Search

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]

Epidemiologic studies have shown that low-density lipoprotein cholesterol (LDL-C) is a strong risk factor, whilst high-density lipoprotein cholesterol (HDL-C) reduces the risk of coronary heart disease (CHD). Therefore, strategies to manage dyslipidemia in an effort to prevent or treat CHD have primarily attempted at decreasing LDL-C and raising HDL-C levels. Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL and LDL. We have published the first report indicating that a group of Japanese patients who were lacking CETP had extremely high HDL-C levels, low LDL-C levels and a low incidence of CHD. Animal studies, as well as clinical and epidemiologic evidences, have suggested that inhibition of CETP provides an effective strategy to raise HDL-C and reduce LDL-C levels. Four CETP inhibitors have substantially increased HDL-C levels in dyslipidemic patients. This review will discuss the current status and future prospects of CETP inhibitors in the treatment of CHD. At present anacetrapib by Merck and evacetrapib by Eli Lilly are under development. By 100mg of anacetrapib HDL-C increased by 138%, and LDL-C decreased by 40%. Evacetrapib 500 mg also showed dramatic 132% increase of HDL-C, while LDL-C decreased by 40%. If larger, long-term, randomized, clinical end point trials could corroborate other findings in reducing atherosclerosis, CETP inhibitors could have a significant impact in the management of dyslipidemic CHD patients. Inhibition of CETP synthesis by antisense oligonucleotide or small molecules will produce more similar conditions to human CETP deficiency and may be effective in reducing atherosclerosis and cardiovascular events. We are expecting the final data of prospective clinical trials by CETP inhibitors in 2015. [ABSTRACT FROM AUTHOR]

Abstract: The mammalian target of rapamycin (mTOR) inhibiting drug rapamycin (Sirolimus) has severe side effects in patients including hyperlipidemia, an established risk factor for atherosclerosis. Recently, it was shown that rapamycin decreases hepatic LDL receptor (LDL-R) expression, which likely contributes to hypercholesterolemia. Scavenger receptor, class B, type I (SR-BI) is the major HDL receptor and consequently regulating HDL-cholesterol levels and the athero-protective effects of HDL. By using the mTOR inhibitor rapamycin, we show that SR-BI is down-regulated in human umbilical vein endothelial cells (HUVECs). This reduction of SR-BI protein as well as mRNA levels by about 50% did not alter HDL particle uptake or HDL-derived lipid transfer. However, rapamycin reduced HDL-induced activation of eNOS and stimulation of endothelial cell migration. The effects on cell migration could be counteracted by SR-BI overexpression, indicating that decreased SR-BI expression is in part responsible for the rapamycin-induced effects. We demonstrate that inhibition of mTOR leads to endothelial cell dysfunction and decreased SR-BI expression, which may contribute to atherogenesis during rapamycin treatment. [Copyright &y& Elsevier]

Abstract: Lipidomics has developed rapidly over the past decade to the point where clinical application may soon be possible. Developments including high throughput technologies enable the simultaneous quantification of several hundred lipid species, thereby providing a global assessment of lipid metabolism. Given the key role of lipids in the pathophysiology of diabetes and cardiovascular disease, lipidomics has the potential to: [i)] Significantly improve prediction of future disease risk, [ii)] Inform on mechanisms of disease pathogenesis, [iii)] Identify patient groups responsive to particular therapies and [iv)] More closely monitor response to therapy. Lipidomic analyses of both whole plasma and lipoprotein subfractions are integral to the current initiative to understand the relationships between lipoprotein composition and function and how these are affected by disease and treatment. This approach will not only aid in appropriate targeting of existing lipid lowering therapies such as statins and fibrates, but will be important in unravelling the controversies surrounding HDL-based therapies which have failed in clinical trials to date. The ultimate utility of lipidomics to clinical practice will depend firstly on the ability of risk prediction models incorporating lipidomic parameters to significantly improve upon conventional clinical risk markers in predicting future disease risk. Secondly, for widespread application, lipidomic-based measurements must be practical and accessible through standard pathology laboratories. This review will cover developments in lipidomics including methodology, bioinformatics/statistics, insights into disease pathophysiology, the effect of therapeutic interventions, the role of large clinical outcome trials in validating lipidomic approaches to patient management and potential applications in clinical practice. [Copyright &y& Elsevier]

Abstract: Cholesteryl ester transfer protein (CETP) is a plasma protein that reduces high density lipoprotein (HDL)-cholesterol (chol) levels and may increase atherosclerosis risk. n-3 and n-6 polyunsaturated fatty acids (PUFAs) are natural ligands, and fibrates are synthetic ligands for peroxisome proliferator activated receptor-alpha (PPARα), a transcription factor that modulates lipid metabolism. In this study, we investigated the effects of PUFA oils and fibrates on CETP expression. Hypertriglyceridemic CETP transgenic mice were treated with gemfibrozil, fenofibrate, bezafibrate or vehicle (control), and normolipidemic CETP transgenic mice were treated with fenofibrate or with fish oil (FO; n-3 PUFA rich), corn oil (CO, n-6 PUFA rich) or saline. Compared with the control treatment, only fenofibrate significantly diminished triglyceridemia (50%), whereas all fibrates decreased the HDL-chol level. Elevation of the CETP liver mRNA levels and plasma activity was observed in the fenofibrate (53%) and gemfibrozil (75%) groups. Compared with saline, FO reduced the plasma levels of nonesterified fatty acid (26%), total chol (15%) and HDL-chol (20%). Neither of the oil treatments affected the plasma triglyceride levels. Compared with saline, FO increased the plasma adiponectin level and reduced plasma leptin levels, whereas CO increased the leptin levels. FO, but not CO, significantly increased the plasma CETP mass (90%) and activity (23%) as well as increased the liver level of CETP mRNA (28%). In conclusion, fibrates and FO, but not CO, up-regulated CETP expression at both the mRNA and protein levels. We propose that these effects are mediated by the activation of PPARα, which acts on a putative PPAR response element in the CETP gene. [Copyright &y& Elsevier]

Objective: Our objective was to examine the role of hypertriglyceridemia on the capacity of HDL to facilitate ABCA-1 mediated cholesterol efflux in type 2 diabetes (T2DM). Methods: HDL mediated cholesterol efflux through the ABCA-1 transporter was measured using BHK cell lines in samples of 71 participants with T2DM in the presence or absence of high triglyceride levels (TG). Additionally, HDL mediated efflux was measured in 13 diabetic and non-diabetic participants fasting and four hours after a high-fat test challenge. Results: HDL mediated cholesterol efflux function was increased in participants with T2DM with hypertriglyceridemia when compared to participants with T2DM without hypertriglyceridemia (efflux ratio mean±standard deviation (SD), T2DM+TG: 1.17±0.25 vs. T2DM − TG: 1.03±0.19, p =0.0098). In the fat challenge study, we observed a significant increase in ABCA-1 mediated cholesterol efflux capacity following an ingestion of high-fat test meal by participants in both groups of T2DM (n=6, efflux ratio, mean±SD, pre: 0.86±0.4 vs. post: 1.34±0.6, p =0.01) and non-diabetic participants (n=7, efflux ratio mean±SD pre: 1.24±0.31 vs. post: 1.39±0.42, p =0.04) that was partly explained by the difference in CETP activity (r=0.6, p =0.03). Conclusion: Our study suggests that high triglyceride levels facilitate ABCA-1 mediated efflux function of HDL in part by activating CETP. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Niacin has been used for more than 50years to treat dyslipidemia, yet the mechanisms underlying its lipid-modifying effects remain unknown, a situation stemming at least in part from a lack of validated animal models. The objective of this study was to determine if the dyslipidemic hamster could serve as such a model. Materials/Methods: Dyslipidemia was induced in Golden Syrian hamsters by feeding them a high-fat, high-cholesterol, and high-fructose (HF/HF) diet. The effect of high-dose niacin treatment for 18days and 28days on plasma lipid levels and gene expression was measured. Results: Niacin treatment produced significant decreases in plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and free fatty acids (FFA), but had no measureable effect on high-density lipoprotein cholesterol (HDL-C) in the dyslipidemic hamster. Niacin treatment also produced significant increases in hepatic adenosine ATP-Binding Cassette A1 (ABCA1) mRNA, ABCA1 protein, apolipoprotein A-I (Apo A-I) mRNA, and adipose adiponectin mRNA in these animals. Conclusions: With the exception of HDL-C, the lipid effects of niacin treatment in the dyslipidemic hamster closely parallel those observed in humans. Moreover, the effects of niacin treatment on gene expression of hepatic proteins related to HDL metabolism are similar to those observed in human cells in culture. The HF/HF-fed hamster could therefore serve as an animal model for niacin’s lowering of proatherogenic lipids and mechanisms of action relative to lipid metabolism. [Copyright &y& Elsevier]

Objectives: This study sought to evaluate the vascular risk of low high-density lipoprotein-cholesterol (HDL-C) in relation to the use and intensity of lipid-lowering medication in patients with clinically manifest vascular diseases. Background: Low levels of HDL-C are associated with an increased risk for vascular diseases and may contribute to residual vascular risk in patients already treated for other risk factors. However, post-hoc analyses from statin trials indicate that the vascular risk associated with low HDL-C may be low or even absent in patients using intensive statin therapy. Methods: We performed a prospective cohort study of 6,111 patients with manifest vascular disease. Cox proportional hazards models were used to evaluate the risk of HDL-C on vascular events in patients using no, usual dose, or intensive lipid-lowering therapy. Results: New vascular events (myocardial infarction, stroke, or vascular death) occurred in 874 subjects during a median follow-up of 5.4 years (interquartile range: 2.9 to 8.6 years). In patients not using lipid-lowering medication at baseline (n = 2,153), a 0.1 mmol/l increase in HDL-C was associated with a 5% reduced risk for all vascular events (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.92 to 0.99). In patients on usual dose lipid-lowering medication (n = 1,910) there was a 6% reduced risk (HR: 0.94; 95% CI: 0.90 to 0.98). However, in patients using intensive lipid-lowering treatment (n = 2,046), HDL-C was not associated with recurrent vascular events (HR: 1.02; 95% CI: 0.98 to 1.07) irrespective of low-density lipoprotein cholesterol level. Conclusions: In patients with clinically manifest vascular disease using no or usual dose lipid-lowering medication, low plasma HDL-C levels are related to increased vascular risk, whereas in patients using intensive lipid-lowering medication, HDL-C levels are not related to vascular risk. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to assess the independent effect of high-density lipoprotein-cholesterol (HDL-C) level on cardiovascular risk in patients with stable ischemic heart disease (SIHD) who were receiving optimal medical therapy (OMT). Background: Although low HDL-C level is a powerful and independent predictor of cardiovascular risk, recent data suggest that this may not apply when low-density lipoprotein-cholesterol (LDL-C) is reduced to optimal levels using intensive statin therapy. Methods: We performed a post-hoc analysis in 2,193 men and women with SIHD from the COURAGE trial. The primary outcome measure was the composite of death from any cause or nonfatal myocardial infarction (MI). The independent association between HDL-C levels measured after 6 months on OMT and the rate of cardiovascular events after 4 years was assessed. Similar analyses were performed separately in subjects with LDL-C levels below 70 mg/dl (1.8 mmol/l). Results: In the overall population, the rate of death/MI was 33% lower in the highest HDL-C quartile as compared with the lowest quartile, with quartile of HDL-C being a significant, independent predictor of death/MI (p = 0.05), but with no interaction for LDL-C category (p = 0.40). Among subjects with LDL-C levels <70 mg/dl, those in the highest quintile of HDL-C had a 65% relative risk reduction in death or MI as compared with the lowest quintile, with HDL-C quintile demonstrating a significant, inverse predictive effect (p = 0.02). Conclusions: In this post-hoc analysis, patients with SIHD continued to experience incremental cardiovascular risk associated with low HDL-C levels despite OMT during long-term follow-up. This relationship persisted and appeared more prominent even when LDL-C was reduced to optimal levels with intensive dyslipidemic therapy. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) [Copyright &y& Elsevier]

Abstract: In this study we have used mass spectrometry in order to characterize the HDL lipidome in three groups of women from the DIWA cohort; one control group, plus two groups with type 2 diabetes with insulin resistance; one dyslipidemic and one normolipidemic. The aim was to investigate whether dyslipidemia is required in addition to insulin resistance for the occurrence of an altered HDL lipidome, which in turn might impact HDL functionality. The dyslipidemic type 2 diabetic subjects were distinguished by obesity, hypertriglyceridemia with elevated apoC3, low HDL-cholesterol and chronic low grade inflammation. In a stepwise multivariate linear regression analysis, including biomarkers of dyslipidemia and insulin resistance as independent variables, only dyslipidemia showed a significant correlation with HDL lipid classes. Small HDL-particles predominated in dyslipidemic subjects in contrast to the normolipidemic diabetic and control groups, and were enriched in lysophosphatidylcholine (+13%), a product of proinflammatory phospholipases, and equally in two core lipids, palmitate-rich triacylglycerols and diacylglycerols (+77 %), thereby reflecting elevated CETP activity. Dyslipidemic small HDL particles were further distinguished not only as the primary carrier of ceramides, which promote inflammation and insulin resistance, but also by a subnormal plasmalogen/apoAI ratio, consistent with elevated oxidative stress typical of type 2 diabetes. From these data we conclude that in type 2 diabetes, dyslipidemia predominates relative to hyperglycemia for the occurrence of an altered HDL lipidome. Furthermore, dyslipidemia alters the cargo of bioactive lipids, with implications for HDL function. [Copyright &y& Elsevier]

Abstract: Cholesteryl ester transfer protein (CETP), a key regulator of high-density lipoprotein (HDL) metabolism, induces HDL remodeling by transferring lipids between apolipoprotein B-containing lipoproteins and HDL, and/or by promoting lipid transfer between HDL subparticles. In this study, we investigated the mechanism as to how CETP induces the generation of lipid-poor particles (pre-β-HDL) from HDL, which increases ATP-binding cassette transporter 1-mediated cholesterol efflux. This CETP-dependent HDL remodeling is enhanced by the CETP modulator dalcetrapib both in plasma and isolated HDL. The interaction of dalcetrapib with cysteine 13 of CETP is required, since this effect was abolished when using mutant CETP in which cysteine 13 was substituted for a serine residue. Other thiol-containing compounds were identified as CETP modulators interacting with cysteine 13 of CETP. In order to mimic dalcetrapib-bound CETP, mutant CETP proteins were prepared by replacing cysteine 13 with the bulky amino acid tyrosine or tryptophan. The resultant mutants showed virtually no CETP-dependent lipid transfer activity but demonstrated preserved CETP-dependent pre-β-HDL generation. Overall, these data demonstrate that the two functions of CETP i.e., cholesteryl ester transfer and HDL remodeling can be uncoupled by interaction of thiol-containing compounds with cysteine 13 of CETP or by introducing large amino acid residues in place of cysteine 13. [Copyright &y& Elsevier]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the α-methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolism that allows these mice to have a normal life span. Intestinal cholesterol absorption in Amacr−/− mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr-deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse. [Copyright &y& Elsevier]

Abstract: During an egg-laying cycle, oviparous animals transfer massive amounts of triglycerides, the major lipid component of very low density lipoprotein (VLDL), from the liver to the developing oocytes. A major stimulus for this process is the rise in estrogen associated with the onset of an egg-laying cycle. In mammals, the microsomal triglyceride transfer protein (MTP) is required for VLDL assembly and secretion. To enable studies to determine if MTP plays a role in basal and estrogen-stimulated VLDL assembly and secretion in an oviparous vertebrate, we have cloned and sequenced the chicken MTP cDNA. This cDNA encodes a protein of 893 amino acids with an N-terminal signal sequence. The primary sequence of chicken MTP is, on average, 65% identical to that of mammalian homologs, and 23% identical to the Drosophila melanogaster protein. We have obtained a clone of chicken embryo fibroblast cells that stably express the avian MTP cDNA and show that these cells display MTP activity as measured by the transfer of a fluorescently labeled neutral lipid. As in mammals, chicken MTP is localized to the endoplasmic reticulum as revealed by indirect immunofluorescence and by the fact that its N-linked oligosaccharide moiety remains sensitive to endoglycosidase H. Endogenous, enzymatically active MTP is also expressed in an estrogen receptor-expressing chicken hepatoma cell line that secretes apolipoprotein B-containing lipoproteins. In this cell line and in vivo, the expression and activity of MTP are not influenced by estrogen. Therefore, up-regulation of MTP in the liver is not required for the increased VLDL assembly during egg production in the chicken. This indicates that MTP is not rate-limiting, even for the massive estrogen-induced secretion of VLDL accompanying an egg-laying cycle. [Copyright &y& Elsevier]

Introduction: Plasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients. Methods: Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects. Results: Among the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24±0.45, 8.16±0.54, 6.70±0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18±0.20, 6.20±0.05 and 4.55±0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P<0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47±0.53 compared to 0.93±0.27μg/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67±13.46 compared to 28.46±8.24nmol/μg/h, P=0.001). Conclusions: Dyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients’ plasma. [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: Background and aims: Vegan diet excludes all foodstuffs of animal origin and leads to cholesterol lowering and possibly reduction of cardiovascular disease risk. The aim was to investigate whether vegan diet improves the metabolic pathway of triglyceride-rich lipoproteins, consisting in lipoprotein lipolysis and removal from circulation of the resulting remnants and to verify whether the diet alters HDL metabolism by changing lipid transfers to this lipoprotein. Methods and results: 21 vegan and 29 omnivores eutrophic and normolipidemic subjects were intravenously injected triglyceride-rich emulsions labeled with 14C-cholesterol oleate and 3H-triolein: fractional clearance rates (FCR, in min−1) were calculated from samples collected during 60 min for radioactive counting. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified in supernatant after chemical precipitation of non-HDL fractions and nanoemulsion. Serum LDL cholesterol was lower in vegans than in omnivores (2.1 ± 0.8, 2.7 ± 0.7 mmol/L, respectively, p < 0,05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegans than in omnivores (0.016 ± 0.012, 0.003 ± 0.003, p < 0.01), whereas triglyceride FCR was equal (0.024 ± 0.014, 0.030 ± 0.016, N.S.). Cholesteryl ester transfer to HDL was lower in vegans than in omnivores (2.7 ± 0.6, 3.5 ± 1.5%, p < 0,05). Free-cholesterol, triglyceride and phospholipid transfer were equal, as well as HDL size. Conclusion: Remnant removal from circulation, estimated by cholesteryl oleate FCR was faster in vegans, but the lipolysis process, estimated by triglyceride FCR was equal. Increased removal of atherogenic remnants and diminution of cholesteryl ester transfer may favor atherosclerosis prevention by vegan diet. [Copyright &y& Elsevier]

Abstract: Dalcetrapib solubility was determined in aqueous and in non-aqueous vehicles and in biorelevant media. In a pure aqueous environment the solubility was low but could be increased by addition of surfactants or complexing agents. This was also reflected in the solubility seen in simulated gastrointestinal (GI) fluids, with almost no solubility in simulated gastric fluid, but reasonable solubilisation in simulated intestinal fluids containing lecithin and bile salt. Additionally, the stability of dalcetrapib was determined in simulated GI fluids with and without pancreatic lipase. In solutions without lipase, dalcetrapib was slowly hydrolysed, but in the presence of lipase the hydrolysis rate was significantly faster depending on pH and enzyme activity. In biological fluids, dissolved dalcetrapib appeared to behave similarly being rapidly hydrolysed in human intestinal fluids with a half-life below 20s with no degradation observed in human gastric fluids at low pH. The results provide supportive evidence that absorption is higher under fed conditions and indicate lipase inhibitors might interfere with oral absorption of dalcetrapib. [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]

Summary: Background and aim: Asian Indians have relatively lower high-density lipoprotein cholesterol (HDL-C) as compared to the other populations. Cholesterol ester transfer protein (CETP) is involved in the transfer of cholesterol esters from HDL-C to other lipoproteins in the plasma. In order to assess the role of CETP polymorphisms and their association with HDL-C, if any, we have studied the TaqIB polymorphism in intron 1 of CETP and its correlation with plasma lipids in 158 normolipidemic healthy subjects. Methods and results: Plasma lipids levels were estimated using commercially available kits from Randox (India) and CETP TaqIB polymorphism were assayed by PCR-RFLP in 158 healthy normolipidemic individuals. The observed allelic frequencies of TaqIB polymorphisms, B1 and B2 were 43.0% and 56.9%, respectively. Lipid parameters were comparable between individuals with the different CETP TaqIB polymorphisms. The individuals categorized on the basis of their HDL-C levels (< or >1.04mmol/l), had comparable distribution of CETP genotypes. CETP activity was assessed in 84 of the total 158 individuals included in the study and did not vary among the CETP TaqIB genotypes. CETP activity in the females (n =39) negatively correlated with HDL-C levels. Conclusion: This study reveals that CETP TaqIB polymorphisms are not associated with the decreased levels of HDL-C in healthy normolipidemic individuals. We are presently involved in studies to assess the precise role of CETP TaqIB polymorphism and CETP activity in hyperlipidemia in Asian Indians. [Copyright &y& Elsevier]

Abstract: The cDNA for cholesteryl ester transfer protein (CETP), a protein that catalyzes cholesteryl ester transfer between very low density and high density lipoproteins in plasma, was isolated from chicken liver. When the recombinant protein was overexpressed in HEK293 cells, cholesteryl ester transfer activity was observed in media and cell lysates. By Northern blot analysis, chicken CETP mRNA expression was detected in liver, brain, heart, and spleen. Changes in chicken CETP mRNA expression and plasma CETP activity with nutritional state were examined and found to increase following dietary supplementation with cholesterol in a similar way as in humans. Both the hepatic CETP mRNA levels and plasma CETP activity were significantly lower in mature (i.e egg-laying) hens than in immature female chickens, but were unaffected by age in male animals. Similar changes to those observed in female chickens were observed upon estradiol administration of males. The present study is the first to report the molecular characterization of an avian CETP, and the impairments of CETP gene and activity, which might be regulated by estrogen, play an important role in egg production in laying hens, demonstrating species-specific differences in the lipid metabolism of avian and mammalian species. [Copyright &y& Elsevier]

Abstract: Objectives: : The aim of our study was to examine the influence of atorvastatin on lipid parameters, particularly on HDL, and on the activity of LCAT and CETP and how they affect the activity of the HDL-associated antioxidant enzyme paraoxonase. Design and methods: : Thirty-three patients with types II.a and II.b primary hyperlipoproteinemia were enrolled into our study. The patients received atorvastatin, 20 mg daily, for 3 months. We measured the serum paraoxonase activity and concentration, oxidized LDL, LCAT and CETP activities. Results: : Atorvastatin significantly reduced the levels of cholesterol, triglyceride, LDL-C and apoB, while it did not influence the levels of HDL-C and apo A-I. The increases in serum PON-specific activity, PON/HDL ratio and LCAT activity were significant, while oxLDL and CETP activities were significantly decreased. Conclusion: : Atorvastatin may influence the composition and function of HDL, thereby possibly increasing the activity of paraoxonase and preventing atherosclerosis. [Copyright &y& Elsevier]

Abstract: Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that mediates the transfer and exchange of cholesteryl ester (CE) and triglyceride (TG) between plasma lipoproteins, and also plays an important role in HDL metabolism. Previous studies have indicated that, compared to wild type mice, human CETP transgenic mice had significantly lower plasma HDL CE levels, which was associated with enhancement of HDL CE uptake by the liver. However, the mechanism of this process is still unknown. To evaluate the possibility that this might be directly mediated by CETP, we utilized CETP transgenic (CETPTg) mice with liver scavenger receptor BI (SR-BI) deficiency [i.e., PDZK1 gene knockout (PDZK1O)], and with receptor associated protein (RAP) overexpression, to block LDL receptor-related protein (LRP) and LDL receptor (LDLR). We found that (1) CETPTg/PDZK1O mice have significantly lower HDL-C than that of PDZK1 KO mice (36%, p <0.01); (2) CETPTg and CETPTg/PDZK1O mice have same HDL-C levels; (3) CETPTg/PDZK1O/RAP mice had significant lower plasma HDL-C levels than that of PDZK1O/RAP ones (50%, p <0.001); (4) there is no incremental transfer of HDL CE radioactivity to the apoB-containing lipoprotein fraction in mice expressing CETP; and (5) CETPTg/PDZK1O/RAP mice had significant higher plasma and liver [3H]CEt-HDL turnover rates than that of PDZK1O/RAP ones (50% and 53%, p <0.01, respectively). These results suggest that CETP expression in mouse increases direct removal of HDL CE in the liver and this process is independent of SR-BI, LRP, and possibly LDLR. [Copyright &y& Elsevier]

Abstract: This study was designed to analyse the prevalence of I405V polymorphism in the cholesteryl ester transfer protein (CETP) gene, the CETP serum concentration, the lipoprotein profile, and certain clinical end-points in two populations, one young and another of very old people. We recruited 100 healthy young people (median age 31 years) and 100 very old people (median age 89 years) and analysed their DNA for the presence of I405V polymorphism. The frequency of the VV genotype in very old people was more than double that in the young population. Subjects with this genotype had lower serum concentrations of CETP. Young people with the V/V genotype had a less atherogenic lipoprotein profile (lower total cholesterol, LDL cholesterol, Apo B, and Apo B/Apo A-I ratio) than those with the I/V or I/I genotypes. The older subjects, particularly the older women with the V/V genotype, had larger LDL than the young people. The prevalence of clinical endpoints was much lower among the very old people with the V/V genotype. In conclusion, the V/V genotype of the I405V CETP polymorphism is more frequent among very old people than young ones, and is associated with a lower incidence of vascular damage. [Copyright &y& Elsevier]

Abstract: Background and aim: Type 2 diabetes mellitus is associated with atherosclerosis, which has been, in part, ascribed to abnormalities in the reverse cholesterol transport system. Among the key actors involved in this pathway is cholesteryl ester transfer protein (CETP) which mediates the transfer of cholesteryl esters (CE) from HDL to apoB-containing lipoproteins. Methods and results: The purpose of this study was to examine CETP activity in 220 patients with type 2 diabetes mellitus (type 2 DM) treated with diet alone or diet and sulphonylurea drugs and to identify the factors that may regulate it in the diabetic state. We also examined the effect of diet on the activity of plasma CETP in a subgroup of type 2 DM women. CETP activity was assessed by measuring plasma-mediated cholesteryl ester transfer (CET) between pooled exogenous HDL and apoB-containing lipoproteins. In 220 patients with type 2 DM, CET was significantly higher in conjunction with higher plasma triglycerides and lower HDL-cholesterol compared to 100 matched healthy controls. Correlation analysis showed that CETP activity was significantly correlated with the HDL-C to apoA1 ratio (r=−0.205, P=0.003) and to LDL-C to HDL-C ratio in diabetic women (P=0.010). Furthermore, CETP activity was correlated marginally with total energy intake (P=0.052) but to a statistically significant extent with the amount of fat consumed daily (P=0.008). A significant negative correlation was found between plasma CETP activity and MUFA of plasma phospholipids or free PUFA (P=0.032), especially with ω3-fatty acids (P=0.001). Conclusion: Our findings indicate that CET is accelerated in patients with type 2 DM and that this may be regulated by dietary fatty acids in the diabetic state. [Copyright &y& Elsevier]

Abstract: Introduction:: Cholesteryl ester transfer protein (CETP), a key protein in reverse cholesterol transport, has a controversial role in atherosclerosis. Objectives:: We investigated CETP activity and polymorphism in Tunisian type II diabetes and its relationship with coronary artery disease (CAD). Design and methods:: 173 type II diabetic patients with or without CAD were compared to 67 controls. Results:: The HDL cholesterol concentration was low in a Tunisian population. The B1 allele of the CETP gene was associated with a low concentration of HDL cholesterol and was more frequent in Tunisians than in other populations. In type II diabetic patients, the B1 allele was associated with increased prevalence of CAD only in men (OR = 0.357, CI = 0.161–0.791, P = 0.01). The CETP activity increased in type II diabetic patients compared to controls (P = 0.05). Furthermore, the CETP activity was increased in patients with double or triple vessel disease compared to those with single vessel disease (P = 0.025). Conclusions:: Our data are in favour of an association between CETP and developing CAD, as well as the extent of CAD. [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]

Abstract: Disentangling the neuroendocrine systems, which regulate energy homeostasis and adiposity, has been a long-standing challenge in pathophysiology, with obesity as an increasingly important public health problem. Adipose tissue has been considered for a long time as only a passive organ for the storage of excess energy in the form of fat. However, compelling evidence gathered during the last decades has revealed adipocytes as extremely active endocrine secretory cells playing a relevant role in the regulation of metabolism, reproduction, immunity, blood pressure, fibrinolysis, coagulation, and angiogenesis, among others. An extensive cross talk at a local and systemic level in response to specific external stimuli or metabolic changes underpins the multifunctional characteristics of fat cells, which rely on their ability to secrete a large number of hormones, growth factors, enzymes, cytokines, complement factors, and matrix proteins, collectively termed as adipokines or adipocytokines, at the same time expressing receptors for most of these factors. [Copyright &y& Elsevier]

Amongst the processes involved in the reverse cholesterol transport (RCT) from organs to liver, including high density lipoproteins-apolipoprotein AI (HDL-apoAI) dependent tissue uptake and cholesteryl ester transfer protein (CETP)-mediated transfers, the selective uptake of cholesteryl ester (CE) is of increasing interest through its antiatherogenic role. The purpose of this report is to develop a simple protocol allowing study of this process in an animal model with easier quantification of CE selective uptake. The dog was chosen essentially because this animal has a low CETP activity and an appropriate size to conduce a kinetic study. Tracer kinetics were performed to estimate in vivo the contributions of the pathways involved in HDL-CE turnover in dogs. Stable isotopes, 13C-acetate and D3-leucine as labeled precursors of CE and apoAI, were infused to fasting dogs. Isotopic enrichments were monitored in plasma unesterified cholesterol and in HDL-CE and apoAI by mass spectrometry. Kinetics were analyzed using compartmental modeling. Results concerned the measurement of the activity of cholesterol esterification (0.13±0.032 h-1), rate of HDL-apoAI catabolism (0.024±0.012 h-1), HDL-CE turnover (0.062±0.010 h-1) and CE selective uptake (0.038±0.014 h-1). Our results show that CE in dogs is mainly eliminated by selective uptake of HDL-CE (60% of HDL-CE turnover), unlike in other species studied by similar methods in our laboratory. This study shows that among species used to analyze cholesterol metabolism, the dog appears to be the animal in whom HDL-CE selective uptake represents the largest part of HDL-CE turnover. [Copyright &y& Elsevier]

We highlight the importance of the low-density lipoprotein (LDL) receptor family and its pharmaceutical implications in the field of drug delivery. The members of the LDL receptor family are a group of cell surface receptors that transport a number of macromolecules into cells through a process called receptor-mediated endocytosis. This process involves the receptor recognizing a ligand from the extracellular membrane (ECM), internalizing it through clathrin-coated pits and degrading it upon fusion with lysosomes. There are nine members of the receptor family, which include the LDL receptor, low-density lipoprotein-related protein (LRP), megalin, very low-density lipoprotein (VLDL) receptor, apoER2 and sorLA/LRP11, LRP1b, MEGF7, LRP5/6; the former six having been identified in humans. Each member is expressed in a number of different tissues and has a wide range of different ligands, not specific to the recognition of the LDL particle. Thus, rather than the original hypothesis that the receptor is only a mediator of cholesterol uptake, it may also be involved in a number of other physiological functions, including the progression of certain disease states and, potentially, cellular drug uptake. A number of studies have suggested that the LDL receptors are involved in endocytosis of drugs and drug formulations including aminoglycosides, anionic liposomes and cyclosporine A (CsA). This article reviews the importance of lipoproteins as a drug delivery system and how LDL receptors are relevant to the design and targeting of specific drugs. [Copyright &y& Elsevier]

The high-density lipoprotein (HDL) system offers an attractive target for novel therapeutic approaches to prevent or treat atherosclerosis. Clinical preventative studies with HDL modulators, both increasing HDL levels [peroxisome proliferator activator receptor (PPAR) α agonists] and stimulating turnover [cholesteryl ester transfer protein (CETP) activators] have led to favorable outcomes. Treatment of preexisting atherosclerosis with novel HDL mimetics, i.e., wild-type recombinant apo A-I, reconstituted HDL from human serum, large unilamellar phospholipid vesicles (LUV), and the recombinant apo A-IMilano dimer (AIM) offer exciting opportunities. Recent findings with AIM are consistent with the hypothesis that direct HDL administration can rapidly regress coronary plaques. [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]

: ObjectivesOn the basis of quantitative coronary angiography data, the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism has been postulated to predict the progression of coronary atherosclerosis and response to cholesterol-lowering therapy.: BackgroundCholesteryl ester transfer protein mediates the exchange of lipids between anti-atherogenic high-density lipoprotein (HDL) and atherogenic apolipoprotein B containing lipoproteins and therefore plays a key role in human lipid metabolism. Hence, CETP gene polymorphisms may alter susceptibility to atherosclerosis.: MethodsTo investigate the significance of the CETP TaqIB gene polymorphism with respect to clinical end points, we used the Cholesterol And Recurrent Events (CARE) cohort. The CARE study was designed to investigate the effect of five years of pravastatin therapy on coronary events.: ResultsWe found that the odds ratios for the primary end point were not significantly different from unity for the three genetic subgroups after five years of placebo treatment. Furthermore, pravastatin induced similar changes in total cholesterol, low-density lipoprotein cholesterol, and HDL cholesterol among TaqIB genotypes, and both nonfatal myocardial infarction and deaths from coronary heart disease were reduced to the same extent in all three genotypes.: ConclusionsIn the CARE cohort, the CETP TaqIB polymorphism does not predict cardiovascular events or discriminate between those who will or will not benefit from pravastatin treatment. [Copyright &y& Elsevier]

Clinical data show that a 1% increase in serum concentrations of high-density lipoprotein cholesterol (HDL-C) can decrease cardiovascular risk by 2% to 3%. Therefore, mechanisms affecting the level and functionality of high-density lipoprotein (HDL) and its constituents are being investigated as targets for the rational development of drugs to prevent or treat cardiovascular disease. High-density lipoprotein-related research may also increase our understanding of the link between atherosclerosis and metabolic disorders. This report and update of the HDL Working Group discusses HDL metabolism and reverse cholesterol transport, impaired HDL as a marker and a cause of proatherogenic states, and experimental and current approaches to HDL-related therapy. [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]

Background: During pregnancy, serum cholesterol (TC) and triglyceride (TG) concentrations are known to increase significantly, but whether remnant lipoprotein particles (RLP) increase has not been shown. Methods: We compared lipid profiles in 22 healthy pregnant women to 31 healthy nonpregnant women and 24 patients with diabetes mellitus (DM), by measuring cholesterol and TG concentrations in major lipoprotein classes after HPLC separation and immunoseparation of RLP. Results: Serum TG and TC concentrations were significantly higher in the pregnant group than in the healthy control or DM groups. Cholesterol and TG concentrations of all major lipoprotein classes were also significantly higher in the pregnant group than the control and DM groups, except for VLDL-TG in the DM group. RLP-C and RLP-TG concentrations were significantly higher in the pregnant group (8.7 mg/dl and 25.4 mg/dl on average) than the control group (2.4 mg/dl and 5.7 mg/dl), but not different from the DM group (8.8 mg/dl and 24.1 mg/dl). RLP-TG to RLP-C ratios were similar among the three groups and correlated with the VLDL-TG to VLDL-C ratio. The percentages of RLP-C in VLDL-C and RLP-TG in VLDL-TG in the pregnant group (15.9% and 15.7%) were significantly lower than those of the control (48.5% and 35.6%) and the DM (32.7% and 20.8%) groups. Conclusions: RLP increased moderately during gestation with the increase in VLDL and TG, but the percentage of RLP in VLDL was significantly lower in the pregnant women compared with the control and DM patients, suggesting that hypertriglyceridemia in pregnancy is not primarily due to an increase in the atherogenic RLP. [Copyright &y& Elsevier]

In mediating the transfer of cholesteryl esters (CE) from antiatherogenic high density lipoprotein (HDL) to proatherogenic apolipoprotein (apo)-B-containing lipoprotein particles (including very low density lipoprotein [VLDL], VLDL remnants, intermediate density lipoprotein [IDL], and low density lipoprotein [LDL]), the CE transfer protein (CETP) plays a critical role not only in the reverse cholesterol transport (RCT) pathway but also in the intravascular remodeling and recycling of HDL particles. Dyslipidemic states associated with premature atherosclerotic disease and high cardiovascular risk are characterized by a disequilibrium due to an excess of circulating concentrations of atherogenic lipoproteins relative to those of atheroprotective HDL, thereby favoring arterial cholesterol deposition and enhanced atherogenesis. In such states, CETP activity is elevated and contributes significantly to the cholesterol burden in atherogenic apoB-containing lipoproteins. In reducing the numbers of acceptor particles for HDL-derived CE, both statins (VLDL, VLDL remnants, IDL, and LDL) and fibrates (primarily VLDL and VLDL remnants) act to attenuate potentially proatherogenic CETP activity in dyslipidemic states; simultaneously, CE are preferentially retained in HDL and thereby contribute to elevation in HDL-cholesterol content.Mutations in the CETP gene associated with CETP deficiency are characterized by high HDL-cholesterol levels (>60 mg/dL) and reduced cardiovascular risk. Such findings are consistent with studies of pharmacologically mediated inhibition of CETP in the rabbit, which argue strongly in favor of CETP inhibition as a valid therapeutic approach to delay atherogenesis. Consequently, new organic inhibitors of CETP are under development and present a potent tool for elevation of HDL in dyslipidemias involving low HDL levels and premature coronary artery disease, such as the dyslipidemia of type II diabetes and the metabolic syndrome. The results of clinical trials to evaluate the impact of CETP inhibition on premature atherosclerosis are eagerly awaited. [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]

A novel bactericidal permeability-increasing protein/lipopolysaccharide (LPS)-binding protein (BPI/LBP) was isolated from common carp Cyprinus carpio L. by EST analysis. This gene showed structural similarity with BPI/LBP gene in mammals. The isolated gene was composed of 1638 bp, which translated to a protein of 473 amino acid residues. The predicted signal peptide was 18 amino acid residues and the LPS-binding domain is conserved in this sequence consisted of residues 57–121 amino acid residues. This LPS-binding domain had high identity (76.9%) to that of rainbow trout LBP/BPI-2. Phylogenetic analysis showed that carp BPI/LBP was similar to BPI or LBP of lipid-interactive protein family in mammals. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that carp BPI/LBP gene was expressed in normal liver, head kidney, spleen, intestine, gill, heart and brain. Liver and head kidney stimulated with LPS (10 μg/ml) for 3, 6, 12, 24 and 48 h expressed carp BPI/LBP gene at all stimulation time periods. Expression level of liver was higher than that of head kidney and high expressions in each tissues was recorded at 3 h post-LPS stimulation. After 3 h, BPI/LBP gene expression level was gradually become less in the stimulated times. [Copyright &y& Elsevier]

Genetically modified laboratory animals provide a powerful approach for studying gene expression and regulation and allow one to directly examine structure-function and cause-and-effect relationships in pathophysiological processes. Today, transgenic mice are available as a research tool in almost every research institution. On the other hand, the development of a relatively large mammalian transgenic model, transgenic rabbits, has provided unprecedented opportunities for investigators to study the mechanisms of human diseases and has also provided an alternative way to produce therapeutic proteins to treat human diseases. Transgenic rabbits expressing human genes have been used as a model for cardiovascular disease, AIDS, and cancer research. The recombinant proteins can be produced from the milk of transgenic rabbits not only at lower cost but also on a relatively large scale. One of the most promising and attractive recombinant proteins derived from transgenic rabbit milk, human α-glucosidase, has been successfully used to treat the patients who are genetically deficient in this enzyme. Although the pronuclear microinjection is still the major and most popular method for the creation of transgenic rabbits, recent progress in gene targeting and animal cloning has opened new avenues that should make it possible to produce transgenic rabbits by somatic cell nuclear transfer in the future. Based on a computer-assisted search of the studies of transgenic rabbits published in the English literature here, we introduce to the reader the achievements made thus far with transgenic rabbits, with emphasis on the application of these rabbits as human disease models and live bioreactors for producing human therapeutic proteins and on the recent progress in cloned rabbits. [Copyright &y& Elsevier]

Background: Estrogen administration is known to increase serum triglyceride concentrations. This study measured changes in lipoproteins of patients with prostate cancer treated with estrogen to determine whether the increased triglyceride concentrations are associated with atherogenic lipoprotein patterns. Methods: Fifteen patients (52–87 years) with histologically diagnosed prostate cancer received diethylstilbestrol diphosphate (250 mg/day). Serum samples were collected before and after 1 and 2 weeks of treatment. Cholesterol and triglyceride profiles of major lipoproteins were determined by HPLC, remnant-like particle cholesterol and triglyceride concentrations by an immunoseparation technique, and apolipoproteins by immunologic methods. Results: Estrogen treatment induced a 63.3% increase in total triglyceride concentrations, which occurred in all major lipoprotein classes with significant increases in HDL-triglycerides (130.4%), LDL-triglycerides (60.7%) and VLDL-triglycerides (56.2%). HDL-cholesterol increased significantly by 26.8%, while LDL-cholesterol decreased (15.6%). Remnant-like particle triglyceride concentrations also increased significantly by 77%, whereas remnant-like particle cholesterol concentrations remained unchanged. Apolipoproteins A-I and A-II increased; apolipoprotein E and Lp(a) decreased. Conclusions: The techniques used here conveniently demonstrated that short-term estrogen treatment in prostate cancer patients resulted in triglyceride enrichment of all major lipoprotein classes but did not induce changes in the lipoprotein profiles generally recognized as increasing risk for cardiovascular disease, except for the elevation of plasma triglyceride and remnant-like particle triglyceride. [Copyright &y& Elsevier]

Background Fetal growth restriction (GR) is associated with perinatal mortality and subsequent metabolic disorders in adulthood. Until now, there is little information regarding changes in the properties of lipoproteins from growth-restricted fetuses and their maternal sera. Objective To identify unique lipoprotein biomarkers for fetal GR in maternal and cord sera from small neonates, we analyzed lipoprotein compositions and functions. Methods Lipoprotein compositions and functions were compared between cord blood and maternal blood among small for gestational age neonates (SGA; n = 15, 2589 ± 50 g) and appropriate for gestational age neonates (AGA; n = 15) in Korea. Results Cord blood from the SGA group showed 2-fold higher triglyceride (TG) and TG/high-density lipoprotein cholesterol levels than the AGA group as well as significantly lower (up to 20%) paraoxonase activity and apolipoprotein (apo) A-I content. The SGA group showed the highest cholesteryl ester transfer protein activities in both cord and maternal sera. SGA neonates showed elevated apo-B content in very low-density lipoprotein, 52% reduction of apo A-I content in high-density lipoprotein, and 30% increased glycation ( P < .001) compared with AGA neonates. Especially, low-density lipoprotein from the SGA group showed 1.9-fold higher sensitivity to oxidation as well as 3-fold greater uptake into macrophages, suggesting stronger proatherosclerotic properties. Lipoproteins from maternal serum of SGA neonates showed greater oxidation along with TG enrichment and loss of antioxidant ability. On microinjection of cord serum (50 nL) into zebrafish embryos, the SGA group showed the most severe embryonic damage. Conclusions Lipoproteins from cord and maternal sera of SGA neonates resulted in severe impairment of functional and structural correlations accompanied by greater pro-oxidant and proatherosclerotic properties. [ABSTRACT FROM AUTHOR]