共查询到20条相似文献,搜索用时 31 毫秒
1.
Paul J. W. H. Kappelle Arie van Tol Bruce H. R. Wolffenbuttel Robin P. F. Dullaart 《Cardiovascular therapeutics》2011,29(6):e89-e99
As delineated in this review, cholesteryl ester transfer protein (CETP) contributes to an atherogenic lipoprotein profile by redistributing cholesteryl esters from high density lipoprotein (HDL) toward apolipoprotein B‐containing lipoproteins, especially when the concentration of acceptor triglyceride‐rich lipoproteins is elevated. However, this lipid transfer protein may have antiatherogenic proprerties as well. Experimental evidence is accumulating which suggests that the atheroprotective reverse cholesterol transport pathway, whereby cholesterol is removed from peripheral macrophages to the liver for metabolism and biliary excretion, is stimulated by CETP in vivo. CETP could also play a role in host defense against infection and inflammatory processes. Moreover, recently published observational studies show that higher CETP levels may confer cardiovascular protection, whereas reported associations of cardiovascular disease (CVD) with CETP gene variations are equivocal. The concept that HDL cholesterol raising through inhibition of CETP may ameliorate CVD risk has been challenged by the failure of the CETP inhibitor, torcetrapib. Adverse clinical outcome associated with the use of this CETP inhibitor has been attributed to off‐target effects, which relate to stimulation of aldosterone. Other CETP inhibitors, such as dalcetrapib and anacetrapib, are unlikely to increase blood pressure. Dalcetrapib is less potent than anacetrapib, which doubles HDL cholesterol. Both inhibitors considerably lower LDL cholesterol.Serious concerns remain about the validity of the concept that HDL cholesterol raising by means of CETP inhibition is a viable strategy. Results of ongoing clinical trials with these drugs will have to be awaited before making up the balance between possible benefits and harms related to pharmacological CETP inhibition. 相似文献
2.
Despite tremendous progress made in the management of CHD, a significant number of fatal and nonfatal CHD events still occur, which leads researchers to target other modifiable risk factors for CHD including low HDL-c (high density lipoprotein cholesterol). Although the torcetrapib experience was a major blow to CETP inhibition and indeed to the entire field of HDL-targeted therapeutics, it was not fatal. The off-target effects of torcetrapib appear to be substantial and may have overridden any potential cardiovascular benefit. Despite continued uncertainty regarding the cardiovascular implications of genetic CETP deficiency and pharmacologic CETP inhibition, there remain reasons to believe in the mechanism and the possibility that clean CETP inhibitors will not only improve plasma lipids but also reduce cardiovascular risk. 相似文献
3.
Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease.
Prediman K Shah 《European heart journal》2007,28(1):5-12
Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a proven strategy for reducing the risk of atherothrombotic cardiovascular disease (CVD). Yet, despite the success of statins in reducing cardiovascular event rates in at-risk patients, many will still experience further events. There is, therefore, a need to develop suitable therapies to reduce this residual risk. Low high-density lipoprotein cholesterol (HDL-C) levels are an important independent risk factor for CVD. Though fibrates, niacin, and statins have been shown to modestly raise HDL-C, there is increasing recognition of the need to develop therapies that can increase HDL-C more robustly. Such therapies may help supplement the LDL-C-lowering benefits of statins. Inhibition of cholesteryl ester transfer protein (CETP) has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy, in terms of increasing HDL-C, in preliminary clinical trials, and clinical trials based on outcomes are ongoing. Two CETP inhibitors, JTT-705 and torcetrapib, are now being evaluated more extensively. 相似文献
4.
目的研究茶叶对人体正常皮肤成纤维细胞(GM细胞)中长寿相关基因胆固醇酯转运蛋白(CETP)编码基因表达的影响。方法采用逆转录PCR法和免疫印迹法分别检测GM细胞中CETP mRNA与蛋白的表达水平。结果高浓度(>2.5μg/μl)普洱茶叶水提取物能抑制GM细胞的生长且下调CETP mRNA表达,低浓度普洱茶叶水提取物(<2.5μg/μl)和绿茶中茶多酚(10μmol/L)能提高CETP mRNA与蛋白的表达,且呈现剂量和时间依赖性。结论 CETP基因可能是茶叶作用的靶点之一。 相似文献
5.
Rittershaus CW Miller DP Thomas LJ Picard MD Honan CM Emmett CD Pettey CL Adari H Hammond RA Beattie DT Callow AD Marsh HC Ryan US 《Arteriosclerosis, thrombosis, and vascular biology》2000,20(9):2106-2112
Using a vaccine approach, we immunized New Zealand White rabbits with a peptide containing a region of cholesteryl ester transfer protein (CETP) known to be required for neutral lipid transfer function. These rabbits had significantly reduced plasma CETP activity and an altered lipoprotein profile. In a cholesterol-fed rabbit model of atherosclerosis, the fraction of plasma cholesterol in HDL was 42% higher and the fraction of plasma cholesterol in LDL was 24% lower in the CETP-vaccinated group than in the control-vaccinated group. Moreover, the percentage of the aorta surface exhibiting atherosclerotic lesion was 39.6% smaller in the CETP-vaccinated rabbits than in controls. The data reported here demonstrate that CETP activity can be reduced in vivo by vaccination with a peptide derived from CETP and support the concept that inhibition of CETP activity in vivo can be antiatherogenic. In addition, these studies suggest that vaccination against a self-antigen is a viable therapeutic strategy for disease management. 相似文献
6.
Syeda F Senault C Delplanque B Le Roy B Thaminy A Gripois D Blouquit MF Ruelland A Mendy F Lutton C 《Nutrition, metabolism, and cardiovascular diseases : NMCD》2003,13(1):28-36
BACKGROUND AND AIM: Plasma cholesterol efflux capacity is stimulated during postprandial (PP) hypertriglycerdemia. Plasma cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are the key proteins in lipoprotein metabolism and remodelling, but their role during the PP cholesterol efflux process remains indeterminate. The aim of this study was to determine the effect of a fatty meal intake on plasma CETP and PLTP activities, and the capacity of plasma to promote cholesterol efflux, as well as to evaluate the relationship between these three key mechanisms of the reverse cholesterol transport process. METHODS AND RESULTS: CETP and PLTP activities and the cholesterol efflux capacity of plasma were measured over eight hours following a fatty meal (1000 kcal, 62% fat) in 13 normolipidemic men. CETP activity and the cholesterol efflux capacity of plasma from Fu5AH cells increased after the meal, reaching a maximum after eight hours (respectively 32%, p = 0.06, and 6.5%, p = 0.045), whereas PLTP activity remained unchanged. CETP and PLTP activities did not correlate with plasma cholesterol efflux capacity in the fasting or PP state. Plasma CETP activity in the fasting state positively correlated with the plasma non-esterified fatty acid (NEFA) levels, but no correlation was found with any lipid or apolipoprotein postprandially. The cholesterol efflux capacity of plasma correlated positively with high-density lipoprotein (HDL) components, the best correlation being with the HDL phospholipid fraction in both the fasting and PP states. CONCLUSIONS: These findings suggest that plasma CETP and PLTP activities in healthy normolipidemic subjects are differently regulated in the PP state, and are not correlated with the increased cholesterol efflux capacity of PP plasma. HDL-phospholipid remains the key factor in the regulation of the capacity of plasma to promote Fu5AH cell cholesterol efflux. 相似文献
7.
Liisanantti MK Huhta K Savolainen MJ 《Alcoholism, clinical and experimental research》2004,28(11):1638-1642
BACKGROUND: Phosphatidylethanol (PEth) is an abnormal phospholipid formed only in the presence of ethanol. It has been recently shown that lipoprotein-associated PEth may mediate the effects of ethanol on endothelial cells, and this may explain, at least in part, the beneficial effect of ethanol on atherosclerosis. This study was performed to investigate the transfer of PEth between lipoproteins and the effects of PEth on cholesteryl ester transfer protein (CETP) activity in plasma. METHODS: Lipoproteins were isolated from the plasma of healthy male volunteers (n = 16) and male alcoholics (n = 13). The transfer of cholesteryl esters and PEth was determined between labeled low-density lipoprotein (LDL) and unlabeled high-density lipoprotein particles in vitro. The electrophoretic mobility of PEth-modified LDL particles was determined by agarose gel electrophoresis. RESULTS: PEth was transferred from PEth-modified LDL to high-density lipoprotein at an initial rate of 25.9 nmol/ml/hr. Monoclonal antibody (TP2) against the putative lipid-binding domain of CETP inhibited the transfer rate of PEth by approximately 64%, whereas the cholesteryl ester transfer was inhibited by 86%. This indicates that most of PEth was transferred by transfer proteins other than CETP. CONCLUSIONS: The transfer of PEth between lipoproteins enables the redistribution of PEth from lipoprotein fractions with a slow turnover to those with a rapid clearance. Moreover, the PEth-induced change in the electrical charge of lipoproteins may affect the binding of lipoproteins to their receptors and binding proteins. This in turn may alter the metabolism of lipoproteins and lipid-mediated signaling pathways in the cells delineating the vascular wall. 相似文献
8.
Weiping Li Xin Liu Chunyi Huang Liusheng Liu Xuerui Tan Xingyu Wang 《Nutrition, metabolism, and cardiovascular diseases : NMCD》2021,31(2):602-607
Background and aimsLoss of the cholesteryl ester transfer protein (CETP) function affects HDLc levels, but its effects on major HDL protein component ApoA1 are not well understood in patients with acute myocardial infarction (AMI).Methods and resultsWe investigated the effects of an East Asian loss-of-function variant (rs2303790; p.D442G) in CETP gene on HDLc and ApoA1 levels and its relationship with AMI. A total of 2327 AMI patients and 2615 age- and sex-matched controls from INTERHEART-China study were included. In controls, both levels of HDLc (1.24 vs. 1.04 mmol/L, P = 0.001) and ApoA1 (1.48 vs. 1.37 mmol/L, P = 0.042) were significantly higher in CETP variant G allele carriers compared to CETP wildtype D allele carriers. In AMI patients, levels of HDLc were significantly higher (1.14 vs. 1.01 mmol/L, P = 0.013) while levels of ApoA1 were not statistically difference (1.31 vs. 1.32 mmol/L, P = 0.468) in CETP variant group compared to CETP wildtype group. Moreover, CETP variant is associated with HDLc increase, but is not associated with AMI risk (P = 0.564), even after adjusting for age, sex, history of hypertension and diabetes, waist to hip ratio, smoking, total cholesterol, LDL cholesterol, triglycerides, physical activity, depression, alcohol, vegetables and fruit consumption.ConclusionsLoss of CETP function is associated with increased HDLc and ApoA1 levels in healthy subjects, and in AMI patients, it is associated with HDLc levels but not ApoA1 levels. The lack of association of CETP variant with AMI may be related to the inability to increase ApoA1 levels and warranted further studies. 相似文献
9.
Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events. 相似文献
10.
Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. 总被引:6,自引:0,他引:6
Philip J Barter John J P Kastelein 《Journal of the American College of Cardiology》2006,47(3):492-499
Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events. 相似文献
11.
12.
Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited. 相似文献
13.
Nicholls SJ 《Current cardiology reports》2012,14(3):245-250
Considerable attention focuses on the ability to develop therapeutic agents that elevate levels of high-density lipoprotein cholesterol (HDL-C). Cholesteryl ester transfer protein (CETP) inhibitors have been developed on the basis of their ability to raise HDL-C to a greater extent than lipid-modifying therapies currently used in clinical practice. Initial enthusiasm for CETP inhibition decreased as a result of adverse clinical outcomes observed with the agent torcetrapib. Elucidating off-target toxicities of torcetrapib has provided hope that other CETP inhibitors may still be of potential benefit. Evacetrapib is a novel CETP inhibitor, with favorable effects on plasma lipids and no adverse effects on blood pressure or mineralocorticoid activity in early clinical evaluation. The potential effects on cardiovascular outcomes remain to be determined. 相似文献
14.
High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. 总被引:1,自引:0,他引:1
Susanna E Borggreve Hans L Hillege Geesje M Dallinga-Thie Paul E de Jong Bruce H R Wolffenbuttel Diederik E Grobbee Arie van Tol Robin P F Dullaart 《European heart journal》2007,28(8):1012-1018
AIMS: High cholesteryl ester transfer protein (CETP) concentrations are associated with increased risk of cardiovascular disease (CVD) in subjects with high triglycerides. We determined the relationship of plasma CETP with incident CVD in a population with relatively low triglycerides. METHODS AND RESULTS: A nested case-control study was performed in men participating in the prospective PREVEND study, after exclusion of CVD, diabetes mellitus, and lipid-lowering drugs use at baseline. Plasma CETP was measured in 111 men who developed a cardiovascular event (cases) during follow-up and in 116 controls who remained free of CVD. Fasting total cholesterol (P < 0.001) and triglycerides (P < 0.001) were higher, HDL cholesterol was lower (P = 0.001), but CETP was similar in cases and controls (P = 0.39). Cox proportional hazards regression analysis showed that CVD risk tended to be lower with higher plasma CETP after adjustment for age and lipids (hazard ratio 0.84; 95% CI 0.69-1.03, P = 0.10). Plasma CETP was lower in cases than in controls (P = 0.05) with triglycerides < or = 1.38 mmol/L (median), but not with higher triglycerides. The age-adjusted hazard ratio for CVD was 0.46 (95% CI 0.24-0.90) in men with triglycerides < or = 1.38 mmol/L and CETP > 2.26 mg/L (median) compared with men with similarly low triglycerides and CETP < or = 2.26 mg/L. With higher triglycerides, the hazard ratio for CVD was similar in both CETP categories. CONCLUSION: Relatively high plasma CETP may favour reduced CVD risk in the context of low triglycerides. 相似文献
15.
Ye D Kraaijeveld AO Grauss RW Willems SM van Vark-van der Zee LC de Jager SC Jauhiainen M Kuivenhoven JA Dallinga-Thie GM Atsma DE Hogendoorn PC Biessen EA Van Berkel TJ Jukema JW van Eck M 《Journal of internal medicine》2008,264(6):571-585
Objective. Cholesterol ester transfer protein (CETP) plays an important role in HDL cholesterol metabolism. Leucocytes, including monocyte‐derived macrophages in the arterial wall synthesize and secrete CETP, but its role in atherosclerosis is unclear. The aim of the current study was to investigate the effect of acute coronary syndromes (ACS) on leucocyte CETP expression. Research design. Peripheral blood mononuclear cells (PBMCs) were freshly isolated from hospitalized ACS patients displaying Braunwald class IIIB unstable angina pectoris (UAP) on admission (t = 0) and at 180 days post inclusion (t = 180) for analysis of CETP expression. In addition, to prove the potential correlation between leucocyte CETP and ACS the effect of acute myocardial infarction on leucocyte CETP expression was studied in CETP transgenic mice. Results. Upon admission, UAP patients displayed ~3–6 fold (P < 0.01) lower CETP mRNA and nearly absent CETP protein expression in PBMCs, as compared to healthy age‐/sex‐matched controls. Interestingly, CETP mRNA and protein levels were significantly elevated in PBMCs isolated from UAP patients (both stabilized and refractory) at t = 180 as compared to t = 0 (P < 0.01), which was correlated with a reduced inflammatory status after medical treatment. In agreement with the data obtained in UAP patients, markedly down‐regulated leucocyte CETP mRNA expression was observed after coronary artery ligation in CETP transgenic mice, which also correlated with increased serum amyloid A levels. Conclusions. We are the first to report that episodes of UAP in humans and myocardial infarction in CETP transgenic mice are associated with reduced leucocyte CETP expression. We propose that the impairment in leucocyte CETP production is associated with an enhanced inflammatory status, which could be clinically relevant for the pathogenesis of ACS. 相似文献
16.
Modulation of plasma cholesteryl ester transfer protein activity by unsaturated fatty acids in Tunisian type 2 diabetic women 总被引:2,自引:0,他引:2
Smaoui M Hammami S Attia N Chaaba R Abid N Kilani N Kchaou H Mahjoub S Abid M Hammami M 《Nutrition, metabolism, and cardiovascular diseases : NMCD》2006,16(1):44-53
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 omega3-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. 相似文献
17.
Dilys J Freeman Nilesh J Samani Valerie Wilson Alex D McMahon Peter S Braund Suzanne Cheng Muriel J Caslake Chris J Packard Dairena Gaffney 《European heart journal》2003,24(20):1833-1842
AIM: The association of cholesteryl ester transfer protein (CETP) gene polymorphisms with risk of a cardiovascular event and whether any association was explained by an influence on high-density lipoprotein (HDL) levels or low-density lipoprotein (LDL) size was tested in the West of Scotland Coronary Prevention Study (WOSCOPS). Gene-smoking and gene-treatment interactions were investigated. METHODS AND RESULTS: Cases (n=498) and controls (n=1108) were typed for TaqIB, C(-631)A, C(-629)A, I405V and D442G CETP polymorphisms. Homozygotes for the TaqIB2 allele (B2B2) had a 30% reduced risk of a cardiovascular event (odds ratio [OR] 0.70, CI(95)0.51-0.96, P=0.03) compared to B1B1 homozygotes. Inclusion of HDL or LDL diameter in multivariate analysis only marginally attenuated the relationships. Non-smokers, but not smokers, showed a dose-dependent association of risk with TaqIB genotype. Treatment benefit was not significantly different in B1B1 (OR 0.71, pravastatin vs placebo), B1B2 (OR 0.68) and B2B2 (OR 0.61) individuals. The other CETP polymorphisms studied had no significant association with cardiovascular risk. Haplotype analysis did not add to the information given by the individual polymorphisms. CONCLUSION: The association between CETP TaqIB genotype and cardiovascular risk is primarily in non-smokers, is not fully explained by effects on HDL levels or LDL size, and the benefit of pravastatin treatment was not influenced by this polymorphism. 相似文献
18.
Jane Armitage Michael V. Holmes David Preiss 《Journal of the American College of Cardiology》2019,73(4):477-487
Cholesteryl ester transfer protein (CETP) facilitates exchange of triglycerides and cholesteryl ester between high-density lipoprotein (HDL) and apolipoprotein B100–containing lipoproteins. Evidence from genetic studies that variants in the CETP gene were associated with higher blood HDL cholesterol, lower low-density lipoprotein cholesterol, and lower risk of coronary heart disease suggested that pharmacological inhibition of CETP may be beneficial. To date, 4 CETP inhibitors have entered phase 3 cardiovascular outcome trials. Torcetrapib was withdrawn due to unanticipated off-target effects that increased risk of death, and major trials of dalcetrapib and evacetrapib were terminated early for futility. In the 30,000-patient REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, anacetrapib doubled HDL cholesterol, reduced non-HDL cholesterol by 17 mg/dl (0.44 mmol/l), and reduced major vascular events by 9% over 4 years, but anaceptrapib was found to accumulate in adipose tissue, and regulatory approval is not being sought. Therefore, despite considerable initial promise, CETP inhibition provides insufficient cardiovascular benefit for routine use. 相似文献
19.
Barter PJ Brewer HB Chapman MJ Hennekens CH Rader DJ Tall AR 《Arteriosclerosis, thrombosis, and vascular biology》2003,23(2):160-167
Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from antiatherogenic HDLs to proatherogenic apolipoprotein B (apoB)-containing lipoproteins, including VLDLs, VLDL remnants, IDLs, and LDLs. A deficiency of CETP is associated with increased HDL levels and decreased LDL levels, a profile that is typically antiatherogenic. Studies in rabbits, a species with naturally high levels of CETP, support the therapeutic potential of CETP inhibition as an approach to retarding atherogenesis. Studies in mice, a species that lacks CETP activity, have provided mixed results. Human subjects with heterozygous CETP deficiency and an HDL cholesterol level >60 mg/dL have a reduced risk of coronary heart disease. Evidence that atherosclerosis may be increased in CETP-deficient subjects whose HDL levels are not increased is difficult to interpret and may reflect confounding or bias. Small-molecule inhibitors of CETP have now been tested in human subjects and shown to increase the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apoB. Thus, it seems important and timely to test the hypothesis in randomized trials of humans that pharmacological inhibition of CETP retards the development of atherosclerosis. 相似文献
20.
Cholesteryl ester transfer protein (CETP) regulates human lipoprotein metabolism. Because reducing CETP increases plasma HDL, CETP inhibitors are currently being investigated for their pharmacologic value. However, complete CETP deficiency may have undesirable consequences. In contrast, based on previous studies with purified components, we hypothesized that partial CETP inhibition, which will still elevate HDL, may induce beneficial changes in plasma lipid metabolism. To address this, CETP activity in human plasma was variably inhibited with monoclonal antibody. In control plasma, VLDL to LDL lipid transfer was >2-fold higher than to HDL(3) with lipid transfer to HDL(2) intermediate. However, individual lipid transfer events were uniquely sensitive to CETP suppression such that when CETP activity was inhibited by 60%, lipid transfer from VLDL to LDL, HDL(2) and HDL(3) were equal. The ratio of lipid transfers to LDL versus HDL declined linearly with CETP inhibition. In mass lipid transfer experiments, 25-50% inhibition of CETP significantly reduced lipid flux between VLDL and LDL but minimally affected cholesteryl ester (CE) loss from HDL. Complete CETP inhibition did not reduce cholesterol esterification rates but completely blocked the delivery of new CE to VLDL, whereas, 50% inhibition of CETP reduced this CE flux to VLDL by <20%. Thus, inhibition of CETP by 相似文献