Cholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cells

The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.

Validation of a single-extraction procedure for sequential analysis of vitamin E, cholesterol, fatty acids, and total fat in seafood

Food lipid major components are usually analyzed by individual methodologies using diverse extractive procedures for each class. A simple and fast extractive procedure was devised for the sequential analysis of vitamin E, cholesterol, fatty acids, and total fat estimation in seafood, reducing analyses time and organic solvent consumption. Several liquid/liquid-based extractive methodologies using chlorinated and non-chlorinated organic solvents were tested. The extract obtained is used for vitamin E quantification (normal-phase HPLC with fluorescence detection), total cholesterol (normal-phase HPLC with UV detection), fatty acid profile, and total fat estimation (GC-FID), all accomplished in <40 min. The final methodology presents an adequate linearity range and sensitivity for tocopherol and cholesterol, with intra- and inter-day precisions (RSD) from 3 to 11 % for all the components. The developed methodology was applied to diverse seafood samples with positive outcomes, making it a very attractive technique for routine analyses in standard equipped laboratories in the food quality control field.

Long-Term and Concentration-Dependent Beneficial Effect of Efavirenz on HDL-Cholesterol in HIV-Infected Patients

AIMS: To investigate the long-term effects of efavirenz on cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL-C) and triglycerides (TG). METHODS: Thirty-four HIV-infected patients who commenced efavirenz therapy were monitored for 36 months. RESULTS: In patients with baseline HDL-C<40 mg.dL-1 an increase in HDL-C from 31+/-1 mg.dL-1 to 44+/-2 mg.dL-1 (95% confidence interval 5.9, 21.9, P<0.01) was observed and remained throughout the follow-up period. Median efavirenz plasma concentration was 1.98 mg.L-1 and a direct correlation between percentage of HDL-C variation or TC/HDL-C ratio and efavirenz plasma concentrations was found. CONCLUSIONS: There is evidence of a long-term and concentration-dependent beneficial effect of efavirenz on HDL-C in HIV-infected patients.

Serum proteins and fractions, HDL-cholesterol and total IgG and IgE levels in cases of acute and chronic paracoccidioidomycosis

This study evaluated serum protein fractions, HDL-cholesterol, total immunoglobulin G and total immunoglobulin E levels in patients with acute and chronic paracoccidioidomycosis, by means of electrophoresis, enzymatic reaction and immunoenzymatic assay. The results demonstrated elevated levels of total immunoglobulin G, total immunoglobulin E, alpha-2 and gamma-globulins, which were more evident in acute than in chronic PCM, but no increase in HDL-cholesterol levels. There was a correlation between the levels of total immunoglobulin E and gamma-globulins and the alpha-2 and beta-globulin fractions in the acute form and between beta and gamma-globulins in both the acute and the chronic form. In conclusion, changes in total immunoglobulin G and immunoglobulin E levels and in the electrophoretic profile may be important markers for the prognosis and therapeutic follow-up of PCM cases, especially because protein electrophoresis is a simple laboratory test that can be applied when specific PCM serological tests are not available. In addition, levels of the gamma-globulin fraction greater than 2.0g/dl may suggest that the patient is developing a more severe form of PCM.

PANDORA - Survey of Brazilian cardiologists about cholesterol reduction

OBJECTIVE: To report about a group of physicians' understanding of the recommendations of the II Brazilian Guidelines Conference on Dyslipidemias, and about the state of the art of primary and secondary prevention of atherosclerosis. METHODS: Through the use of a questionnaire on dyslipidemia, atherosclerosis prevention, and recommendations for lipid targets established by the II Brazilian Guidelines Conference on Dyslipidemias, 746 physicians, 98% cardiologists, were evaluated. RESULTS:Eighty-seven percent of the respondents stated that the treatment of dyslipidemia changes the natural history of coronary disease. Although most of the participants followed the total cholesterol recommendations (<200mg/dL for atherosclerosis prevention), only 55.8% would adopt the target of LDL-C <100 mg/dL for secondary prevention. Between 30.5 and 36.7% answered, in different questions, that the recommended level for HDL-C should be <35mg/dL. Only 32.7% would treat their patients indefinitely with lipid- lowering drugs. If the drug treatment did not reach the proposed target, only 35.5% would increase the dosage, and 29.4% would change the medication. Participants did not know the targets proposed for diabetics. CONCLUSION: Although the participating physicians valued the role played by lipids in the prevention of atherosclerosis, serious deficiencies exist in their knowledge of the recommendations given during the II Brazilian Guidelines Conference on Dyslipidemias.

Cholesterol pericarditis. A specific but rare cause of pericardial disease

During a diagnostic investigation in a 40-year-old male with pericardial effusion associated with hypothyroidism, cholesterol pericarditis was detected. We report a brief review on the etiopathogeny, clinical findings, and therapeutical possibilities of this entity.

Impact of nutritional counseling in reducing serum cholesterol in public health service patients

OBJECTIVE: To assess the impact of nutritional attention on the lipid profile and nutritional status of hypercholesterolemic patients attended in health centers of Belo Horizonte. METHODS: Using nutritional attendance patient record cards from two health units, the evolution of the lipid profile and the nutritional state (BMI) was monitored of 96 hypercholesterolemic patients who received diet. The patients were appraised at the following moments: initial (1st consultation), after 3 months (2nd consultation) and last consultation (variable for each patient). RESULTS: On the first attendance, 44,4% of the patients presented not only high total cholesterol and LDL-c, but also hypertriglyceridemia and 70.3% were overweight or obese, but most patients (75.6%) presented adequate HDL-c levels. There was significant reduction in the BMI, total cholesterol, LDL-c values (p < 0.01) and also in the triglyceride levels (p < 0.05) in the first three months, without alteration in the HDL-c levels. A significant reduction (p < 0.01) was observed in the frequency of individuals with high cholesterol (from 89.6% down to 47.9%), high and very high LDL-c (from 82.6% down to 45.7%), as well as high and very high triglyceride (from 43.6% down to 16.7%). The observed reduction in frequency of the low HDL-c was statistically meaningless. CONCLUSION: This study evidences the effect of the nutritional attention on lipid profile in hypercholesterolemic patients, reinforcing the need for a multiprofessional team to attend them at the public health services.

National alert campaign about increased cholesterol: determination of cholesterol levels in 81,262 Brazilians

OBJECTIVE: To determine the levels of total cholesterol in a significant sample of the Brazilian population. METHODS: Blood cholesterol was determined in 81.262 individuals > 18 years old (51% male, 44.7 ± 15.7 years), using Accutrend equipment, in the cities São Paulo, Campinas, Campos do Jordão, São José dos Campos, Santos, Santo André, Ribeirão Preto, Porto Alegre, Rio de Janeiro, Belo Horizonte, Curitiba, Brasília, Salvador and documented in the presence of other risk factors (RF) for coronary artery disease (CAD) (systemic hypertension, CAD in the family, smoking, and diabetes). Participants were classified according to sex, age, and the presence or absence of RF, respectively, as 0 RF, 1 RF and > 2 RF. The percentage of individuals with cholesterol > 200 mg/dL and > 240 mg/dL was evaluated. RESULTS: The prevalence of individuals with 0, 1, and > 2 risk factors was 30% (n = 24,589), 36% (n =29,324), and 34% (n = 27,349) respectively, (P=0.657), and the mean total cholesterol of the population was 199.0 ± 35.0 mg/dL. Cholesterol levels above 200 and 240 mg/dL were found, respectively, in 40% (n = 32,515) and 13% (10.942) of individuals. The greater the number of risk factors the higher the levels of cholesterol (P<0.0001) and the greater the proportion of individuals with cholesterol > 200 mg/dL (P=0.032). No difference existed in the proportion of individuals with cholesterol > 240 mg/dL (P=0.11). CONCLUSION: A great percentage of individuals with cholesterol levels above those recommended to prevent coronary artery disease was found.

Cellular cholesterol efflux mediated by HDL isolated from subjects with low HDL levels and coronary artery disease

OBJECTIVE: The aim of this study was to verify whether HDL particles isolated from patients with coronary artery disease (CAD) and low HDL-C had diminished ability to promote cholesterol efflux from cultured cells compared with HDL isolated from subjects without CAD and with normal HDL-C. METHODS: Smooth muscle cells isolated from human aortas cultured and radiolabeled with ³H-cholesterol were loaded with cholesterol and incubated with increasing concentrations of HDL isolated from 13 CAD patients with low HDL-C (CAD group) or from 5 controls without CAD (C group). Efflux of cellular cholesterol was measured by cellular depletion of radiolabeled cholesterol and by the appearance of ³H-cholesterol into experimental medium expressed as a percentage of total labeled cholesterol. RESULTS: Cholesterol efflux increased with the amount of HDL present in the medium, and no difference was found between groups at various HDL protein concentrations: efflux was 28 ± 6.3% (C) and 25.5 ± 8.9% (CAD) with 25 mg/mL; 34 ± 4.3% (C) and 31.9 ± 6.6% (CD) with 50 mg/mL and 39.5 ± 3.5% (C) and 37.1 ± 4.4% (CAD) with 100 mg/mL, HDL. CONCLUSION: Because the HDL fraction of CAD patients with low HDL-C have normal ability to extract cholesterol from cells of the vessel wall, it is suggested that low HDL-C atherogenicity should be ascribed to diminished concentrations of HDL particles rather than to the qualitative properties of the HDL fraction.

Fatty Acid and Cholesterol Concentrations in Usually Consumed Fish in Brazil

Background: Several studies have demonstrated clinical benefits of fish consumption for the cardiovascular system. These effects are attributed to the increased amounts of polyunsaturated fatty acids in these foods. However, the concentrations of fatty acids may vary according to region. Objective: The goal of this study was to determine the amount of,cholesterol and fatty acids in 10 Brazilian fishes and in a non-native farmed salmon usually consumed in Brazil. Methods: The concentrations of cholesterol and fatty acids, especially omega-3, were determined in grilled fishes. Each fish sample was divided in 3 sub-samples (chops) and each one was extracted from the fish to minimize possible differences in muscle and fat contents. Results: The largest cholesterol amount was found in white grouper (107.6 mg/100 g of fish) and the smallest in badejo (70 mg/100 g). Omega-3 amount varied from 0.01 g/100 g in badejo to 0.900 g/100 g in weakfish. Saturated fat varied from 0.687 g/100 g in seabass to 4.530 g/100 g in filhote. The salmon had the greatest concentration of polyunsaturated fats (3.29 g/100 g) and the highest content of monounsaturated was found in pescadinha (5.98 g/100 g). Whiting and boyfriend had the best omega-6/omega 3 ratios respectively 2.22 and 1.19, however these species showed very little amounts of omega-3. Conclusion: All studied Brazilian fishes and imported salmon have low amounts of saturated fat and most of them also have low amounts of omega-3.

Hemorheological and Glycemic Parameters and HDL Cholesterol for the Prediction of Cardiovascular Events

Abstract Background: Hemorheological and glycemic parameters and high density lipoprotein (HDL) cholesterol are used as biomarkers of atherosclerosis and thrombosis. Objective: To investigate the association and clinical relevance of erythrocyte sedimentation rate (ESR), fibrinogen, fasting glucose, glycated hemoglobin (HbA1c), and HDL cholesterol in the prediction of major adverse cardiovascular events (MACE) and coronary heart disease (CHD) in an outpatient population. Methods: 708 stable patients who visited the outpatient department were enrolled and followed for a mean period of 28.5 months. Patients were divided into two groups, patients without MACE and patients with MACE, which included cardiac death, acute myocardial infarction, newly diagnosed CHD, and cerebral vascular accident. We compared hemorheological and glycemic parameters and lipid profiles between the groups. Results: Patients with MACE had significantly higher ESR, fibrinogen, fasting glucose, and HbA1c, while lower HDL cholesterol compared with patients without MACE. High ESR and fibrinogen and low HDL cholesterol significantly increased the risk of MACE in multivariate regression analysis. In patients with MACE, high fibrinogen and HbA1c levels increased the risk of multivessel CHD. Furthermore, ESR and fibrinogen were significantly positively correlated with HbA1c and negatively correlated with HDL cholesterol, however not correlated with fasting glucose. Conclusion: Hemorheological abnormalities, poor glycemic control, and low HDL cholesterol are correlated with each other and could serve as simple and useful surrogate markers and predictors for MACE and CHD in outpatients.

No interaction between alcohol consumption and HDL-related genes on HDL cholesterol levels.

OBJECTIVE: To assess the relationships and possible interactions between polymorphisms related to HDL levels and alcohol consumption. METHODS: Cross-sectional population-based study including 2863 women and 2546 men aged 35-75 years (CoLaus study). Alcohol intake was assessed by the reported alcohol consumption of the last 7 days. Nineteen candidate genes known to influence HDL levels were studied. RESULTS: Alcohol consumption increased HDL cholesterol levels in both genders. After multivariate adjustment for gender, age, body mass index, smoking, hypolipidaemic drug treatment, physical activity and alcohol consumption, APOA5, CETP, LIPC and LPL gene polymorphisms were significantly (10(-5) threshold) related with HDL cholesterol levels, while no genexalcohol intake interaction was found for all SNPs studied. ABCA1 polymorphisms were related to HDL cholesterol levels on bivariate analysis but the relationship was no longer significant after multivariate analysis. CONCLUSION: Our data confirm the association of alcohol consumption and of APOA5, CETP, LIPC and LPL gene polymorphisms with HDL cholesterol levels. Conversely, no genexalcohol consumption interactions were found, suggesting that the effect of alcohol consumption on HDL cholesterol levels is not mediated via a modulation of HDL related genes.

Cholestérol, pression artérielle et fumée de cigarette dans la population en Suisse: le projet MONICA. [Cholesterol, blood-pressure and cigarette-smoking in switzerland - the MONICA-project].

Elevated plasma cholesterol, high blood pressure and cigarette smoking are three major risk factors for coronary heart disease. Within the framework of Switzerland's participation in the multicenter study MONICA (MONItoring of trends and determinants in CArdiovascular disease), proposed by the WHO, a first risk factor survey was conducted in a representative sample of the population (25-74 years) of two reporting units (cantons of Vaud and Fribourg, canton of Tessin). A high blood cholesterol level (>6,7 mmol/l) is the most common risk factor for coronary heart disease among the studied population. Among men, about 13% have elevated blood pressure, the proportion being about one in ten among women; these proportions increase with age and are slightly above these values in Tessin. Cigarette smoking is still a common behavior; between 25 and 45 years one third of the population (male and female) regularly smoke cigarettes.