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Diabetic kidney disease (DKD) and retinopathy (DR) develop in a considerable number of subjects with Type 2 Diabetes (T2D) despite the achievement of the recommended targets for glycaemia and blood pressure. Atherogenic dyslipidemia may play a relevant role, especially in T2DM women. We report our findings on the effect of diabetic dyslipidaemia, the HDL subclasses distribution and the common cholesteryl ester transfer protein (CETP)TaqIB variant on the incidence or the progression of DKD and DR in 97 T2D women, after a ∼9years of follow-up. At baseline, T2D women presented with low HDL-C levels and higher levels of large lipid rich α-1 (16.34mg/dl), α-2 (33.39mg/dl) and pre- α1 (4.81mg/dl) HDL subparticles. The CETP TaqIB polymorphism and baseline HbA1c, triglycerides, and HDL-C levels as well as specific HDL subpopulations were associated to the occurrence of RD after ∼9years of follow-up. At stepwise regression analysis, HbA1c, triglycerides and the less atheroprotective α-3 HDL particles were the only factors independently associated to the incidence of RD. These same variables were also associated with the progression from background to proliferative RD. BMI, LDL/HDL ratio and low levels of α-1 HDL particles were associated to the occurrence of DKD at univariate analysis, although BMI was the only significant predictor at stepwise multivariate regression analysis. In T2D women, atherogenic dyslipidemia as well as subtle modifications in lipoprotein particles profile are associated with incidence and progression of microvascular disease. Show less

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Management Guideline recommends moderate-intensity to high-intensity statin therapy in eligible patients. To examine adoption of the 2013 ACC/AHA guideline in US cardiology practices. Among 161 cardiology practices, trends in the use of moderate-intensity to high-intensity statin and nonstatin lipid-lowering therapy (LLT) were analyzed before (September 1, 2012, to November 1, 2013) and after (February 1, 2014, to April 1, 2015) publication of the 2013 ACC/AHA guideline among 4 mutually exclusive risk groups within the ACC Practice Innovation and Clinical Excellence Registry. Interrupted time series analysis was used to evaluate for differences in trend in use of moderate-intensity to high-intensity statin and nonstatin LLT use in hierarchical logistic regression models. Participants were a population-based sample of 1 105 356 preguideline patients (2 431 192 patient encounters) and 1 116 472 postguideline patients (2 377 219 patient encounters). Approximately 97% of patients had atherosclerotic cardiovascular disease (ASCVD). Moderate-intensity to high-intensity statin and nonstatin LLT use before and after publication of the 2013 ACC/AHA guideline. Time trend in the use of moderate-intensity to high-intensity statin and nonstatin LLT. In the study cohort, the mean (SD) age was 69.6 (12.1) years among 1 105 356 patients (40.2% female) before publication of the guideline and 70.0 (11.9) years among 1 116 472 patients (39.8% female) after publication of the guideline. Although there was a trend toward increasing use of moderate-intensity to high-intensity statins overall and in the ASCVD cohort, such a trend was already present before publication of the guideline. No significant difference in trend in the use of moderate-intensity to high-intensity statins was observed in other groups. The use of moderate-intensity to high-intensity statin therapy was 62.1% (before publication of the guideline) and 66.6% (after publication of the guideline) in the overall cohort, 62.7% (before publication) and 67.0% (after publication) in the ASCVD cohort, 50.6% (before publication) and 52.3% (after publication) in the cohort with elevated low-density lipoprotein cholesterol levels (ie, ≥190 mg/dL), 52.4% (before publication) and 55.2% (after publication) in the diabetes cohort, and 41.9% (before publication) and 46.9% (after publication) in the remaining group with 10-year ASCVD risk of 7.5% or higher. In hierarchical logistic regression models, there was a significant increase in the use of moderate-intensity to high-intensity statins in the overall cohort (4.8%) and in the ASCVD cohort (4.3%) (P < .01 for slope for both). There was no significant change for other risk cohorts. Nonstatin LLT use remained unchanged in the preguideline and postguideline periods in the hierarchical logistic regression models for all of the risk groups. Adoption of the 2013 ACC/AHA Cholesterol Management Guideline in cardiology practices was modest. Timely interventions are needed to improve guideline-concordant practice to reduce the burden of ASCVD. Show less

Despite a high prevalence of metabolic trait related diseases in Arabian Peninsula, there is a lack of convincingly identified genetic determinants for metabolic traits in this population. Arab populations are underrepresented in global genome-wide association studies. We genotyped 1965 unrelated Arab individuals from Kuwait using Cardio-MetaboChip, and tested SNP associations with 13 metabolic traits. Models based on recessive mode of inheritance identified Chr15:40531386-rs12440118/ZNF106/W->R as a risk variant associated with glycated-hemoglobin at close to 'genome-wide significant' p-value and five other risk variants 'nominally' associated (p-value ≤ 5.45E-07) with fasting plasma glucose (rs7144734/[OTX2-AS1,RPL3P3]) and triglyceride (rs17501809/PLGRKT; rs11143005/LOC105376072; rs900543/[THSD4,NR2E3]; and Chr12:101494770/IGF1). Furthermore, we identified 33 associations (30 SNPs with 12 traits) with 'suggestive' evidence of association (p-value < 1.0E-05); 20 of these operate under recessive mode of inheritance. Two of these 'suggestive' associations (rs1800775-CETP/HDL; and rs9326246-BUD13/TGL) showed evidence at genome-wide significance in previous studies on Euro-centric populations. Involvement of many of the identified loci in mediating metabolic traits was supported by literature evidences. The identified loci participate in critical metabolic pathways (such as Ceramide signaling, and Mitogen-Activated Protein Kinase/Extracellular Signal Regulated Kinase signaling). Data from Genotype-Tissue Expression database affirmed that 7 of the identified variants differentially regulate the up/downstream genes that mediate metabolic traits. Show less

Sphingosine-1-phosphate (S1P) is a vasoprotective lipid mediator. About two thirds of plasma S1P rides on high-density lipoprotein (HDL), and several pleiotropic properties of HDL have been ascribed to S1P. In human subjects, CETP (cholesteryl ester transfer protein) greatly influences HDL quantities. In this study, we attempted to elucidate the roles of CETP in the metabolism of S1P. We overexpressed CETP in mice that lacked CETP and found that CETP overexpression decreased the HDL level but failed to modulate the levels of S1P and apolipoprotein M (apoM), a carrier of S1P, in the total plasma. We observed, however, that the distribution of S1P and apoM shifted from HDL to apoB-containing lipoproteins. When we administered C CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P. Show less

We evaluated possible changes in VLDLcharacteristics, and metabolic related factors, in MetS-associated NAFLD and accompanying liver fibrosis. We studied 36 MetS patients with biopsy-proven NAFLD (MetS+NAFLD) and 24 MetS without ultrasound NAFLD evidence. Further, MetS+NAFLD was sub-divided according to fibrosis stage into, non-to-moderate (F0-F2, n=27) and severe (F3-F4, n=9) fibrosis. We measured: lipid profile, VLDL composition and size (size exclusion-HPLC), CETP and lipoprotein lipase (LPL) activities and adiponectin. Additionally, in MetS+NAFLD type IV collagen 7S domain was measured. MetS+NAFLD showed increased VLDL-mass, VLDL particle number, VLDL-triglyceride% and large VLDL-% (p<0.04). CETP activity tended to increase in MetS+NAFLD (p=0.058), while LPL activity was unchanged. Moreover, in MetS+NAFLD, adiponectin was decreased (p<0.001), and negatively correlated with VLDL-mass and VLDL particle number (p<0.05), independently of insulin-resistance. Within MetS+NAFLD group, despite greater insulin-resistance, patients with severe fibrosis showed lower plasma triglycerides, VLDL-mass, VLDL-triglyceride%, large VLDL-% and CETP activity (p<0.05), while type IV collagen was increased (p=0.009) and inversely correlated with large VLDL-% (p=0.045). In MetS, NAFLD is associated with larger and triglyceride over-enriched circulating VLDLs, of greater atherogenicity. However, when NAFLD progresses to severe fibrosis, circulating VLDL features apparently improved, probably due to early alterations in hepatic synthetic function. Show less

A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC Show less

Increasing high-density lipoprotein(HDL) cholesterol levels predict improved cardiovascular outcomes. However, inhibiting cholesteryl ester transfer protein (CETP) to increase HDL cholesterol, with the 'cetrapibs' (torcetrapib and dalcetrapib), did not improve cardiovascular clinical outcomes. Despite these findings, the clinical outcomes trial with evacetrapib continued. Areas covered: Treatment with evacetrapib increased the levels of HDL by ~130%, and decreased low-density lipoprotein (LDL) cholesterol by ~37%. However, The Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial did not show reduced cardiovascular outcomes with this cetrapib. Evacetrapib may have failed because increasing HDL cholesterol may not be beneficial in the presence of coronary artery disease and/or it is possible that evacetrapib has toxic effects that counter any beneficial effects. Expert opinion: In addition to our understanding of the relationships between CETP, HDL cholesterol and cardiovascular disease being incomplete, recent meta-analysis evidence suggests that increasing HDL cholesterol does not improve cardiovascular outcomes in subjects taking statins, and this may explain the failure of evacetrapib. Also, the preclinical characteristics of the cetrapibs, especially off-target mechanisms, were not explored prior to clinical trial, and may have contributed to the failure of cetrapibs, including evacetrapib. Show less

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. Show less

Hibiscus sabdariffa L. (HS) and Gynostemma pentaphyllum Makino (GP) have been used as traditional medicines to treat diabetes and hypercholesterolemia. Nevertheless, there is interindividual variation in the metabolic responses to HS and GP consumption. This may be due to genetic factors. The aim of this study was to investigate the effects of HS and GP tea consumption on anthropometric data, fasting blood glucose (FBG), and lipid concentrations in hypercholesterolemia subjects with different genotypes of the APOE and CETP TaqIB polymorphisms. Forty-eight subjects with hypercholesterolemia were given either HS or GP tea for 30 days. Anthropometric and biochemical variables were determined, and APOE and CETP TaqIB polymorphisms were analyzed using the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). E4 (p=0.008) and homozygous B1B1 (p=0.010) carriers had significantly decreased HDL-C concentrations after HS consumption; in addition, B2 carriers who consumed HS showed significantly decreased triglyceride (TG) concentrations (p=0.039). Regarding GP consumption, non-E4 carriers had significantly decreased HDL-C (p=0.009) and FBG (p=0.042) concentrations. Furthermore, B2 carriers had significantly decreased total cholesterol (TC) (p=0.045), HDL-C (p=0.004), and FBG (p=0.026) concentrations. HS consumption may have beneficial effects with respect to TG concentrations in the B2 carriers, but it may adversely affect HDL-C concentrations in homozygous B1B1 and E4 carriers. In contrast, GP consumption may have favorable effects on TC and FBG concentrations but not on HDL-C concentrations for B2 and/or non-E4 carriers. Show less

Epidemiological studies state that dementia has multiple etiologies including genetic mutation, genetic variation, and environmental factors. Accumulating evidence suggests that dysregulation of cholesterol homeostasis is the major etiological factor in initiating neurodegeneration. Apolipoprotein E (APOE) polymorphic alleles and associated polymorphism of lipoprotein lipase (LPL) and cholesteryl ester transfer protein (CETP) that are important components in regulating cholesterol metabolism are implicated in neurodegenerative diseases. Therefore, the current study focused on identifying the association between several common polymorphism (viz., APOE, CETP, and LPL) to that of change in serum lipid levels and memory symptoms. Volunteer subjects aged 50 and above from rural and tribal areas of the Dharmapuri district, Tamilnadu, India were chosen for the current study and polymorphism was analyzed using PCR-RFLP. Fasting lipid profile and memory function using simplified version of Global Clinical Dementia rating were assessed. Significant difference in the major lipid profile parameters were observed (TC, TGL, LDL, VLDL) among rural and tribal populations that were associated with significant genotypic variation of APOE, CETP, and LPL. Regression analysis revealed significant risk for memory loss that are dependent on age and genetic variants like CETP. These data predict positive correlation between cholesterol-associated genes and their relationship to altered lipid profile and memory symptoms, which possibly link gene-polymorphism and susceptibility ratio for aging and dementia. Show less

Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal. This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (β quantification). Treatment with evacetrapib 130 mg daily for 12 weeks resulted in a statistically significant treatment difference of -25.70% compared with placebo in percentage decrease in LDL-C (95% CI: -34.73 to -16.68; P<0.001). Treatment with evacetrapib 130 mg also resulted in a statistically significant difference of 126.39% in the change in high-density lipoprotein cholesterol (HDL-C) compared with placebo (95% CI: 113.54-139.24; P<0.001). No deaths or serious adverse events were reported. Four patients (3 in the evacetrapib group and 1 in the ezetimibe group) discontinued due to adverse events. Evacetrapib daily in combination with atorvastatin was superior to placebo in lowering LDL-C after 12 weeks, and resulted in a statistically significant increase of HDL-C compared with placebo. Also, no new safety risks were identified. Show less

Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates bidirectional transfers of cholesteryl esters and triglycerides between low-density lipoproteins and high-density lipoproteins (HDL). Because low levels of plasma CETP are associated with increased plasma HDL-cholesterol, therapeutic inhibition of CETP activity is considered an attractive strategy for elevating plasma HDL-cholesterol, thereby hoping to reduce the risk of cardiovascular disease. Interestingly, only a few laboratory animals, such as rabbits, guinea pigs, and hamsters, have plasma CETP activity, whereas mice and rats do not. It is not known whether all CETPs in these laboratory animals are functionally similar to human CETP. In the current study, we compared plasma CETP activity and characterized the plasma lipoprotein profiles of these animals. Furthermore, we studied the three CETP molecular structures, physicochemical characteristics, and binding properties with known CETP inhibitors in silico. Our results showed that rabbits exhibited higher CETP activity than guinea pigs and hamsters, while these animals had different lipoprotein profiles. CETP inhibitors can inhibit rabbit and hamster CETP activity in a similar manner to human CETP. Analysis of CETP molecules in silico revealed that rabbit and hamster CETP showed many features that are similar to human CETP. These results provide novel insights into understanding CETP functions and molecular properties. Show less

A key to effective treatment of cardiovascular disease is to understand the body's complex lipoprotein transport system. Reverse cholesterol transport (RCT) is the process of cholesterol movement from the extrahepatic tissues back to the liver. Lipoproteins containing apoA-I [highdensity lipoprotein (HDL)] are key mediators in RCT, whereas non-high-density lipoproteins (non-HDL, lipoproteins containing apoB) are involved in the lipid delivery pathway. HDL particles are heterogeneous; they differ in proportion of proteins and lipids, size, shape, and charge. HDL heterogeneity is the result of the activity of several factors that assemble and remodel HDL particles in plasma: ATP-binding cassette transporter A1 (ABCA1), lecithin cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), hepatic lipase (HL), phospholipid transfer protein (PLTP), endothelial lipase (EL), and scavenger receptor class B type I (SR-BI). The RCT pathway consists of the following steps: 1. Cholesterol efflux from peripheral tissues to plasma, 2. LCAT-mediated esterification of cholesterol and remodeling of HDL particles, 3. direct pathway of HDL cholesterol delivery to the liver, and 4. indirect pathway of HDL cholesterol delivery to the liver via CETP-mediated transfer There are several established strategies for raising HDL cholesterol in humans, such as lifestyle changes; use of drugs including fibrates, statins, and niacin; and new therapeutic approaches. The therapeutic approaches include CETP inhibition, peroxisome proliferator-activated receptor (PPAR) agonists, synthetic farnesoid X receptor agonists, and gene therapy. Results of clinical trials should be awaited before further clinical management of atherosclerotic cardiovascular disease. Show less

The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development. Show less

CETP transfers cholesteryl esters (CEs) and triglycerides (TGs) between different lipoproteins and came in limelight as a drug-target against CVD. In the search for detailed mechanism of lipid transfer through CETP, enormous effort is devoted employing crystallographic, cryo-EM, and Molecular Dynamics (MD) studies. However, these studies primarily focused on CE-bound CETP structure and CE transfer mechanism. With the reported correlation that CETP looses significant CE transfer activity upon inhibiting TG transfer, it is of tremendous importance to understand the structure and dynamics of TG-bound CETP. Our results from large-scale all-atom and coarse-grained MD simulations show that CETP can accommodate two TG molecules in parallel N-N orientation with TG oleate chains majorly attaining the tuning-fork conformation. In TG-bound form, CETP not only maintained its secondary structures but also exhibited similar bending-twisting motions as reported for CE-CETP crystal structure. Obtained structural information are further validated by correlating to available functional data of 2-8 fold slower transfer rate of TG through CETP, where we show that TGs make 20% additional contacts with CETP compared to CEs. Identified CETP residues facilitating TG binding also match very well with reported mutagenesis data. The study could accelerate the drug-designing processes to combat CETP functionality and CVD. Show less

Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using Anacetrapib reduces Lp(a) levels by decreasing its production. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808. Show less

High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP (cholesteryl ester transfer protein) inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease. Dalcetrapib is a CETP modulator for which effects on cardiovascular outcomes were demonstrated in the dal-OUTCOMES trial to be influenced by correlated polymorphisms in the Show less

Low high density lipoprotein cholesterol (HDL-C) levels represent an independent risk factor for cardiovascular disease; in addition to the reduced HDL-C levels commonly observed in patients at cardiovascular risk, the presence of dysfunctional HDL, i.e. HDL with reduced atheroprotective properties, has been reported. Despite the established inverse correlation between HDL-C levels and cardiovascular risk, several clinical trials with HDL-C-increasing drugs (such as niacin, CETP inhibitors or fibrate) failed to demonstrate that a significant rise in HDL-C levels translate into a cardiovascular benefit. Statins, that are the most used lipid-lowering drugs, can also increase HDL-C levels, although this effect is highly variable among studies and statins; the most recent developed statin, pitavastatin, beside its role as LDL-C-lowering agent, increases HDL-C levels at a significantly higher extent and progressively upon treatment; such increase was observed also when patients where shifted from another statin to pitavastatin. The stratification by baseline HDL-C levels revealed that only pitavastatin significantly increased HDL-C levels in patients with baseline HDL-C ≤45 mg/dl, while no changes were observed in patients with higher baseline HDL-C levels. In the last years the hypothesis that functional properties of HDL may be more relevant than HDL-C levels has risen from several observations. The treatment with pitavastatin not only increased HDL-C levels, but also increased the phospholipid content of HDL, increased the HDL efflux capacity and their anti-oxidant properties. These observations suggest that, besides its high LDL-C-lowering effect, pitavastatin also exhibits a significantly higher ability to increase HDL-C levels and may also positively affect the quality and functionality of HDL particles. Show less

AMP = adenosine monophosphate CETP = cholesteryl ester transfer protein FOXO = Forkhead box O GH = growth hormone HDL = high-density lipoprotein IGF-1 = insulin-like growth factor 1 LDL = low-density lipoprotein miRNA = microRNA mTOR = mammalian target of rapamycin SIRT = sirtuin T4 = thyroxine TSH = thyroid-stimulating hormone "The Moving Finger writes; and, having writ, Moves on: nor all thy Piety nor Wit Shall lure it back to cancel half a Line, Nor all thy Tears wash out a Word of it." Omar Khayyam ( 1 ). Show less

BACKGROUND Liver X receptor (LXR) is a nuclear receptor presenting in macrophages; it works indispensably in lipid metabolism control and also negatively regulates the expression of inflammatory genes in macrophages. There are many LXR-related studies in adults with metabolic syndrome but rare reports in obese children with obstructive sleep apnea-hypopnea syndrome (OSAHS). The aim of this study was to investigate the expression of LXR, cholesterol ester transfer protein (CETP), and cyclooxygenase-2 (COX-2) genes in obese children with OSAHS compared with obese children without OSAHS and non-obese children. MATERIAL AND METHODS Sleep monitoring was conducted in 80 obese children with sleep disorders. Fasting morning blood samples from the 80 obese children and 51 normal children were collected and separated, so that macrophages were obtained after culture. Fluorescence quantitative real-time PCR (RT-PCR) was used to detect expression levels of the LXR, CETP, and COX-2 genes. RESULTS LXR, COX-2, and CETP levels in the OSAHS group were higher than those in the other two groups (P<0.05), and the LXR levels in the group of obese children without OSAHS were higher than those in control group (P<0.05). COX-2 expression in the group with moderate to severe OSAHS was higher than that in the group with mild OSAHS (P<0.05). Meanwhile, there were no significant differences in the LXR and CETP levels between the moderate to severe OSAHS group and the mild OSAHS group (P>0.05). CONCLUSIONS LXR gene expression was significantly increased in obese children with OSAHS. The severity of OSAHS was positively correlated with COX-2 levels. Show less

Hyperlipidemia has unique adverse effects on pregnant women and their offspring. The underlying genetic factors related to lipid levels in pregnant populations need more studies. This study aimed to investigate the relationship between 6 single-nucleotide polymorphisms (SNPs) and plasma lipid levels during pregnancy. A total of 2060 pregnant women were recruited. Fasting plasma lipids were measured in the third trimester of pregnancy. Six SNPs (rs1260326 in GCKR, rs1800775 in CETP, rs515135 in APOB, rs1800588 in LIPC, rs964184 in ZPR1, and and rs4420638 in APOC1 of each participant were genotyped using TaqMan allelic discrimination assays. The relationships between the 6 loci and plasma lipids were analyzed using a multiple linear regression method. Two variants, rs1260326 (β = 0.220, 95% confidence interval [CI] = 0.148-0.291; P = 2.048 × 10 Loci found by genome-wide association studies to be associated with plasma lipid levels in the general population were also related to lipid levels in the third trimester of pregnancy. This finding implies that changes to lipid profiles during gestation may be associated with SNPs of lipid-related genes. Variants of lipid-related genes are important predictors for estimating lipid concentrations during the pregnancy. Show less

Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long-term care (>90 days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193 ± 36 vs 160 ± 43, p = 0.005), LDL (124 ± 3 vs 96 ± 33 p = 0.003) and HDL-cholesterol (45 ± 10 vs 36 ± 13, p = 0.008), apolipoprotein A-I (134 ± 20 vs 111 ± 24, p = 0.001) and oxidized LDL (53 ± 13 vs 43 ± 12, p = 0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL-cholesterol levels. Concentrations of IL-1β, IL-6, IL-8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL-cholesterol, apolipoprotein A-I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition. Show less

Oxidative modification of lipoproteins is a crucial step in atherosclerosis development. Isotopic-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to reactive oxygen species-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-)PUFAs. We aimed at investigating the effect of D-PUFA treatment on lipid peroxidation, hypercholesterolemia and atherosclerosis development. Transgenic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, were pre-treated with D-PUFAs or control H-PUFAs-containing diet (1.2%, w/w) for 4 weeks. Thereafter, mice were fed a Western-type diet (containing 0.15% cholesterol, w/w) for another 12 weeks, while continuing the D-/H-PUFA treatment. D-PUFA treatment markedly decreased hepatic and plasma F D-PUFAs reduce body weight gain, improve cholesterol handling and reduce atherosclerosis development by reducing lipid peroxidation and plasma cholesterol levels. D-PUFAs, therefore, represent a promising new strategy to broadly reduce rates of lipid peroxidation, and combat hypercholesterolemia and cardiovascular diseases. Show less

Preβ1-high-density lipoprotein (preβ1-HDL), plays an important role in reverse cholesterol transport and exhibits potent risk for coronary artery disease (CAD). However, the association of plasma preβ1-HDL and cholesterol ester transfer protein (CETP) levels in CAD patients and the relationship of preβ1-HDL with extent of CAD are debatable. Preβ1-HDL and CETP levels were measured by enzymed-linked immunosorbent assay (ELISAs) in 88 acute coronary syndromes (ACS), 79 stable coronary artery disease (SCAD) patients and 85 control subjects. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. The preβ1-HDL and CETP levels in ACS patients were significantly higher than those in SCAD patients and both of them were higher than controls'. Preβ1-HDL levels were positively associated with CETP (R = 0.348, P = 0.000), the diameter of stenosis (R = 0.253, P = 0.005), the number of vessel disease (R = 0.274, P = 0.002) and Gensini score (R = 0.227, P = 0.009) in CAD patients. Stepwise multiple linear regression analyses showed that CETP was one of the determinants of preβ1-HDL levels. Logistic regression analysis revealed that elevated preβ1-HDL and CETP were potential risk factors for both ACS and SCAD. The elevated preβ1-HDL levels may change with CETP concentrations in CAD patients and were related to the presence and severity of CAD. Show less

The association between cholesteryl ester transfer protein (CETP) TaqIB polymorphism and ischemic stroke (IS) risk has generated conflicting results. To investigate whether the TaqIB polymorphism of the CETP gene was associated with the risk of IS, a meta-analysis was performed. Studies were retrieved by searching PubMed, Web of Science, the Chinese National Knowledge Infrastructure, the Chinese Wanfang Database, and the Chinese VIP Database before January 16, 2017. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association. Depending on the heterogeneity the fixed-effects model or the random-effects model was used. A total of 6 case-control studies were identified with 1494 cases and 1370 controls. Overall, an association of CETP TaqIB polymorphism with IS was found in the 4 genetic models (B2B2 versus B1B1: OR = .63, 95% CI = .51-.79, P < .001; B1B2 + B2B2 versus B1B1: OR = .75, 95% CI = .64-.87, P < .001; B2B2 versus B1B2 + B1B1: OR = .70, 95% CI = .57-.85, P < .001; B2 versus B1: OR = .78, 95% CI = .70-.87, P < .001). In the subgroup analysis by ethnicity, similar risks were also observed in Asian population. This meta-analysis indicates that CETP TaqIB polymorphism is associated with IS risk, and the B2 allele is a protective factor for IS. Show less

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model. Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control. AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta. Show less

To explore the association between A total of 571 individuals which were randomly selected from 5692 Uyghur adults were subdivided into two groups, including 280 patients with MS and 291 control subjects, using the group-matching method after matching for gender. We detected (1) Significant differences were found involving the frequency distribution of genotypes and alleles of rs1800775, rs3764261, rs12149545, rs711752, and rs708272 between the control and MS groups (all Show less

Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events. Despite years of development, no cholesterol ester transfer protein inhibitor has yet been approved for clinical use. We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib. Published reports and registration records were extracted for patient demographic characteristics and study authors' recommendations of clinical usage or further testing. We used Accumulating Evidence and Research Organization graphing to depict the portfolio of research activities and a Poisson model to examine trends. We identified 100 studies for analysis that involved 96 944 human subjects. The data from only 41 201 (42%) of the human subjects had been presented in a published report. For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipid-modification end points followed by negative results using clinical end points. Inefficiencies and harms can arise if a biomarker hypothesis continues to drive trials despite successive failures. Regulators, research funding bodies, and public policy makers may need to play a greater role in evaluating and coordinating biomarker-driven research programs. Show less

Persons with type 2 diabetes mellitus (T2DM) have an elevated risk of atherosclerosis. High-density lipoproteins (HDL) normally protect against cardiovascular disease (CVD), but this may be attenuated by serum amyloid A (SAA). In a case-control study of young females, blood samples were compared between subjects with T2DM ( Show less