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Fish oil (FO) supplementation reduces the risk of CVD. However, it is not known if FO of different qualities have different effects on lipoprotein subclasses in humans. We aimed at investigating the effects of oxidised FO and high-quality FO supplementation on lipoprotein subclasses and their lipid concentrations in healthy humans. In all, fifty-four subjects completed a double-blind randomised controlled intervention study. The subjects were randomly assigned to receive high-quality FO (n 17), oxidised FO (n 18) or high-oleic sunflower oil capsules (HOSO, n 19) for 7 weeks. The concentration of marine n-3 fatty acids was equal in high-quality FO and oxidised FO (1·6 g EPA+DHA/d). The peroxide value (PV) and anisidine value (AV) were 4 mEq/kg and 3 in high-quality FO and HOSO, whereas the PV and AV in the oxidised FO were 18 mEq/kg and 9. Blood samples were collected at baseline and end of study. NMR spectroscopy was applied for the analysis of lipoprotein subclasses and their lipid concentrations. High-quality FO reduced the concentration of intermediate-density lipoprotein (IDL) particles and large, medium and small LDL particles, as well as the concentrations of total lipids, phospholipids, total cholesterol, cholesteryl esters and free cholesterol in IDL and LDL subclasses compared with oxidised FO and HOSO. Hence, high-quality FO and oxidised FO differently affect lipid composition in lipoprotein subclasses, with a more favourable effect mediated by high-quality FO. In future trials, reporting the oxidation levels of FO would be useful. Show less

Anacetrapib is a novel cholesteryl-ester transfer protein (CETP) inhibitor in late-stage clinical development, shown in preceding clinical trials to have residual pharmacological activity after prolonged washout after chronic dosing. Preclinical findings suggest that white adipose tissue is a potential depot and that accumulation into adipose tissue governs the long-term kinetics of anacetrapib in mice. A phase I study performed to test this hypothesis in humans revealed that plasma exposure was correlated with fat content in food administered with the drug. Plasma concentrations of anacetrapib seemed to reach plateau faster than adipose concentrations. Anacetrapib continued to accumulate in adipose during the treatment period despite apparent plateau in plasma with only minimal decline in adipose levels up to 1 year postdose. Because of its high lipophilicity, anacetrapib partitions into adipose tissue, this likely forms a drug reservoir that, in turn, contributes to the long residence time of the drug in plasma. Show less

Tubular lipid binding proteins (TULIPs) have become a focus of interest in the cell biology of lipid signalling, lipid traffic and membrane contact sites. Each tubular domain has an internal pocket with a hydrophobic lining that can bind a hydrophobic molecule such as a lipid. This allows TULIP proteins to carry lipids through the aqueous phase. TULIP domains were first found in a large family of extracellular proteins related to the bacterial permeability-inducing protein (BPI) and cholesterol ester transfer protein (CETP). Since then, the same fold and lipid transfer capacity have been found in SMP domains (so-called for their occurrence in synaptotagmin, mitochondrial and lipid binding proteins), which localise to intracellular membrane contact sites. Here the methods for identifying known TULIPs are described, and used to find previously unreported TULIPs, one in the silk polymer and another in prokaryotes illustrated by the E. coli protein YceB. The bacterial TULIP alters views on the likely evolution of the domain, suggesting its presence in the last universal common ancestor. The major function of TULIPs is to handle lipids, but we still do not know how they work in detail, or how many more remain to be discovered. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann. Show less

High density lipoprotein (HDL) cholesterol is not decreased in hypercortisolism despite high triglycerides, which may be ascribed to effects on the cholesteryl ester transfer protein (CETP) pathway. We explored if CETP mRNA expression is modulated by glucocorticoid treatment in vitro. Effects of doubling the hydrocortisone (HCT) replacement dose on plasma CETP activity, and HDL characteristics were tested in patients with secondary adrenal insufficiency. Human THP-1 macrophages were incubated with corticosterone in vitro in the presence or absence of a liver X receptor (LXR) agonist, followed by determination of CETP mRNA levels by quantitative real-time PCR. In addition, a randomised double-blind cross-over study was performed in 47 patients with secondary adrenal insufficiency (university medical setting; 10 weeks exposure to a higher HCT dose (0·4-0·6 mg/kg body weight) vs. 10 weeks of a lower HCT dose (0·2-0·3 mg/kg body weight). Corticosterone dose dependently decreased CETP mRNA in THP-1 macrophages. Corticosterone also decreased CETP mRNA expression after LXR pretreatment. In patients, CETP activity decreased with doubling of the HCT dose (P = 0·049), coinciding with an increase in HDL cholesterol, apolipoprotein A-I and the HDL cholesterol/apolipoprotein A-I ratio (reflecting HDL size; P < 0·01 for each). The increase in the HDL cholesterol/apolipoprotein A-I ratio was correlated with the decrease in plasma CETP activity (r = -0·442, P = 0·002). Glucocorticoids downregulate CETP gene expression in a human macrophage cell system. In line, a higher glucocorticoid replacement dose decreases plasma CETP activity in patients, thereby contributing to higher HDL cholesterol and an increase in estimated HDL size. Show less

High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice. Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETP mice on high cholesterol diet and treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day) or placebo. Cholesterol efflux was assessed ex-vivo in mice treated with CETP inhibitors for 3 weeks on a normal chow diet. Endothelial function was analyzed at week 21 in isolated aortic rings, and serum lipoproteins assessed by fast-performance liquid chromatography. Anacetrapib and evacetrapib increased HDL-C levels (5- and 3.4-fold, resp.) and reduced triglycerides (-39% vs. placebo, p = 0.0174). Total cholesterol levels were reduced only in anacetrapib-treated mice (-32%, p = 0.0386). Cholesterol efflux and PON-1 activity (+45% and +35% vs. control, p < 0.005, resp.) were increased, while aortic ROS production was reduced with evacetrapib (-49% vs. control, p = 0.020). Anacetrapib, but not evacetrapib, impaired endothelium dependent vasorelaxation (p < 0.05). In contrast, no such effects were observed in E3L mice for all parameters tested. Notwithstanding a marked rise in HDL-C, evacetrapib did not improve endothelial function, while anacetrapib impaired it, suggesting that CETP inhibition does not provide vascular protection. Anacetrapib exerts unfavorable endothelial effects beyond CETP inhibition, which may explain the neutral results of large clinical trials in spite of increased HDL-C. Show less

Circulating lipid concentrations are among the strongest modifiable risk factors for coronary artery disease (CAD). Most genetic studies have focused on Caucasian populations with little information available for populations of African ancestry. Using a cohort of ~2800 African-Americans (AAs) from a biobank at Vanderbilt University (BioVU), we sought to trans-ethnically replicate genetic variants reported by the Global Lipids Genetics Consortium to be associated with lipid traits in Caucasians, followed by fine-mapping those loci using all available variants on the MetaboChip. In AAs, we replicated one of 56 SNPs for total cholesterol (TC) (rs6511720 in LDLR, P=2.15 × 10 Show less

Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% ( Show less

Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the To test whether protein-truncating variants (PTVs) at the We sequenced the exons of the Compared with noncarriers, carriers of PTV at Show less

N,N-Substituted amine derivatives were designed by utilizing a bioisosterism strategy. Consequently, twenty-two compounds were synthesized and evaluated for their inhibitory activity against CETP. Structure-activity relationship (SAR) studies indicate that hydrophilic groups at the 2-position of the tetrazole and 3,5-bistrifluoromethyl groups on the benzene ring provide important contributions to the potency. Among these compounds, compound 17 exhibited excellent CETP inhibitory activity (IC Show less

High levels of plasma high-density lipoprotein-cholesterol (HDL-C) are inversely associated with the risk of atherosclerosis and other cardiovascular diseases; thus, pharmacological inhibition of cholesteryl ester transfer protein (CETP) is considered to be a therapeutic method of raising HDL-C levels. However, many CETP inhibitors have failed to achieve a clinical benefit despite raising HDL-C. In the study, we generated transgenic (Tg) rabbits that overexpressed the human CETP gene to examine the influence of CETP on the development of atherosclerosis. Both Tg rabbits and their non-Tg littermates were fed a high cholesterol diet for 16 weeks. Plasma lipids and body weight were measured every 4 weeks. Gross lesion areas of the aortic atherosclerosis along with lesional cellular components were quantitatively analyzed. Overexpression of human CETP did not significantly alter the gross atherosclerotic lesion area, but the number of macrophages in lesions was significantly increased. Overexpression of human CETP did not change the plasma levels of total cholesterol or low-density lipoprotein cholesterol but lowered plasma HDL-C and increased triglycerides. These data revealed that human CETP may play an important role in the development of atherosclerosis mainly by decreasing HDL-C levels and increasing the accumulation of macrophage-derived foam cells. Show less

Retinopathy of prematurity (ROP) is a neurovascular complication in preterm babies, leading to severe visual impairment, but the underlying mechanisms are yet unclear. The present study aimed at unraveling the molecular mechanisms underlying the pathogenesis of ROP. A comprehensive screening of candidate genes in preterms with ROP ( Show less

We aimed to assess the effects of cholesteryl ester transfer protein inhibitor anacetrapib added to statin ± other lipid-modifying therapies (LMT) in Japanese patients with dyslipidemia who were not at their LDL-C goal. Patients on a stable dose of statin ± other LMT with LDL-C ≥100 mg/dL to <145 mg/dL, ≥120 mg/dL to <165 mg/dL, ≥140 mg/dL or ≥160 mg/dL for patients with a history of coronary heart disease (CHD), high-, moderate- and low-risk patients respectively, were randomized 2:1, stratified by background therapy, to double-blind anacetrapib 100 mg (n = 204) or placebo (n = 103) for 24 weeks, followed by a 28-week open-label extension phase (anacetrapib 100 mg) and a 12-week off-drug safety follow-up phase. The primary endpoint was percent change from baseline in LDL-C (beta-quantification method), as well as the safety profile of anacetrapib at Week 24; HDL-C was a key secondary endpoint. Anacetrapib 100 mg further reduced LDL-C (38.0%), non-HDL-C (35.1%), ApoB (28.7%), and Lp(a) (48.3%) and increased HDL-C (148.9%) and ApoAI (50.7%) versus placebo (p < 0.001 for all). There were no meaningful differences between the groups in the proportion of patients with liver enzymes elevations (2.0% vs. 0%), creatine kinase elevations overall (0.5% vs. 0%) or with muscle symptoms (0.5% vs. 0%), blood pressure, electrolytes or adjudicated cardiovascular events (0.5% vs. 0%). In the open-label period, sustained effects on lipid parameters were observed with anacetrapib and the treatment was generally well tolerated. Long-term treatment with anacetrapib 100 mg substantially reduced LDL-C, increased HDL-C and was well tolerated in Japanese patients with dyslipidemia (ClinicalTrials.gov number NCT01760460). Show less

Undertake a systematic investigation into associations between genetic predictors of lipid fractions and age-related macular degeneration (AMD) risk. Two-sample Mendelian randomization investigation using published data. A total of 33 526 individuals (16 144 cases, 17 832 controls) predominantly of European ancestry from the International Age-related Macular Degeneration Genomics Consortium. We consider 185 variants previously demonstrated to be associated with at least 1 of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides at a genome-wide level of significance, and test their associations with AMD. We particularly focus on variants in gene regions that are proxies for specific pharmacologic agents for lipid therapy. We then conduct a 2-sample Mendelian randomization investigation to assess the causal roles of LDL-cholesterol, HDL-cholesterol, and triglycerides on AMD risk. We also conduct parallel investigations for coronary artery disease (CAD) (viewed as a positive control) and Alzheimer's disease (a negative control) for comparison. Diagnosis of AMD. We find evidence that HDL-cholesterol is a causal risk factor for AMD, with an odds ratio (OR) estimate of 1.22 (95% confidence interval [CI], 1.03-1.44) per 1 standard deviation increase in HDL-cholesterol. No causal effect of LDL-cholesterol or triglycerides was found. Variants in the CETP gene region associated with increased circulating HDL-cholesterol also associate with increased AMD risk, although variants in the LIPC gene region that increase circulating HDL-cholesterol have the opposite direction of association with AMD risk. Parallel analyses suggest that lipids have a greater role for AMD compared with Alzheimer's disease, but a lesser role than for CAD. Some genetic evidence suggests that HDL-cholesterol is a causal risk factor for AMD risk and that increasing HDL-cholesterol (particularly via CETP inhibition) will increase AMD risk. Show less

Extensive studies have demonstrated that biochanin A (BCA) has a significant hypolipidemic effect. However, its mechanism of action is not clear. In this context, the effect of BCA on a high-fat diet (HFD)-induced hyperlipidemia in mice was determined. The results showed that treatment with a medium dose of biochanin A (BM) significantly decreased low-density lipoprotein cholesterol (LDL-C) 85% (from 1.196 ± 0.183 to 0.181 ± 0.0778 mM) and total cholesterol (TC) 39% (from 5.983 ± 0.128 to 3.649 ± 0.374 mM) levels, increased lipoprotein lipase (LPL) 96% (from 1.421 ± 0.0982 to 2.784 ± 0.177 U/mg protein) and hepatic triglyceride lipase (HTGL) 78% (from 1.614 ± 0.0848 to 2.870 ± 0.0977 U/mg protein) activities, significantly improved fecal lipid levels, and lowered the epididymal fat index in hyperlipidemic mice compared with the HFD control mice (p < 0.05). In vitro, the high antioxidant capacity of BCA was determined by the FRAP assay, ABTS Show less

There is few evidence of cholesterol ester transfer protein (CETP) in subjects with obesity and diabetes mellitus. We examined the association of the polymorphism (rs1800777) of CETP gene on anthropometric parameters, lipid profile and adipokines in subjects with obesity and diabetes mellitus type 2. A population of 229 obese subjects with diabetes mellitus type 2 was enrolled. An electrical bioimpedance, blood pressure, dietary intake, exercise and biochemical analyses were recorded. Two hundred and seventeen subjects (94.8%) had genotype GG and 12 GA (5.2%) (genotype AA was not detected). Weight (delta: 14.4 ± 2.1 kg, p = 0.01), body mass index (delta: 2.2 ± 1.1 kg/m2, p = 0.01), fat mass (delta: 11.2 ± 3.1 kg, p = 0.02), waist circumference (delta: 3.9 ± 2.0 cm, p = 0.02), waist to hip ratio (delta: 0.04 ± 0.02 cm; p = 0.01), tryglicerides (delta: 48.6 ± 9.1 mg / dl, p = 0.03) and leptin levels (delta: 58.6 ± 15.9 mg/dl, p = 0.02) were higher in A allele carriers than non A allele carriers. Levels of HDL-cholesterol were lower in A allele carriers than non-carriers (delta: 5.6 ± 1.1 mg/dl, p = 0.03). In regression analysis, HDl cholesterol, weight and fat mass remained in the model with the SNP. Our results show an association of this CETP variant at position +82 on HDL cholesterol, levels and adiposity parameters in obese subjects with diabetes mellitus type 2. Show less

Treatment of blood cholesterol is part of a strategy to lower atherosclerotic cardiovascular (ASCVD) risk. While use of HMG-CoA reductase inhibitors to modify cholesterol levels is the primary means of lowering the risk of an ASCVD event, residual risk remains. A new strategy being investigated is the use of cholesterol ester transfer protein (CETP) inhibitors to raise the levels of high-density lipoprotein cholesterol (HDL-C) and lower low-density lipoprotein cholesterol (LDL-C). While initial large-scale studies demonstrated no reduction of cardiovascular events, one CETP inhibitor, anacetrapib, has demonstrated a reduction in cardiovascular events in the REVEAL trial. Show less

Association of cholesteryl ester transfer protein (CETP) Gene -629C/A Polymorphism with angiographically proven atherosclerosis CETP gene has been linked to CAD risk via its role in HDL and LDL metabolism. There is no agreement of whether CETP is atherogenic or not. Furthermore, various genotypes of CETP gene have been associated with CETP levels and thus with atherosclerosis risk. Our aim was to study the association of CETP -629C/A gene polymorphism with CETP and HDL levels and their association if any with atherosclerosis. Study population consisted of angiographically documented 50 cases with coronary artery atherosclerosis and 50 controls negative for atherosclerosis of coronary artery. Serum lipid profile was measured on SYNCHRON CX-9 using standard kits. Serum CETP levels were measured by ELISA method. CETP -629C/A gene polymorphism was studied using PCR-RFLP method. There was no significant difference in lipid profile of the two groups. However, serum CETP level was significantly higher (46.44 ± 21.75 ng/ml) in cases than controls (37.10 ± 21.92 ng/ml) with Show less

Cholesteryl ester transfer protein (CETP) facilitates movement of esterified cholesterol between high-density lipoproteins (HDLs) and apolipoprotein B-containing lipoproteins. By virtue of their ability to raise HDL cholesterol and lower low-density lipoprotein cholesterol, pharmacological inhibitors of CETP have received considerable attention as potential new agents in cardiovascular prevention. While early studies of CETP inhibitors have demonstrated a lack of clinical efficacy and potential toxicity, development of the potent CETP inhibitor, anacetrapib, has moved forward, with emerging evidence suggesting a role in reducing cardiovascular events. The experience with anacetrapib and its potential for use in clinical practice are reviewed here. Show less

Despite an enormous success in reducing morbidity and mortality in cardiovascular disease (CVD), statins and modern antihypertensive medications are not universally effective. Research has focused on potential molecular targets in dyslipidemia. Decades-long, expensive trial with CETP (cholesterylester transfer protein) inhibitor evacetrapib, came in April 2016 to crash landing. Despite dramatic improvement in "good" HDL-cholesterol and decline in "bad" LDL-C, the effect of evacetrapib in CVD patients was comparable to placebo. Notwithstanding failure in this molecular target field, results with another agent the PCSK9 inhibitor, may identify the molecular site that would normalize dyslipidemia, without harming physiologically essential lipids (Fig. 2, Ref. 19). Show less

Coronary artery disease (CAD) occurring in less than 45 years of age is termed as young CAD. Recent studies show a prevalence of 1.2% of CAD cases in this age group. Ethnic wise south Asians especially Indians are more vulnerable to have CAD in young age group with a prevalence of 5% to 10%. Conventional risk factors such as smoking, diabetes, hypertension, obesity and family history seems to be as important as in older CAD subjects. But the prevalence of these risk factors seems to vary in younger subjects. By far the most commonly associated risk factor is smoking in young CAD. Several genes associated with lipoprotein metabolism are now found to be associated with young CAD like cholesterol ester transfer protein ( Show less

In this study, for the first time, MF59 adjuvant was used to develop a cholesteryl ester transfer protein (CETP) vaccine. The efficacy of the vaccine was compared with the efficacy of CETP vaccine formulated with Alum/CpG, the formulation that its immunogenicity has been already demonstrated in rabbit and mice. Tetanus toxoid- CETP peptide (TT-CETP) was mixed with Alum/CpG or MF59-like and administered subcutaneously for total five times in rabbit model of atherosclerosis. Anti-TT-CETP specific antibody, CETP activity in sera and mRNA level of cytokine IL-4 and IFN-γ in peripheral mononuclear cells were determined. Therapeutic response was also examined by tracking serum lipoprotein levels and pathologic observation of atherosclerotic lesions at aortic site. More anti-TT-CETP antibody was found in Alum/CpG vaccinated rabbits compared to buffer ( It is concluded that MF59-adjuvanted CETP vaccine showed anti-atherosclerosis properties, but the protective effect could not be directly attributed to the immune response induced by anti TT-CETP antibody and CETP inhibition. Further studies are needed to explain the anti-atherosclerosis properties of MF59 in the presence of TT-CETP peptide. Show less

Cholesterol and its metabolites act as steroid hormone precursors, which promote estrogen receptor positive (ER+) breast cancer (BC) progression. Development of cholesterol targeting anticancer drugs has been hindered due to the lack of knowledge of viable molecular targets. Till now, Cholesteryl ester transfer protein (CETP) has been envisaged as a feasible molecular target in atherosclerosis, but for the first time, we show that Show less

Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF) < 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P = 1.03 × 10−6, odds ratio (OR) = 2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations. Show less