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Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL-cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed. Most data have been accumulated with proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors, which reduce LDL-cholesterol by 50-55%. A large CVD outcome trial with evolocumab, in which 40% of participants had diabetes, achieved a LDL-cholesterol of 0.8 mmol/l and showed a consistent 20% relative risk reduction within 2 years, including in people with diabetes. Trials to increase HDL-cholesterol using cholesterol ester transfer protein (CETP) inhibitors have generally underwhelmed. Although anacetrapib reduced coronary ischaemic events by 7% in a population with chronic CVD, more expansive CVD endpoints were not improved. The complex nature of CETP inhibitor trial outcomes means that these compounds are not being developed further. Trials targeting inflammation-associated lipids have been generally unsuccessful but recent data on the interleukin-1B receptor antagonist canakinumab have shown a reduction in acute coronary intervention, validating this target although at the cost of increased infections. The ability to achieve low LDL-cholesterol with off-patent medications and the costs of novel therapies will confine the use of novel agents to subgroups of people at highest risk of CVD. Show less

We investigated the antihypertensive effect of policosanol on spontaneously hypertensive rats (SHR). For this, we analyzed blood pressure, blood lipid, and lipoprotein properties in male SHR after consumption of Cuban policosanol (PCO). The experimental groups were as follows: normotensive Wistar Kyoto (WKY) control, SHR group fed normal diet (ND), SHR group fed 20 mg of PCO, SHR group fed 100 mg of PCO, and SHR group fed 200 mg of PCO per kg of body weight. After eight weeks, the SHR control group showed gradual increases up to 21% in systolic blood pressure (SBP) and diastolic blood pressure (DBP) compared with values at week 0. However, policosanol consumption had a dose-dependent reduction effect on SBP and also reduced DBP up to 17% in a dose-dependent manner. Heart rate (HR) bpm increased by six percent in the SHR control, whereas the 20 mg, 100 mg, and 200 mg of policosanol groups showed a reduction of 36%, 28%, and 34% respectively. Although serum total cholesterol (TC) level of SHR was not affected by policosanol consumption (70⁻80 mg/dL), serum triglyceride (TG) level significantly decreased in the SHR + 200 mg of PCO group. Serum high-density lipoprotein cholesterol (HDL-C) level was also significantly elevated by policosanol consumption. The % HDL-C/TC ratio was elevated in the policosanol group up to 67⁻70%, whereas the SHR control group showed a ratio of 58%. Serum cholesteryl ester transfer protein (CETP) activity was reduced by policosanol in a dose-dependent manner. Although the serum glutamate oxaloacetate transaminase (GOT)/ glutamate pyruvate transaminase (GPT) were similar across all groups, policosanol consumption caused reduction of reactive oxygen species (ROS) levels in hepatic tissue. The SHR control group showed a 2.1-fold higher serum C-reactive protein (CRP) level than the WKY group, whereas the CRP level decreased in the SHR + 200 mg of PCO group (up to 45%) than SHR control group. Aldosterone level was reduced in the policosanol group (up to 34%) in a dose-dependent manner compared to the control. In conclusion, eight weeks of policosanol consumption in SHR resulted in remarkable reduction of blood pressure, serum aldosterone, and serum TG levels along with the elevation of HDL-C and improvement of hepatic inflammation. Show less

Obesity is associated with a lower HDL-mediated cholesterol efflux from macrophages and a higher CETP (cholesteryl ester transfer protein) activity, but effects of weight loss are not clear. In addition, associations with visceral and subcutaneous adipose tissue are not known. We therefore investigated effects of diet-induced weight loss on HDL-mediated cholesterol efflux and cholesterol ester (CE) transfer in abdominally obese men. Differences between normal-weight and abdominally obese men were also examined. Twenty-five apparently healthy, normal-weight men (waist circumference: <94 cm) and 52 abdominally obese men (waist circumference: 102-110 cm) were included. Abdominally obese subjects were randomly allocated to a dietary weight-loss intervention group or a no-weight loss control group. Individuals from the intervention group followed a very-low-calorie diet for 6 weeks to obtain a waist circumference below 102 cm, followed by a 2-week weight-stable period. Cholesterol efflux was measured in BODIPY-labeled murine J774 macrophages. CE transfer was measured by quantifying the transfer of CE from radiolabeled exogenous HDL to apoB-containing lipoproteins. Cholesterol efflux capacity was 9 percentage point (pp) lower in abdominally obese than in normal-weight men (p≤0.001), while CE transfer was 5 pp higher (p≤0.01). Diet-induced weight-loss of 10.3 kg did not change cholesterol efflux and CE transfer. In addition, stepwise regression analysis did not suggest that the different fat depots are differently related to efflux capacity and CE transfer. After a 2-week weight-stable period, dietary weight loss of 10 kg did not improve ABCA1-mediated cholesterol efflux and CE transfer in abdominally obese men. Show less

Platelet markers [soluble p selectin (sP-selectin) and soluble CD40 ligand (sCD40L)] are associated with platelet activation and cardiovascular risk. Both policosanol and 10-dehydrogingerdione are natural products with proven CETP inhibitory and antiatherogenic effects. Present work aimed mainly to investigate the levels of platelet activation biomarkers in the serum of dyslipidemic rabbits and the potential of these phytochemicals either alone or in a combination form to protect against atherogenicity. Additionally, this work clarified their effect on PCSK9, a key player in atherosclerosis progression. Daily administration of policosanol and/or 10-dehydrogingerdione at a dose level 10 mg/kg bw resulted in a CETP inhibitory activity, increasing HDL-C level. This protective effect was associated with improvement in lipid profile components and a reduction in PCSK9 level. Interestingly, this combination strengthened the CETP inhibitory activity of these phytochemicals, leading to a greater increase in serum HDL-C level than monotherapy. However, this combination did not enhance the reduction in PCSK9 level. Both drugs also decreased platelet activation and inflammation markers such as sCD40L, sP-selectin, and interferon-gamma (IFN-γ), and their combination showed a synergistic effect. Therefore, such phytochemicals may be regarded as promising agents in the protection against atherothrombosis risk. Show less

Spherical reconstituted high density lipoprotein (rHDL) can target atherosclerotic lesions by the very low density lipoprotein (VLDL) receptor, which is seldom expressed in liver. By promoting this pathway, the targeting efficiency was hyphothesized to be improved due to avoiding undesired uptake in liver mediated by the scavenger receptor class B type I (SR-BI). In this study, how fatty acid modification in spherical rHDL influenced the VLDL receptor-mediated endocytosis pathway was investigated. Stearic acid (SA) and arachidonic acid (AA) with different saturation levels were utilized to modify the lovastatin-loaded rHDL (LS-rHDL). Phagocytosis test on foam cells with or without cholesteryl ester transfer protein (CETP) expression was conducted to observe the cellular uptake of the SA or AA modified rHDL and the non-modified one. Raman spectroscopy, guanidine hydrochloride (Gdn-HCl) denaturation experiment and in vitro evaluation of drug release were used to analyze the related mechanism. In comparison with the non-modified rHDL, AA modification could reduce the packing order of the rHDL phospholipid acyl chains, leading to the decreased apoA-I binding extent with lipid and the increased drug release, while the opposite was true for SA modification. The AA-modified rHDL exhibited a higher uptake of foam cells expressing CETP than the non-modified one, while the SA-modified one showed the lowest cellular uptake among the three rHDLs. Increased unsaturation level can facilitate lipid-interchange process where the cargo in rHDL core may transfer to VLDL more easily, and then promote the endocytosis mediated by the VLDL receptor. Show less

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program. Show less

We aimed to identify independent genetic determinants of circulating CETP (cholesteryl ester transfer protein) to assess causal effects of variation in CETP concentration on circulating lipid concentrations and cardiovascular disease risk. A genome-wide association discovery and replication study on serum CETP concentration were embedded in the NEO study (Netherlands Epidemiology of Obesity). Based on the independent identified variants, Mendelian randomization was conducted on serum lipids (NEO study) and coronary artery disease (CAD; CARDIoGRAMplusC4D consortium). In the discovery analysis (n=4248), we identified 3 independent variants ( This is the first genome-wide association study identifying independent variants that largely determine CETP concentration. Although high-density lipoprotein cholesterol is not a causal risk factor for CAD, it has been unequivocally demonstrated that low-density lipoprotein cholesterol lowering is proportionally associated with a lower CAD risk. Therefore, the results of our study are fully consistent with the notion that CETP concentration is causally associated with CAD through low-density lipoprotein cholesterol. Show less

Current cholesteryl ester transfer protein (CETP) inhibitors are designed based on the unglycosylated crystal structure, and most of them have failed to cure cardiovascular disease (CVD). It is particularly important for us to investigate the glycosylation structure of CETP (CETP-G) and effect of glycans on the structure and function of CETP. Here, we used a total of 3.0-μs molecular dynamics (MD) trajectories of nascent structure of CETP (CETP-N) and CETP-G to study their structural differentiations, to shed new light on the CETP-mediated lipid exchange. In accordance with our simulations and previous mutation studies, relative to CETP-N, CETP-G adopts a more stretched shape with higher hydrophobic and hydrophilic solvent-accessible surface area (SASA) of N-terminal oscillating with larger amplitude, in which Glycan88 provides partial assistance for CEs through the N-terminal. Glycan341 reduces the flexibility of neck flap, with the interference of CEs through the neck region. Besides, Glycan240 reduces the flexibility of Helix-X to interfere the CEs transfer. Glycan396 decreases the flexibility and increases the hydrophobic SASA of C-terminal. Overall, these glycans affect the dynamics and structure of CETP through forming H-bonds with surrounding residues, and the sampled conformations of glycan is also affected by its surrounding residues. Thus, glycans are an integral part of CETP, further studies on the CETP inhibition and treatment of CVD should fully consider the effect of glycans. Show less

There is little evidence of the association between CETP SNPs and obesity and/or related metabolic parameters. To analyze the association of the polymorphism rs1800777 of the CETP gene with anthropometric parameters, lipid profile, metabolic syndrome and its components, and adipokine levels in obese subjects without type 2 diabetes mellitus or hypertension. A population of 1005 obese subjects was analyzed. Electrical bioimpedance was performed, and blood pressure, presence of metabolic syndrome, dietary intake, physical activity, and biochemical tests were recorded. Nine hundred and sixty eight patients (96.3%) had the GG genotype, 37 patients the GA genotype (3.7%) (no AA genotype was detected). Fat mass (delta: 4.4±1.1kg; p=0.04), waist circumference (delta: 5.6±2.1cm; p=0.02), and waist to hip ratio (delta: 0.04±0.01cm; p=0.01) were higher in A allele carriers than in non-A allele carriers. HDL cholesterol levels were lower in A allele carriers than in non-A allele carriers (delta: 4.2±1.0mg/dL; p=0.04). In the logistic regression analysis, the GA genotype was associated to an increased risk of central obesity (OR 7.55, 95% CI 1.10-55.70, p=0.02) and low HDL cholesterol levels (OR 2.46, 95% CI 1.23-4.91, p=0.014). The CETP variant at position +82 is associated to lower HDL cholesterol levels, increased fat mass, and central obesity in obese subjects. These results may suggest a potential role of this variant gene in pathophysiology of adipose tissue. Show less

Two weight gain prevention strategies, one targeting small changes to diet and physical activity and a second targeting large changes, significantly reduced weight gain in young adulthood. We examined whether weight gain prevention blunts genetic risk for body weight increase and/or high density lipoprotein cholesterol (HDL-C) lowering over two years. Participants were 524 male and female young adults (mean age = 28.2, SD = 4.3; mean BMI = 25.5, SD = 2.6). Obesity-related SNPs accounting for ≥ 0.04% of the variance were genotyped and combined into a genetic risk score. For HDL-C, SNPs within CETP, LIPC and FADS2 were genotyped. The obesity-related genetic risk score did not predict change in BMI independently or in interaction with treatment arm. However, consistent with the prior literature, each copy of the HDL-C risk, C, allele at CETP rs3764261 was associated with lower HDL-C at baseline. Moreover, significant interaction between SNP and treatment arm for change in HDL-C was observed (p = 0.02). In the control group, HDL-C change was dependent upon rs3764261 (p = 0.004) with C allele carriers showing a continued reduction in HDL-C. In contrast, within the two intervention groups, HDL-C increased on average with no differential effect of rs3764261 (p > 0.24). Notably, even among carriers of the CC genotype, small and large change arms were associated with increased HDL-C and the control arm a reduction (p = 0.013). The C allele at CETP rs3764261 is a strong risk factor for low HDL-C in young adulthood but weight gain prevention may mitigate this risk. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: clinicaltrials.gov Identifier: NCT01183689, https://clinicaltrials.gov/. Show less

Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Adcy9-inactivated ( Adcy9 Adcy9 Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone. Show less

Mannan oligosaccharides (MOS) have proven effective at improving growth performance, while also reducing hyperlipidemia and inflammation. As atherosclerosis is accelerated both by hyperlipidemia and inflammation, we aim to determine the effect of dietary MOS on atherosclerosis development in hyperlipidemic ApoE*3-Leiden.CETP (E3L.CETP) mice, a well-established model for human-like lipoprotein metabolism. Female E3L.CETP mice were fed a high-cholesterol diet, with or without 1% MOS for 14 weeks. MOS substantially decreased atherosclerotic lesions up to 54%, as assessed in the valve area of the aortic root. In blood, IL-1RA, monocyte subtypes, lipids, and bile acids (BAs) were not affected by MOS. Gut microbiota composition was determined using 16S rRNA gene sequencing and MOS increased the abundance of cecal Bacteroides ovatus. MOS did not affect fecal excretion of cholesterol, but increased fecal BAs as well as butyrate in cecum as determined by gas chromatography mass spectrometry. MOS decreased the onset of atherosclerosis development via lowering of plasma cholesterol levels. These effects were accompanied by increased cecal butyrate and fecal excretion of BAs, presumably mediated via interactions of MOS with the gut microbiota. Show less

To identify novel loci for susceptibility to MetS, we conducted genome-wide association and exome wide association studies consisting of a discovery stage cohort (KARE, 1946 cases and 6427 controls), and a replication stage cohort (HEXA, 430 cases and 3,264 controls). For finding genetic variants for MetS, with its components, we performed multivariate analysis for common and rare associations, using a standard logistic regression analysis for MetS. From the discovery and replication GWA studies, we confirmed 21 genome-wide signals significantly associated with MetS. Of these 21, four were previously unreported to associate with any MetS components: rs765547 near LPL; rs3782889 in MYL2; and rs11065756 and rs10849915 in CCDC63. Using exome chip variants, gene-based analysis of rare variants revealed three genes, CETP, SH2B1, and ZFP2, in the discovery stage, among which only CETP was confirmed in the replication stage. Finally, CETP D442G (rs2303790) associated, as a less common variant, with decreased risk of MetS. In conclusion, we discovered a total of five new MetS-associated loci, and their overlap with other disease-related components, suggest roles in the various etiologies of MetS, and its possible preventive strategies. Show less

Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from the nonatherogenic high density lipoprotein (HDL) fraction to potentially proatherogenic non-HDL fractions. Inhibition of CETP reduces the concentration of non-HDL cholesterol, enhances HDL functionality, and increases the concentration of HDL cholesterol and apoA-I. Despite an absence of benefit in earlier trials of CETP inhibition, the REVEAL trial has shown that treatment with the CETP inhibitor anacetrapib reduces the risk of having a coronary event in high-risk, statin-treated patients. Show less

Apolipoprotein B-containing lipoproteins and low-density lipoprotein play a key role in atherosclerotic vascular disease. Modified forms of low-density lipoprotein drive inflammation, an integral aspect of plaque progression. High-density lipoprotein particles are equipped to protect low-density lipoprotein from enzymatic and nonenzymatic modification. Under normal conditions, high-density lipoproteins facilitate cholesterol efflux from tissues, preventing its accumulation with deleterious consequences. However, the high-density lipoprotein particles characteristic of dyslipidemic states associated with premature atherosclerosis are typically dysfunctional as a result of alteration in their metabolism and consequently their structure and composition. Such an effect indirectly enhances low-density lipoprotein atherogenicity. Show less

Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized with the light/dark cycle. Highest uptake was found at the onset of the active period, which coincided with high lipoprotein lipase expression and low angiopoietin-like 4 expression by BAT. Diurnal rhythmicity in BAT activity determined the rate at which lipids were cleared from the circulation, thereby imposing the daily rhythm in plasma lipid concentrations. In mice as well as humans, postprandial lipid excursions were nearly absent at waking. We anticipate that diurnal BAT activity is an important factor to consider when studying the therapeutic potential of promoting BAT activity. Show less

Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl esters (CEs) from antiatherogenic high-density lipoproteins to proatherogenic low-density lipoproteins. Inhibition of CETP is therefore being pursued as a potential strategy to reduce cardiovascular risk. The crystal structure of CETP has revealed the existence of two neutral CEs and two charged phospholipids (PLs) in its hydrophobic tunnel. This is in direct contrast to the other lipid-binding proteins that contain only two bound lipids. Moreover, previous animal studies on mice showed no detectable PL-transfer activity of CETP. Thus, the role of bound PLs in CETP is completely unknown. Here, we employ molecular dynamics simulations and free-energy calculations to unravel the primary effects of bound PLs on CETP structure and dynamics and attempt to correlate the observed changes to its function. Our results suggest that the structure of CETP is elastic and can attain different conformations depending on the state of bound PLs. In solution, these PLs maintain CETP in a bent-untwisted conformation that can uphold neutral lipids in its core tunnel. Results also suggest that although both PLs complement each other in their action, the C-terminal PL (C-PL) imparts greater influence on CETP by virtue of its tighter binding. Our finding fits very well with the recent inhibitor-bound CETP crystal structure, where the inhibitor displaced the N-terminal PL for binding to CETP's central domain without disrupting the binding of C-PL. We speculate that the observed increased flexibility of CETP in the absence of PLs could play a crucial role in its binding with lipoproteins and subsequent lipid-transfer activity. Show less

Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment. Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function. Show less

We evaluated whether CETP and LCAT gene polymorphisms are statistically associated with the high-density lipoprotein (HDL) size distribution, the cholesterol level of HDL subclasses, and the acute coronary syndrome (ACS) susceptibility. Two CETP gene polymorphisms (rs4783961 and rs708272) and one LCAT polymorphism (rs2292318) were genotyped by 5' exonuclease TaqMan assays in 619 patients with ACS and 607 control individuals. For HDL analysis, a subgroup of 100 healthy individuals was recruited; the HDL subclasses were separated via ultracentrifugation and polyacrylamide gradient gel electrophoresis under native conditions. Under a dominant model, the G allele of the rs708272 polymorphism was associated with an increased risk of ACS (odds ratios [OR] = 1.45, corrected p-value [pC Show less

Cardiovascular diseases are still the main cause of death in Poland and throughout the world. Independent risk factors of cardiovascular disease, in addition to elevated LDL cholesterol, are both low HDL levels and high levels of non-HDL cholesterol. Plasma phospholipid-transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) both play a major role in the metabolism of those lipoproteins. A lack of these proteins increases HDL and lowers LDL levels. In the light of current knowledge, it seems reasonable to search for compounds that may decrease the activity of CETP, and thus reduce the incidence of cardiovascular disease. Whereas on the one hand there are reports about the adverse effect of torcetrapib and the lack of therapeutic effects of dalcetrapib, on the other hand the question arises whether the CETP inhibitors that are currently in clinical trials will rise to the challenges before them. Currently, it is known that the activity of PLTP, while affecting the metabolism of lipoproteins, especially HDL, plays a major role in atherogenesis. Still, there are some contradictions and controversies about the effect of PLTP on reverse cholesterol transport (RCT). There are a number of studies about the role that PLTP plays in the pathogenesis of various diseases. Further studies are needed to clearly determine the impact of PLTP activity on the formation and development of pathological processes in the cardiovascular system. Show less

Mechanisms of metabolic syndrome (MetS) causation are complex, genetic and environmental factors are important factors for the pathogenesis of MetS In this study, we aimed to evaluate familial and genetic influences on metabolic syndrome risk factor and also assess association between FTO (rs1558902 and rs7202116) and CETP(rs1864163) genes' single nucleotide polymorphisms (SNP) with low HDL_C in the Tehran Lipid and Glucose Study (TLGS). The design was a cross-sectional study of 1776 members of 227 randomly-ascertained families. Selected families contained at least one affected metabolic syndrome and at least two members of the family had suffered a loss of HDL_C according to ATP III criteria. In this study, after confirming the familial aggregation with intra-trait correlation coefficients (ICC) of Metabolic syndrome (MetS) and the quantitative lipid traits, the genetic linkage analysis of HDL_C was performed using conditional logistic method with adjusted sex and age. The results of the aggregation analysis revealed a higher correlation between siblings than between parent-offspring pairs representing the role of genetic factors in MetS. In addition, the conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant. In summary, a high risk of MetS was found in siblings confirming the genetic influences of metabolic syndrome risk factor. Moreover, the power to detect linkage increases in the one parameter conditional logistic model regarding the use of age and sex as covariates. Show less

Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in HDL metabolism but its influence on atherosclerosis remains controversial for decades both in animal and clinical studies. Because lack of cholesteryl ester transfer protein (CETP) is a major difference between murine and humans in lipoprotein metabolism, we aimed to create a novel Syrian Golden hamster model deficient in LCAT activity, which expresses endogenous CETP, to explore its metabolic features and particularly the influence of LCAT on the development of atherosclerosis. CRISPR/CAS9 gene editing system was employed to generate mutant LCAT hamsters. The characteristics of lipid metabolism and the development of atherosclerosis in the mutant hamsters were investigated using various conventional methods in comparison with wild type control animals. Hamsters lacking LCAT activity exhibited pro-atherogenic dyslipidemia as diminished high density lipoprotein (HDL) and ApoAI, hypertriglyceridemia, Chylomicron/VLDL accumulation and significantly increased ApoB100/48. Mechanistic study for hypertriglyceridemia revealed impaired LPL-mediated lipolysis and increased very low density lipoprotein (VLDL) secretion, with upregulation of hepatic genes involved in lipid synthesis and transport. The pro-atherogenic dyslipidemia in mutant hamsters was exacerbated after high fat diet feeding, ultimately leading to near a 3- and 5-fold increase in atherosclerotic lesions by aortic en face and sinus lesion quantitation, respectively. Our findings demonstrate that LCAT deficiency in hamsters develops pro-atherogenic dyslipidemia and promotes atherosclerotic lesion formation. Show less

Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. In CETP-transgenic mice, LPS markedly decreased hepatic Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80 Show less

Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. A meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. Four eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81-0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=-1.13, P=0.26). CETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration. Show less

High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943. Show less

The actions of the cholesteryl ester transfer protein (CETP) inhibitors (torcetrapib, dalcetrapib and evacetrapib) include increasing high-density lipoprotein (HDL) cholesterol, but they do not reduce cardiovascular outcomes in subjects with high cardiovascular risk. Anacetrapib also inhibits CETP, increases HDL cholesterol and lowers low-density lipoprotein (LDL) cholesterol. Areas covered: This evaluation is of the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, which was a cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk. Consideration is given as to whether increasing HDL cholesterol, lowering LDL cholesterol or other mechanisms/factors underlying the positive outcome with this CETP inhibitor. Expert opinion: After three years, the REVEAL trial with anacetrapib, demonstrated cardiovascular benefits, but not a reduction in coronary artery deaths. The reductions were not significant in years one and two. Thus, in my opinion, the benefits of anacetrapib were not major, and may not apply in 'real' world populations where adherence to medicines is lower than in REVEAL. Also, lowering LDL cholesterol and off-target mechanisms of anacetrapib may have contributed to any beneficial and/or toxic effects. Anacetrapib has a good safety profile. Show less

Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized. Show less