PPAR-β/δ activation promotes phospholipid transfer protein expression.

The peroxisome proliferator-activated receptor (PPAR)-β/δ has emerged as a promising therapeutic target for treating dyslipidemia, including beneficial effects on HDL cholesterol (HDL-C). In the current study, we determined the effects of the PPAR-β/δ agonist GW0742 on HDL composition and the expression of liver HDL-related genes in mice and cultured human cells. The experiments were carried out in C57BL/6 wild-type, LDL receptor (LDLR)-deficient mice and PPAR-β/δ-deficient mice treated with GW0742 (10mg/kg/day) or a vehicle solution for 14 days. GW0742 upregulated liver phospholipid transfer protein (Pltp) gene expression and increased serum PLTP activity in mice. When given to wild-type mice, GW0742 significantly increased serum HDL-C and HDL phospholipids; GW0742 also raised serum potential to generate preβ-HDL formation. The GW0742-mediated effects on liver Pltp expression and serum enzyme activity were completely abolished in PPAR-β/δ-deficient mice. GW0742 also stimulated PLTP mRNA expression in mouse J774 macrophages, differentiated human THP-1 macrophages and human hepatoma Huh7. Collectively, our findings demonstrate a common transcriptional upregulation by GW0742-activated PPAR-β/δ of Pltp expression in cultured cells and in mouse liver resulting in enhanced serum PLTP activity. Our results also indicate that PPAR-β/δ activation may modulate PLTP-mediated preβ-HDL formation and macrophage cholesterol efflux.

Abacavir/Lamivudine Versus Tenofovir/Emtricitabine in Virologically Suppressed Patients Switching from Ritonavir-Boosted Protease Inhibitors to Raltegravir

There are few clinical data on the combination abacavir/lamivudine plus raltegravir. We compared the outcomes of patients from the SPIRAL trial receiving either abacavir/lamivudine or tenofovir/emtricitabine at baseline who had taken at least one dose of either raltegravir or ritonavir-boosted protease inhibitors. For the purpose of this analysis, treatment failure was defined as virological failure (confirmed HIV-1 RNA ≥50 copies/ml) or discontinuation of abacavir/lamivudine or tenofovir/emtricitabine because of adverse events, consent withdrawal, or lost to follow-up. There were 143 (72.59%) patients with tenofovir/emtricitabine and 54 (27.41%) with abacavir/lamivudine. In the raltegravir group, there were three (11.11%) treatment failures with abacavir/lamivudine and eight (10.96%) with tenofovir/emtricitabine (estimated difference 0.15%; 95% CI -17.90 to 11.6). In the ritonavir-boosted protease inhibitor group, there were four (14.81%) treatment failures with abacavir/lamivudine and 12 (17.14%) with tenofovir/emtricitabine (estimated difference -2.33%; 95% CI -16.10 to 16.70). Triglycerides decreased and HDL cholesterol increased through the study more pronouncedly with abacavir/lamivudine than with tenofovir/emtricitabine and differences in the total-to-HDL cholesterol ratio between both combinations of nucleoside reverse transcriptase inhibitors (NRTIs) tended to be higher in the raltegravir group, although differences at 48 weeks were not significant. While no patient discontinued abacavir/lamivudine due to adverse events, four (2.80%) patients (all in the ritonavir-boosted protease inhibitor group) discontinued tenofovir/emtricitabine because of adverse events (p=0.2744). The results of this analysis do not suggest that outcomes of abacavir/lamivudine are worse than those of tenofovir/emtricitabine when combined with raltegravir in virologically suppressed HIV-infected adults.

Inflammatory and metabolic responses to high-fat meals with and without dairy products in men.

Postprandial inflammation is an important factor for human health since chronic low-grade inflammation is associated with chronic diseases. Dairy products have a weak but significant anti-inflammatory effect on postprandial inflammation. The objective of the present study was to compare the effect of a high-fat dairy meal (HFD meal), a high-fat non-dairy meal supplemented with milk (HFM meal) and a high-fat non-dairy control meal (HFC meal) on postprandial inflammatory and metabolic responses in healthy men. A cross-over study was conducted in nineteen male subjects. Blood samples were collected before and 1, 2, 4 and 6 h after consumption of the test meals. Plasma concentrations of insulin, glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, TAG and C-reactive protein (CRP) were measured at each time point. IL-6, TNF-α and endotoxin concentrations were assessed at baseline and endpoint (6 h). Time-dependent curves of these metabolic parameters were plotted, and the net incremental AUC were found to be significantly higher for TAG and lower for CRP after consumption of the HFM meal compared with the HFD meal; however, the HFM and HFD meals were not different from the HFC meal. Alterations in IL-6, TNF-α and endotoxin concentrations were not significantly different between the test meals. The results suggest that full-fat milk and dairy products (cheese and butter) have no significant impact on the inflammatory response to a high-fat meal.

A short screener is valid for assessing mediterranean diet adherence among older spanish men and women

Ensuring the accuracy of dietary assessment instruments is paramount for interpreting diet-disease relationships. The present study assessed the relative and construct validity of the 14-point Mediterranean Diet Adherence Screener (MEDAS) used in the Prevencio´n con Dieta Mediterra´nea (PREDIMED) study, a primary prevention nutrition-intervention trial. A validated FFQ and the MEDAS were administered to 7146 participants of the PREDIMED study. The MEDASderived PREDIMED score correlated significantly with the corresponding FFQ PREDIMED score (r = 0.52; intraclass correlation coefficient = 0.51) and in the anticipated directions with the dietary intakes reported on the FFQ. Using Bland Altman"s analysis, the average MEDAS Mediterranean diet score estimate was 105% of the FFQ PREDIMED score estimate. Limits of agreement ranged between 57 and 153%. Multiple linear regression analyses revealed that a higher PREDIMED score related directly (P , 0.001) to HDL-cholesterol (HDL-C) and inversely (P , 0.038) to BMI, waist circumference, TG, the TG:HDL-C ratio, fasting glucose, and the cholesterol:HDL-C ratio. The 10-y estimated coronary artery disease risk decreased as the PREDIMED score increased (P , 0.001). The MEDAS is a valid instrument for rapid estimation of adherence to the Mediterranean diet and may be useful in clinical practice.

A short screener is valid for assessing mediterranean diet adherence among older spanish men and women

Ensuring the accuracy of dietary assessment instruments is paramount for interpreting diet-disease relationships. The present study assessed the relative and construct validity of the 14-point Mediterranean Diet Adherence Screener (MEDAS) used in the Prevencio´n con Dieta Mediterra´nea (PREDIMED) study, a primary prevention nutrition-intervention trial. A validated FFQ and the MEDAS were administered to 7146 participants of the PREDIMED study. The MEDASderived PREDIMED score correlated significantly with the corresponding FFQ PREDIMED score (r = 0.52; intraclass correlation coefficient = 0.51) and in the anticipated directions with the dietary intakes reported on the FFQ. Using Bland Altman"s analysis, the average MEDAS Mediterranean diet score estimate was 105% of the FFQ PREDIMED score estimate. Limits of agreement ranged between 57 and 153%. Multiple linear regression analyses revealed that a higher PREDIMED score related directly (P , 0.001) to HDL-cholesterol (HDL-C) and inversely (P , 0.038) to BMI, waist circumference, TG, the TG:HDL-C ratio, fasting glucose, and the cholesterol:HDL-C ratio. The 10-y estimated coronary artery disease risk decreased as the PREDIMED score increased (P , 0.001). The MEDAS is a valid instrument for rapid estimation of adherence to the Mediterranean diet and may be useful in clinical practice.

HDLs, diabetes, and metabolic syndrome.

The prevalence of type 2 diabetes mellitus and of the metabolic syndrome is rising worldwide and reaching epidemic proportions. These pathologies are associated with significant morbidity and mortality, in particular with an excess of cardiovascular deaths. Type 2 diabetes mellitus and the cluster of pathologies including insulin resistance, central obesity, high blood pressure, and hypertriglyceridemia that constitute the metabolic syndrome are associated with low levels of HDL cholesterol and the presence of dysfunctional HDLs. We here review the epidemiological evidence and the potential underlying mechanisms of this association. We first discuss the well-established association of type 2 diabetes mellitus and insulin resistance with alterations of lipid metabolism and how these alterations may lead to low levels of HDL cholesterol and the occurrence of dysfunctional HDLs. We then present and discuss the evidence showing that HDL modulates insulin sensitivity, insulin-independent glucose uptake, insulin secretion, and beta cell survival. A dysfunction in these actions could play a direct role in the pathogenesis of type 2 diabetes mellitus.

Did Dumbo suffer a heart attack? independent association between earlobe crease and cardiovascular disease.

BACKGROUND: Earlobe crease (ELC) has been associated with cardiovascular diseases (CVD) or risk factors (CVRF) and could be a marker predisposing to CVD. However, most studies studied only a small number of CVRF and no complete assessment of the associations between ELC and CVRF has been performed in a single study. METHODS: Population-based study (n = 4635, 46.7 % men) conducted between 2009 and 2012 in Lausanne, Switzerland. RESULTS: Eight hundred six participants (17.4 %) had an ELC. Presence of ELC was associated with male gender and older age. After adjusting for age and gender (and medication whenever necessary), presence of ELC was significantly (p < 0.05) associated with higher levels of body mass index (BMI) [adjusted mean ± standard error: 27.0 ± 0.2 vs. 26.02 ± 0.07 kg/m(2)], triglycerides [1.40 ± 0.03 vs. 1.36 ± 0.01 mmol/L] and insulin [8.8 ± 0.2 vs. 8.3 ± 0.1 μIU/mL]; lower levels of HDL cholesterol [1.61 ± 0.02 vs. 1.64 ± 0.01 mmol/L]; higher frequency of abdominal obesity [odds ratio and (95 % confidence interval) 1.20 (1.02; 1.42)]; hypertension [1.41 (1.18; 1.67)]; diabetes [1.43 (1.15; 1.79)]; high HOMA-IR [1.19 (1.00; 1.42)]; metabolic syndrome [1.28 (1.08; 1.51)] and history of CVD [1.55 (1.21; 1.98)]. No associations were found between ELC and estimated cardiovascular risk, inflammatory or liver markers. After further adjustment on BMI, only the associations between ELC and hypertension [1.30 (1.08; 1.56)] and history of CVD [1.47 (1.14; 1.89)] remained significant. For history of CVD, further adjustment on diabetes, hypertension, total cholesterol and smoking led to similar results [1.36 (1.05; 1.77)]. CONCLUSION: In this community-based sample ELC was significantly and independently associated with hypertension and history of CVD.

Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.

The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby regulating metabolic gene expression for optimal liver function.

Hepatic circadian clock oscillators and nuclear receptors integrate microbiome-derived signals.

The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby regulating metabolic gene expression for optimal liver function.

Randomized, crossover, double-blind, placebo-controlled trial to assess the lipid lowering effect of co-formulated TDF/FTC

Abstract INTRODUCTION: Previous studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1-3] It is unknown, however, if TDF has an intrinsic lipid-lowering effect or such findings are due to the addition or removal of other offending agents or other reasons. MATERIALS AND METHODS: RESULTS: 46 subjects with a median age of 43 (40-48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL-cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL-cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL-cholesterol (p<0.001) and HDL-cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total-cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL-cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure. CONCLUSION: Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF.

Carbohydrate intake in children - associations with dietary intakes, growth, serum lipids,and dental health. The STRIP Project

This study is part of the STRIP study, which is a long-term, randomized controlled trial, designed to decrease the exposure of children in the intervention group (n=540) to known risk factors of atherosclerosis. The main focus of the intervention was the quality of dietary fat. The control group (n=522) did not receive any individualized counselling. Food consumption was evaluated with food records, and blood samples were drawn and growth was measured regularly for all participating children from 13 months to 9 years. A subsample of 66 children participated in a dental health survey. The number of studies on children’s carbohydrate intake, especially fibre intake, is insufficient. The current international recommendations for fibre intake in children are based on average assumptions and data extrapolated from intakes in adults and intake recommendations for adults. Finnish nutrition recommendations lack strict recommendations for dietary fibre in children. Due to fibre’s high bulk volume, excessive dietary fibre is considered to decrease energy density and hence it may have an adverse effect on growth. If fats are reduced from the diet, the low-fat diet may become high in sucrose. Therefore, especially in the STRIP study, it is important to determine the use of fibre and sucrose in children and possible associations with growth and nutrition as well as dental health. The results of the present study indicate that a high fibre intake does not displace energy or disturb growth in children and that children with high fibre intake have better quality of diet than those with low fibre intake. Additionally, dietary fibre intake associated inversely with serum cholesterol concentration. Other carbohydrates also affected serum lipid levels as well, since total carbohydrates, sucrose, and fructose increased serum triglyceride concentration. Total carbohydrate intake reduced HDL cholesterol concentration only in children with apoE3 or apoE4 phenotype. Over the period from the 1970s to the 1990s the dental health of children in Finland has substantially improved despite an increase in sucrose intake. The improvement was thought to be due to improved dental hygiene and the use of fluorine. However, during the past twenty years improvement in dental health has stopped. The present study showed that high long-term sugar intake increases risk of caries in children. High intake of sugar had also negative effects on the diet of children, because it worsens dietary quality by displacing essential nutrients. Furthermore, the quality of dietary fat was worse in children with high sucrose intake. In this study the children’s high sucrose intake was not associated with overweight, but interestingly, it associated inversely with growth.

The effect of soy dietary supplement and low dose of hormone therapy on main cardiovascular health biomarkers: a randomized controlled trial

PURPOSE: To assess the effects of a soy dietary supplement on the main biomarkers of cardiovascular health in postmenopausal women compared with the effects of low-dose hormone therapy (HT) and placebo.METHODS: Double-blind, randomized and controlled intention-to-treat trial. Sixty healthy postmenopausal women, aged 40-60 years, 4.1 years mean time since menopause were recruited and randomly assigned to 3 groups: a soy dietary supplement group (isoflavone 90mg), a low-dose HT group (estradiol 1 mg plus noretisterone 0.5 mg) and a placebo group. Lipid profile, glucose level, body mass index, blood pressure and abdominal/hip ratio were evaluated in all the participants at baseline and after 16 weeks. Statistical analyses were performed using the χ2 test, Fisher's exact test, Kruskal-Wallis non-parametric test, analysis of variance (ANOVA), paired Student's t-test and Wilcoxon test.RESULTS: After a 16-week intervention period, total cholesterol decreased 11.3% and LDL-cholesterol decreased 18.6% in the HT group, but both did not change in the soy dietary supplement and placebo groups. Values for triglycerides, HDL-cholesterol, glucose level, body mass index, blood pressure and abdominal/hip ratio did not change over time in any of the three groups.CONCLUSION: The use of dietary soy supplement did not show any significant favorable effect on cardiovascular health biomarkers compared with HT. Clinical Trial Registry: The trial is registered at the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos - ReBEC), number RBR-76mm75.

Apolipoprotein and lipid abnormalities in chronic liver failure

Total serum lipids, as well as apolipoproteins A-I (apo A-I) and B (apo B), were determined in 74 patients with chronic liver failure without cholestasis and in 82 normal subjects. The VLDL, LDL and HDL lipid fractions were reduced in the liver failure group by 36%, 24% and 46%, respectively (P<0.001). Apolipoproteins A-I and B were also reduced by 26% and 25%, respectively (P<0.001). However, the reduction of HDL cholesterol (HDLc) was more pronounced than that of apo A-I and the HDLc:apo A-I ratio was significantly lower in the liver failure group. After separating these patients into groups with plasma albumin lower than 3.0, between 3.0 and 3.5, and higher than 3.5 g/dl, the HDLc:apo A-I ratio was proportional to plasma albumin, but the correlation was not statistically significant. When these patients were separated by the Child classification of liver function, there was a correlation between the HDLc:apo A-I ratio and liver function. The differences in the HDLc:apo A-I ratio between the Child groups B and C, and A and C were statistically significant (P<0.05). We conclude that there is a more pronounced reduction in HDL cholesterol than in apo A-I in liver failure patients. Therefore, the HDLc:apo A-I ratio is a marker of liver function, probably because there is a decreased lecithin-cholesterol acyltransferase production by the diseased liver

Association of apolipoprotein E polymorphism with plasma lipids and Alzheimer's disease in a Southern Brazilian population

Apolipoprotein E (protein: apo E; gene: APOE) plays an important role in the multifactorial etiology of both Alzheimer's disease (AD) and lipid level concentrations. The polymerase chain reaction (PCR) was used to investigate the APOE gene polymorphism in 446 unrelated Caucasians, among them 23 AD patients, and 100 Afro-Brazilians living in Porto Alegre, Brazil. The frequencies of the APOE*2, APOE*3 and APOE*4 alleles were 0.075, 0.810 and 0.115 in Caucasians and 0.075, 0.700 and 0.225 in Afro-Brazilians, respectively (c2 = 8.72, P = 0.013). A highly significant association was observed between the APOE*4 allele and AD in this population-based sample. The APOE*4 frequency in AD patients (39%) was about four times higher than in the general Caucasian population (11.5%). The influence of each of the three common APOE alleles on lipid traits was evaluated by the use of the average excess statistic. The E*2 allele is associated with lower levels of triglycerides and of total and non-HDL cholesterol in both men and women. Conversely, the E*4 allele is associated with higher levels of these traits in women only. The effect of APOE alleles was of greater magnitude in women.

Lack of antidiabetic effect of a Eugenia jambolana leaf decoction on rat streptozotocin diabetes

Streptozotocin-diabetic rats were treated for 17 days with a decoction of Eugenia jambolana (Myrtaceae) leaves (15%, w/v) as a substitute for water. Body weight, food and fluid intake, urine volume, glycemia, urinary glucose and urea were evaluated every 5 days. The animals were sacrificed by decapitation and blood samples collected for the determination of glycemia, serum cholesterol, HDL-cholesterol, triglycerides and angiotensin-converting enzyme. The weight of adipose and muscle tissues was also determined. There were no statistically significant differences between treated and untreated rats for any of the biochemical or physiological parameters. We conclude that, at least in this experimental model, Eugenia jambolana leaf decoction has no antidiabetic activity.