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Introduction Genetic inhibition of Cholesteryl Ester Transfer Protein (CETP) might be associated with insulin resistance and incident type 2 diabetes mellitus (T2DM). This study investigated the relation between a genetic variant in the CETP gene and measures of insulin resistance and incident T2DM in patients with manifest cardiovascular disease (CVD). Furthermore the effect on risk of recurrent cardiovascular events was investigated. Methods SMART is a prospective cohort study performed in 5601 patients with clinically manifest CVD. We selected a variant (rs3764261) associated with reduced CETP activity and increased levels of HDL cholesterol (HDL-C). Patients were divided in three groups: 2640 wild type patients (GG), 2420 heterozygotes for rs3764261 (GT) and 541 homozygotes for rs3764261 (TT). Regression analyses were performed using an additive model. Results The study population consisted of 4656 patients without T2DM and 945 patients with T2DM at baseline. Presence of rs3764261 was associated with increased HDL-C in patients without T2DM (β 0.106, 95%CI 0.083–0.128) and with T2DM (β 0.043, 95%CI 0.007–0.078). During a median follow up of 7.2 years (IQR 4.7–10.2) 427 incident T2DM occurred. Presence of rs3764261 was not related to incident T2DM (HR 0.96, 95%CI 0.83–1.11) in patients without T2DM at baseline. Furthermore, presence of rs3764261 was not related to insulin resistance (glucose, insulin, HOMA-IR, HbA1c) or recurrent CVD (HR 0.92, 95%CI 0.84–1.02). Conclusion Presence of CETP SNP rs3764261 is not associated with insulin resistance and incident T2DM in patients with clinically manifest vascular disease. Furthermore, no effect of rs3764261 on the risk of recurrent CVD was observed. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recent findings suggest that DNA methylation, a well-known epigenetic mechanism, is involved in high-density lipoprotein cholesterol (HDL-C) metabolism and increased cardiovascular disease risk. The aim of this study was thus to assess whether DNA methylation within key genes of lipoprotein metabolism is associated with blood lipid profile variability. Methods and results: Ninety-eight untreated familial hypercholesterolaemia patients (61 men and 37 women) were recruited for leucocyte DNA methylation analyses at the LDLR, CETP, LCAT and LPL gene promoter loci using bisulfite pyrosequencing. LPL DNA methylation was correlated with HDL-C (r = 0.22; p = 0.031) and HDL particle size (r = 0.47, p = 0.013). In both sex, CETP DNA methylation was negatively associated with low-density lipoprotein cholesterol levels (r < −0.32; p < 0.05). In men, CETP DNA methylation was associated with HDL-C (r = −0.36; p = 0.006), HDL-triglyceride levels (r = 0.59; p < 0.001) and HDL particle size (r = −0.44, p = 0.019). In visceral adipose tissue from 30 men with severe obesity, the associations between LPL DNA methylation, HDL-C (r = −0.40; p = 0.03) and LPL mRNA levels (r = −0.61, p < 0.001) were confirmed. Conclusion: CETP and LPL DNA methylation levels are associated with blood lipid profile, suggesting that further studies of epipolymorphisms should most certainly contribute to a better understanding of the molecular bases of dyslipidemia. [Copyright &y& Elsevier]

Abstract: Objective: Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects. Methods: Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900mg, ezetimibe 10mg, dalcetrapib 900mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption. Results: Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p =0.001), 32% (p <0.001), and 12% (p =0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p =0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56–148%, p <0.001) and with dalcetrapib+ezetimibe (32–38%, p <0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p =0.04) and 72% (p =0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma 3H-cholesterol level but increased 3H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol. Conclusion: Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis. [Copyright &y& Elsevier]

Abstract: Objective:: In order to determine the influence of the lipid status on the ability of cholesteryl ester transfer protein (CETP) to modify the plasma lipoprotein profile, the effect of hypercholesterolemia versus hypertriglyceridemia were compared in wild-type and CETP-transgenic (CETPTg) rats expressing CETP at a constant level. Methods and results:: Wild-type and CETPTg rats were fed either a chow diet, a high fat/high cholesterol (HF/HC) diet, or a sucrose diet. As compared to wild-type rats, CETPTg rats fed the standard chow exhibited lower high-density lipoproteins (HDL)–cholesterol concentration (-65%, p<0.01), but similar non-HDL–cholesterol concentrations. Both wild-type and CETPTg rats fed the HF/HC diet displayed pronounced increases in total and non-HDL–cholesterol levels, with no influence of CETP expression in this case. In contrast, the sucrose diet produced significant changes only in CETPTg rats which then exhibited a 82% increase in non-HDL–cholesterol in addition to a 80% reduction in HDL cholesterol when compared to sucrose-fed, wild-type rats (p<0.01 in both cases). The triglyceride to cholesterol ratio in very low-density lipoprotein (VLDL) was 10-fold lower in ‘HF/HC’ rats than in ‘chow’ and ‘sucrose’ rats (p<0.005 and p<0.01, respectively), and VLDL from ‘HF/HC’ animals were proven to constitute poor cholesteryl ester acceptors. Conclusions:: CETP expression modified dramatically the lipoprotein phenotype in ‘sucrose’ rats but not in ‘HF/HC’ rats. These observations suggest that a CETP inhibitor treatment is susceptible to produce profound changes in hypertriglyceridemia or combined hyperlipidemia. [Copyright &y& Elsevier]

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Subsequently, cholesterol ester (CE) on HDL in humans is transported to apolipoprotein B-containing lipoproteins by cholesteryl ester transfer protein (CETP). CETP deficiency, which is common in the Japanese population, leads to a marked increase in HDL-cholesterol levels due to impaired CE transport from HDL to LDL. It has been reported that the HDL observed in CETP deficiency is an atherogenic lipoprotein, as it contains a large amount of CE. Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free cholesterol between HDL and cells. In the present study, the interaction between SR-BI and CE-rich HDL from CETP-deficient patient was studied in order to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport. When CE-rich HDL was added to the medium of SR-BI-transfected CHO (SR-BI CHO) cells, more CE accumulated in SR-BI CHO cells compared to control HDL. In contrast, the amount of cholesterol efflux from SR-BI CHO cells into HDL was almost the same between the two HDLs. Therefore, when CE-rich HDL was added to the medium of SR-BI CHO cells, the intracellular CE content increased significantly. Moreover, the particle size of HDL in CETP-deficient patient decreased significantly when the HDL was added to the medium of SR-BI CHO cells, and this HDL showed an increment of CE efflux from foam cells. These results indicate that SR-BI reduces the cholesterol content and size of the CE-rich HDL from CETP deficiency, which ultimately activate reverse cholesterol transport system. [Copyright &y& Elsevier]

Background: Inhibition of cholesteryl ester transfer protein (CETP) is an effective way to increase HDL levels in animals and humans. The effects of a CETP inhibitor, JTT-705, on the in vivo kinetics of apolipoprotein (apo) A-I and apo A-I gene expression in the liver and intestine were investigated. Methods: Japanese White rabbits were randomly fed normal rabbit chow LRC-4 (n=10, control) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10, treated) for 7 months. An in vivo kinetics study of apo A-I was performed by injecting rabbit 125I-apo A-I, and apo A-I mRNA levels were quantified by RT-PCR. Results: JTT-705 significantly inhibited CETP activities, increased serum levels of HDL-cholesterol (C), HDL2-C, HDL-phospholipid, and apo A-I, and decreased HDL-triglyceride levels. The synthetic rate of apo A-I was higher in the treated rabbits than in control rabbits (13.7±2.6 versus 9.5±1.3 mg/kg per day, P<0.05), while the fractional catabolic rate was similar in the two groups. JTT-705 increased apo A-I mRNA levels in the liver without affecting those in the intestine. Conclusion: Inhibition of CETP activity by JTT-705 increases HDL levels by increasing the synthesis of apo A-I, suggesting that it could be a promising therapeutic approach for atherosclerosis. [Copyright &y& Elsevier]

Objectives: To explore the therapeutic potential of fibrates to attenuate premature atherosclerosis and cardiovascular disease in the atherogenic dyslipidemias typical of Type II diabetes, Metabolic Syndrome, and the Type IIB (mixed) lipid phenotype; such dyslipidemias frequently feature peripheral insulinoresistance. Background: Recent epidemiological data reveal that a marked increase in the prevalence of Type II diabetes, obesity and the Metabolic Syndrome has occurred on a worldwide scale. Dyslipidemia is an integral component of the metabolic perturbations which characterise these disorders, and is intimately associated with premature atherosclerosis and elevated cardiovascular risk. The atherogenic dyslipidemias of Type II diabetes, the Metabolic Syndrome and mixed (IIB) hyperlipidemia feature moderate to marked elevation of triglyceride-rich lipoproteins, low HDL-C cholesterol levels, and a dense LDL phenotype; equally, they feature an inflammatory state. Fibrates, agonists of PPARα, act to modulate the expression of key genes of lipid transport and metabolism in organs such as the liver and adipose tissue; equally, they exert pleiotropic, anti-inflammatory effects downregulating expression of genes encoding acute phase proteins and inflammatory cytokines. By inducing elevation of HDL-C levels, reduction in triglyceride-rich lipoproteins and a shift in the dense LDL phenotype to receptor-active, buoyant LDL, and by diminishing the inflammatory state, fibrates act to attenuate the atherosclerotic burden in atherogenic dyslipidemia. Such actions translate into significant clinical benefit as demonstrated by the reduction in cardiovascular morbi-mortality observed in both primary and secondary intervention trials (VA-HIT, Helsinki Heart Study, SENDCAP, DAIS, BECAIT). Conclusions: Fibrate therapy represents a cost effective approach to the clinical management of a wide spectrum of atherogenic dyslipidemias involving low HDL-C and elevated TGRL levels, and which include Type II diabetes and the Metabolic Syndrome. Optimised clinical application of these lipid modulating, anti-inflammatory drugs in these disorders in the context of either monotherapy or in combination with low dose statin is, therefore, warranted. [Copyright &y& Elsevier]