CA). Plasma lipoproteins and apolipoproteins were determined and PON1 activity was measured using paraoxon as a substrate. High-resolution ß-mode ultrasonography was used to measure cIMT and the presence of carotid atherosclerotic plaques in a subgroup of individuals (n = 317). RESULTS: The presence of p.192Q was associated with a significant increase in PON1 activity (RR = 12.30 (11.38); RQ = 46.96 (22.35); QQ = 85.35 (24.83) µmol/min; p < 0.0001), HDL-C (RR= 45 (37); RQ = 62 (39); QQ = 69 (29) mg/dL; p < 0.001) and apo A-I (RR = 140.76 ± 36.39; RQ = 147.62 ± 36.92; QQ = 147.49 ± 36.65 mg/dL; p = 0.019). Stepwise regression analysis revealed that heterozygous and p.192Q carriers influenced by 58% PON1 activity towards paraoxon. The univariate linear regression analysis demonstrated that p.Q192R SNP was not associated with mean cIMT; as a result, in the multiple regression analysis, no variables were selected with 5% significance. In logistic regression analysis, the studied parameters were not associated with the presence of carotid plaques. CONCLUSION: In low-risk individuals, the presence of the p.192Q variant of PON1 is associated with a beneficial plasma lipid profile but not with carotid atherosclerosis.

HDL size is more accurate than HDL cholesterol to predict carotid subclinical atherosclerosis in individuals classified as low cardiovascular risk.

BACKGROUND: Misclassification of patients as low cardiovascular risk (LCR) remains a major concern and challenges the efficacy of traditional risk markers. Due to its strong association with cholesterol acceptor capacity, high-density lipoprotein (HDL) size has been appointed as a potential risk marker. Hence, we investigate whether HDL size improves the predictive value of HDL-cholesterol in the identification of carotid atherosclerotic burden in individuals stratified to be at LCR. METHODS AND FINDINGS: 284 individuals (40-75 years) classified as LCR by the current US guidelines were selected in a three-step procedure from primary care centers of the cities of Campinas and Americana, SP, Brazil. Apolipoprotein B-containing lipoproteins were precipitated by polyethylene glycol and HDL size was measured by dynamic light scattering (DLS) technique. Participants were classified in tertiles of HDL size (<7.57; 7.57-8.22; >8.22 nm). Carotid intima-media thickness (cIMT) <0.90 mm (80th percentile) was determined by high resolution ultrasonography and multivariate ordinal regression models were used to assess the association between cIMT across HDL size and levels of lipid parameters. HDL-cholesterol was not associated with cIMT. In contrast, HDL size >8.22 nm was independently associated with low cIMT in either unadjusted and adjusted models for age, gender and Homeostasis Model Assessment 2 index for insulin sensitivity, ethnicity and body mass index (Odds ratio 0.23; 95% confidence interval 0.07-0.74, p = 0.013). CONCLUSION: The mean HDL size estimated with DLS constitutes a better predictor for subclinical carotid atherosclerosis than the conventional measurements of plasma HDL-cholesterol in individuals classified as LCR.

Increased 27-hydroxycholesterol plasma level in men with low high density lipoprotein-cholesterol may circumvent their reduced cell cholesterol efflux rate.

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.

Chemical modification of high density lipoprotein subfractions - HDL2 and HDL3 - after use of atorvastatin.

Regardless of its effect on the concentrations of serum cholesterol, statins exert pleiotropic effects, including the regulation of endothelial function, reduced oxidative stress and inflammation, as well as a slight improvement in the concentrations of high density lipoprotein (HDL). However, its role on the composition of HDL is not yet established. The aim of this study was to evaluate the composition of HDL subfractions, HDLsub>2 and HDL3, after 14 days of placebo and atorvastatin (10 mg/day) use in 30 asymptomatic volunteers. The serum parameters and the HDL subfractions compositions were determined using radiometric, nephelometric and biochemical enzymatic methods. We observed significant reductions of total cholesterol, low density lipoprotein (LDL) and apolipoprotein B-100 by 28%, 40% and 38%, respectively. The analyses of chemical composition of the subfractions revealed a lower lipid protein ratio in HDL2, suggesting enrichment in proteins, and also lower in HDL3, probably by an increase in the number of particles. Several mechanisms can be suggested for the effects observed after the use of atorvastatin, such as a possible action on the reverse cholesterol transport (decreased activity of hepatic lipase and increased phospholipid transfer protein, PLTP), which would explain the enrichment of HDL. The results suggest that statin use may be relevant in the primary prevention of atherosclerosis not only by its lowering effect on LDLcholesterol and its anti-inflammatory effect but also by beneficial changes in HDL subfractions.

Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects.

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.

Plasma 27-hydroxycholesterol/cholesterol ratio is increased in low high density lipoprotein-cholesterol healthy subjects.

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.

Impact of seasonality on the prevalence of dyslipidemia: a large population study.

Assessment of lipid profile parameters has been considered a cornerstone in classifying individuals and populations at risk for cardiovascular disease. Recently, however, preliminary data have raised the possibility of seasonal variations in these parameters, which may cause under- or overestimation. Biological rhythms and seasonal variation of lipid profile was investigated in 227 359 consecutive individuals who underwent health checkups in primary care centers between 2008 and 2010. Plasma low-density lipoprotein cholesterol (LDL-C) >130 mg/dL was 8% more prevalent during winter than summer, with a larger difference among women and middle-aged adults (p < 0.001). High-density lipoprotein cholesterol (HDL-C) <40 mg/dL and triglycerides (TG) >150 mg/dL were respectively 9% and 5% more prevalent during the summer (p < 0.001). Variation amplitude was 3.4 ± 0.3 mg/dL for HDL-C (p = 0.005), 7 ± 2 mg/dL for LDL-C (p = 0.047), and 12 ± 9 mg/dL for TG (p = 0.058). Based on a large population sample, this study confirms the existence of biological rhythms and seasonal variation in lipid profile. This finding must be particularly accounted for in cross-sectional analyses of relative risk, prevalence, or the rate of goal achievement for lipid parameters.

Development of a clinical laboratory data base of hyper and hypo alpha lipoproteins in Campinas-SP and neighboring region / Construção de um banco de dados clínico laboratorial de hiper e hipoalfalipoproteinêmicos em Campinas-SP e região

INTRODUCTION: The development of research for diagnosis, prevention and treatment of atherosclerotic cardiovascular disease is of utmost importance due to the fact that it is the main cause of morbidity and mortality in Brazil. OBJECTIVE: To demonstrate the phases of the selection process for candidates with the aim to develop a clinical-laboratorial database of hyper alpha lipoproteinemic patients (hyper A) - high density lipoprotein cholesterol (HDL-C) ≥ 68 mg/dl) and hypo alpha lipoproteinemic patients (hypo A) - HDL-C < 39 mg/dl. MATERIAL AND METHODS: The volunteers were contacted after selection of lipid profiles from individuals treated at the Sistema Único de Saúde (SUS), Campinas-SP and neighboring area. Afterwards, the selected patients went through blood collection, clinical examinations and answered questionnaires on dietary frequency and physical activity. After this preliminary evaluation, some individuals were convened to another blood collection and, subsequently, were submitted to an ultrasonographic exam of the carotid arteries. RESULTS: Only 0.6% and 0.3% from 598,288 lipid profiles were selected for hyper A and hypo A groups, respectively, including gender disparity. Lack of effective questionnaires (75%), missing calls (60%) and non-inclusion were the major hindrances in the construction of this database. DISCUSSION: The difficulties to obtain eligible candidates were also due to the low prevalence of both groups hypo A and hyper A and the high prevalence of pathologies that contribute to non-genetic variations of HDL-C. CONCLUSION: In spite of the obstacles in the development of this database, this study brought about several scientific publications. Furthermore, the development of molecular analyzes and functionality will shortly generate other findings, contributing to the diagnosis and follow-up of HDL dyslipidemias.

INTRODUÇÃO: O desenvolvimento de pesquisa para diagnóstico e prevenção da doença aterosclerótica cardiovascular no Brasil é de grande importância por esta ser a principal causa de morbimortalidade no país. OBJETIVO: Demonstrar as etapas do processo de seleção de voluntários para a construção de um banco de dados clínico-laboratorial de indivíduos hiperalfalipoproteinêmicos (hiper A) - colesterol da lipoproteína de alta densidade (HDL-C) ≥ 68 mg/dl - e hipoalfalipoproteinêmicos (hipo A) - HDL-C < 39 mg/dl. MATERIAL E MÉTODOS: Os voluntários são contatados a partir de resultados de perfis lipídicos de indivíduos atendidos pelo Sistema Único de Saúde (SUS) de Campinas-SP e região e, se selecionados, são convidados para coleta de sangue, exames clínicos e responder a questionários de atividade física e de frequência alimentar. Após essa avaliação, os indivíduos podem ser convocados para nova coleta de sangue e, posteriormente, para a ultrassonografia de carótidas. RESULTADOS: Entre 598.288 perfis lipídicos recebidos das redes públicas, apenas 0,6% e 0,3% compuseram os nossos grupos hiper A e hipo A, com disparidade entre os gêneros. A falta de questionários efetivos (75%), das chamadas não atendidas (60%) e a não inclusão foram os pontos mais difíceis na construção do banco de dados. DISCUSSÃO: A dificuldade de obtenção de voluntários elegíveis também se deve à baixa prevalência de hipo A e hiper A e à alta prevalência de patologias que contribuem para variações não genéticas do HDL-C. CONCLUSÃO: Apesar das dificuldades na criação da base de dados, este estudo gerou várias publicações e, com o desenvolvimento das análises moleculares e da funcionalidade, muitas outras seguirão em curto período, fatos contribuintes para o diagnóstico e o acompanhamento das dislipidemias envolvendo a HDL.

Efeitos da atorvastatina e do polimorfismo T-786C do gene eNOS sobre parâmetros do metabolismo lipídico plasmático / Effects of atorvastatin and T-786C polymorphism of eNOS gene on plasma metabolic lipid parameters

FUNDAMENTO: A atividade do óxido nítrico sintase endotelial (eNOS) pode ser modulada pelo colesterol da lipoproteína de alta densidade (HDL-C), estatinas ou polimorfismos, como o T-786C de eNOS. OBJETIVO: Este estudo teve como objetivo avaliar se o polimorfismo T-786C está associado a alterações nos efeitos da atorvastatina no perfil lipídico, nas concentrações de metabólitos de óxido nítrico (NO) e da proteína C reativa de alta sensibilidade (PCR-as). MÉTODOS: Trinta voluntários do sexo masculino, assintomáticos, com idade entre 18-56 anos foram genotipados e classificados de acordo com a ausência (TT, n = 15) ou presença (CC, n = 15) do polimorfismo. Eles foram selecionados aleatoriamente para a utilização de placebo e atorvastatina (10 mg/dia por 14 dias). Após cada tratamento foram medidos lípides, lipoproteínas, frações HDL2 e HDL3, atividade da proteína de transferência de colesteril éster (CETP), metabólitos de NO e PCR-as. RESULTADOS: As comparações entre genótipos após a administração de placebo mostraram aumento da atividade da CETP polimorfismo-dependente (TT, 12 ± 7; CC, 22 ± 12, p < 0,05). As análises da interação entre os tratamentos indicaram que a atorvastatina tem efeito sobre colesterol, LDL, nitrito e razões lípides/proteínas (HDL2 e HDL3) (p < 0,001) em ambos os genótipos. É interessante notar as interações genótipo/droga sobre a CETP (p < 0,07) e a lipoproteína (a) [Lp(a)] (p < 0,056), levando a uma diminuição limítrofe da CETP, embora sem afetar a Lp(a). A PRC-as não mostrou alterações. CONCLUSÃO: Os resultados sugerem que o tratamento com estatinas pode ser relevante para a prevenção primária da aterosclerose em pacientes com o polimorfismo T-786C do eNOS, considerando os efeitos no metabolismo lipídico.

BACKGROUND: Endothelial nitric oxide synthase (eNOS) activity may be modulated by high-density lipoprotein cholesterol (HDL-C), statins or polymorphisms, such as the T-786C of eNOS. OBJECTIVE: This study aimed at evaluating if the T-786C polymorphism is associated with changes of atorvastatin effects on the lipid profile, on the concentrations of metabolites of nitric oxide (NO) and of high sensitivity C-reactive protein (hsCRP). METHODS: Thirty male volunteers, asymptomatic, aged between 18 and 56 years were genotyped and classified according to absence (TT, n = 15) or presence (CC, n = 15) of the polymorphism. They were randomly selected for the use of placebo or atorvastatin (10 mg/day/14 days). After each treatment lipids, lipoproteins, HDL2 and HDL3 composition, cholesteryl ester transfer protein (CETP) activity, metabolites of NO and hsCRP were evaluated. RESULTS: The comparisons between genotypes after placebo showed an increase in CETP activity in a polymorphism-dependent way (TT, 12±7; CC, 22±12; p < 0.05). The interaction analyses between treatments indicated that atorvastatin has an effect on cholesterol, LDL, nitrite and lipid-protein ratios (HDL2 and HDL3) (p < 0.001) in both genotypes. Interestingly, we observed genotype/drug interactions on CETP (p < 0.07) and lipoprotein (a) (Lp(a)) (p < 0.056), leading to a borderline decrease in CETP, but with no effect on Lp(a). HsCRP showed no alteration. CONCLUSION: These results suggest that statin treatment may be relevant for primary prevention of atherosclerosis in patients with the T-786C polymorphism of eNOS, considering the effects on lipid metabolism.

Effects of atorvastatin and T-786C polymorphism of eNOS gene on plasma metabolic lipid parameters.

BACKGROUND: Endothelial nitric oxide synthase (eNOS) activity may be modulated by high-density lipoprotein cholesterol (HDL-C), statins or polymorphisms, such as the T-786C of eNOS. OBJECTIVE: This study aimed at evaluating if the T-786C polymorphism is associated with changes of atorvastatin effects on the lipid profile, on the concentrations of metabolites of nitric oxide (NO) and of high sensitivity C-reactive protein (hsCRP). METHODS: Thirty male volunteers, asymptomatic, aged between 18 and 56 years were genotyped and classified according to absence (TT, n = 15) or presence (CC, n = 15) of the polymorphism. They were randomly selected for the use of placebo or atorvastatin (10 mg/day/14 days). After each treatment lipids, lipoproteins, HDL2 and HDL3 composition, cholesteryl ester transfer protein (CETP) activity, metabolites of NO and hsCRP were evaluated. RESULTS: The comparisons between genotypes after placebo showed an increase in CETP activity in a polymorphism-dependent way (TT, 12±7; CC, 22±12; p < 0.05). The interaction analyses between treatments indicated that atorvastatin has an effect on cholesterol, LDL, nitrite and lipid-protein ratios (HDL2 and HDL3) (p < 0.001) in both genotypes. Interestingly, we observed genotype/drug interactions on CETP (p < 0.07) and lipoprotein (a) (Lp(a)) (p < 0.056), leading to a borderline decrease in CETP, but with no effect on Lp(a). HsCRP showed no alteration. CONCLUSION: These results suggest that statin treatment may be relevant for primary prevention of atherosclerosis in patients with the T-786C polymorphism of eNOS, considering the effects on lipid metabolism.

The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis.

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a major role in lipid metabolism, but studies on the association of CETP polymorphisms with risks of cardiovascular disease are inconsistent. This study investigated whether the CETP gene I405V and Taq1B polymorphisms modified subclinical atherosclerosis in an asymptomatic Brazilian population sample. METHODS: The polymorphisms were analyzed using polymerase chain reaction in 207 adult volunteers. Serum lipid profiles, oxLDL Ab titers, C-reactive protein and tumor necrosis factor-α concentrations and CETP and phospholipid transfer protein (PLTP) activities were determined, and common carotid artery intima-media thickness (cIMT) was measured using ultrasonography. RESULTS: No differences in cIMT were observed between the presence or absence of the minor B2 and V alleles in either polymorphism. However, inverse correlations between mean cIMT and CETP activity in the presence of these polymorphisms were observed, and positive correlations of these polymorphisms with PLTP activity and oxLDL Ab titers were identified. Moreover, logistic multivariate analysis revealed that the presence of the B2 allele was associated with a 5.1-fold (CI 95%, OR: 1.26 - 21.06) increased risk for cIMT, which was equal and above the 66th percentile and positively interacted with age. However, no associations with the V allele or CETP and PLTP activities were observed. CONCLUSIONS: None of the studied parameters, including CETP activity, explained the different relationships between these polymorphisms and cIMT, suggesting that other non-determined factors were affected by the genotypes and related to carotid atherosclerotic disease.

Oxidized low-density lipoproteins and their antibodies: relationships with the reverse cholesterol transport and carotid atherosclerosis in adults without cardiovascular diseases.

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.

Differences and similarities of postprandial lipemia in rodents and humans.

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.

A reduction of CETP activity, not an increase, is associated with modestly impaired postprandial lipemia and increased HDL-cholesterol in adult asymptomatic women.

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.