胆固醇酯转运蛋白抑制剂的研究进展

流行病学研究证明,低密度脂蛋白(LDL)和高密度脂蛋白(HDL)是调整心血管疾病风险的独立因子,如何升高HDL日益受到人们的重视。研究表明胆固醇酯转运蛋白(CETP)抑制剂具有较强的升高HDL和抗动脉粥样硬化作用,本文对CETP抑制剂的研究进展综述如下。     

胆固醇酯转运蛋白抑制剂的研究进展

流行病学研究证明,低密度脂蛋白（LDL）和高密度脂蛋白（HDL）是调整心血管疾病风险的独立因子,如何升高HDL日益受到人们的重视。研究表明胆固醇酯转运蛋白（CETP）抑制剂具有较强的升高HDL和抗动脉粥样硬化作用,本文对CETP抑制剂的研究进展综述如下。     

胆固醇酯转运蛋白抑制剂研究进展

升高高密度脂蛋白胆固醇水平是降低动脉粥样硬化危险的一个可能的有益治疗靶标。胆固醇酯转运蛋白抑制剂虽然能有效升高高密度脂蛋白胆固醇水平,但目前对其是否能有效减少动脉粥样硬化的危险程度尚不明确。     

胆固醇酯转运蛋白基因突变的研究进展

胆固醇酯转运蛋白促进脂蛋白中各种中性脂质转运和交换，在胆固醇逆转运中起关键作用。胆固醇酯转运蛋白基因突变和基因缺陷导致血浆胆固醇酯转运蛋白含量或活性降低，引起脂蛋白代谢发生显著变化，高密度脂蛋白水平升高，常伴有高α-脂蛋白血症。胆固醇酯转运蛋白基因变异和脂蛋白代谢异常及动脉粥样硬化的相关研究，已成为脂代谢和冠心病研究热点之一。本文综述了胆固醇酯转运蛋白基因突变及其限制片段长度多态性的研究进展。     

中国北方老年人和散发型阿尔茨海默病患者胆固醇酯转运蛋白基因L296Q突变的缺失

目的探讨胆固醇酯转运蛋白(CETP)基因的一个新发多态位点——L296Q与散发型阿尔茨海默病(SAD)易感性的关系。方法应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)、变性高效液相色谱(DHPLC)和测序等方法检测107例SAD患者和115名健康老年人L296Q基因多态性。结果无论是哪种方法均未发现SAD组和对照组存在Q等位基因或LQ和QQ基因型。结论在研究人群中未发现此多态位点,可能与研究人群间的种族、年龄差异或技术问题有关。     

胆固醇酯转运蛋白与动脉粥样硬化

胆固醇酯转运蛋白是胆固醇逆向运输的关键蛋白质，是血浆高密度脂蛋白水平的主要决定因素之一。关于胆固醇酯转运蛋白与动脉粥样硬化的关系目前尚有争论，现有研究资料表明它具有促动脉粥样硬化和抗动脉粥样硬化的双重作用。多数胆固醇酯转运蛋白基因的突变导致胆固醇酯转运蛋白水平下降，高密度脂蛋白水平上升，而使动脉粥样硬化风险降低；但在高密度脂蛋白水平正常或较低的个体，胆固醇酯转运蛋白水平的下降去使冠状动脉疾病的发病率升高，转基因动物的研究表明，胆固醇酯转运蛋白对动脉粥样硬化的影响与脂蛋白代谢背景有关。     

胆固醇酯转运蛋白基因突变的研究进展

胆固醇酯转运蛋白促进脂蛋白中各种中性脂质转运和交换,在胆固醇逆转运中起转运蛋白基因突变和基因缺陷导致血浆胆固醇酯转运蛋白含量或活性降低,引起脂蛋白代谢发生显著变化,高密度脂蛋白水平升高,常伴有高α-脂蛋白血症.胆固醇酯转运蛋白基因变异和脂蛋白代谢异常及动脉粥样硬化的相关研究,已成为脂代谢和冠心病研究热点之一.本文综述了胆固醇酯转运蛋白基因突变及其限制片段长度多态性的研究进展.     

冠心病患者血浆胆固醇酯转运蛋白水平与

目的　探讨冠心病患者胆固醇酯转运蛋白（CETP）水平与血浆高密度脂蛋白（HDL）亚类组成的关系。方法　收集冠心病患者血浆116例和健康对照组血浆87例,采用双向电泳-免疫印迹检测法分析其HDL亚类浓度,用酶联免疫法测定CETP浓度。按CETP浓度均值加或减去一个标准差作为分割点,将冠心病患者分为3组：低CETP组（CETP≤0.69　mg/L）、中CETP组（0.69＜CETP<1.59　mg/L）、高CETP组（CETP≥1.59　mg/L）。结果     

胆固醇酯转运蛋白D~(442)→G突变对高密度脂蛋白胆固醇水平的影响

目的探讨胆固醇酯转运蛋白D442→G变异对国人血脂水平的影响。方法收集天津地区189例健康人群,检测其血脂水平,并应用聚合酶链反应限制片长多态性分析方法对胆固醇酯转运蛋白D442→G突变进行检测。结果高密度脂蛋白胆固醇水平较高组与对照组D442→G等位基因频率分别为6.03%和1.53%,具有统计学差异(P<0.05)。D442→G基因变异携带组高密度脂蛋胆固醇水平显著高于对照组(P<0.01),其它血脂水平无显著性差异。结论胆固醇酯转运蛋白第15外显子D442→G突变与高密度脂蛋白胆固醇水平升高密切相关。     

对于升高高密度脂蛋白药物胆固醇酯转运蛋白抑制剂的研究进展及其机制的探讨

高密度脂蛋白(HDL)通过其特有的胆固醇逆转运功能起到了抗动脉粥样硬化及冠心病的作用。大量临床及流行病研究已证实高密度脂蛋白胆固醇(HDL-C)的含量水平与心血管风险呈负相关,因此如何提高HDL-C水平已成为了各方关注的焦点,但升高HDL-C药物的研发却屡屡受挫。进一步探讨HDL的结构,功能有助于分析升高HDL-C药物失败的可能原因及机制,对于临床和基础研究有着重要的意义。     

胆固醇酯转运蛋白与血脂、血糖的关系

目的　研究胆固醇酯转运蛋白 (CETP)与各种类型的血脂异常和血糖异常的关系。方法　 1999年 9月至 10月 ,在北京市自然人群中采用分层随机抽样方法进行危险因素的横断面调查。分析了 719名 4 5～ 6 4岁的男女两性的血浆CETP浓度与血脂、血糖的关系。结果　 (1)在正常甘油三酯 (TG)组 ,CETP低于第 2 5百分位数与高于第 75百分位数时低高密并脂蛋白胆固醇 (HDL C)的患病率分别为 7 4 %和 5 3%。在高TG组 ,CETP低于第 2 5百分位数时低HDL C的患病率也仅为3 6 % ,与正常TG组相似 ;但CETP大于第 75百分位数时低HDL C的患病率为 35 7% ,是CETP低于第 2 5百分位数组的 10倍 ,且高低密度脂蛋白胆固醇 (LDL C)和高极低密度脂蛋白胆固醇 (VLDL C)的患病率也最高。 (2 )高TG合并低HDL C组 ,CETP高于第 75百分位数者占 5 0 0 % ,明显高于其他各组(P <0 0 5 )。 (3)采用Logistic回归模型调整了年龄、性别、吸烟、饮酒、肥胖、血糖和总胆固醇后 ,CETP大于第 75百分位数组与小于第 2 5百分位数组相比患高TG低HDL C型血脂异常的危险显著增加 ,OR =10 94 ,P =0 0 2 5。 (4 )高TG和 (或 )低HDL C者合并高血糖的患病率亦较高 (P <0 0 0 1) ,但仅在CETP较高者中 ,高血糖患病率增加有显著性 (P <0 0 0 1)。结论　CETP     

Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients

Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL₂-CE (r= −0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL₂-CE remained unchanged. Postprandial HDL₃ of controls were enriched with phospholipid (PL) (30.3 ± 2.6% at 6 h) with respect to fasting (25.6 ± 2.5%, P < 0.01) and to NIDDM-HDL₃ (25.8 ± 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL₂-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL₃ with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL₃ enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile.     

High level of serum cholesteryl ester transfer protein in active hepatitis C virus infection

AIM: To determine the significance of cholesteryl ester transfer protein(CETP) in lipoprotein abnormalities in chronic hepatitis C virus(HCV) infection.METHODS: We evaluated the significance of the serum concentration of CETP in 110 Japanese patients with chronic HCV infection. Fifty-five patients had active HCV infection, and HCV eradication had been achieved in 55. The role of CETP in serum lipoprotein abnormalities, specifically, in triglyceride(TG) concentrations in the four major classes of lipoproteins, was investigated using Pearson correlations in conjunction with multiple regression analysis and compared them between those with active HCV infection and those in whom eradication had been achieved. RESULTS: The serum CETP levels of patients with active HCV infection were significantly higher than those of patients in whom HCV eradication was achieved(mean ± SD, 2.84 ± 0.69 μg/m L vs 2.40 ± 1.00 μg/m L, P = 0.008). In multiple regression analysis, HCV infection status(active or eradicated) was an independent factor significantly associated with the serum CETP level. TG concentrations in low-density lipoprotein(mean ± SD, 36.25 ± 15.28 μg/m L vs 28.14 ± 9.94 μg/m L, P = 0.001) and high-density lipoprotein(HDL)(mean ± SD, 25.9 ± 7.34 μg/m L vs 17.17 ± 4.82 μg/m L, P 0.001) were significantly higher in patientswith active HCV infection than in those in whom HCV eradication was achieved. The CETP level was strongly correlated with HDL-TG in patients with active HCV infection(R = 0.557, P 0.001), whereas CETP was not correlated with HDL-TG in patients in whom HCV eradication was achieved(R =-0.079, P = 0.56). CONCLUSION: Our results indicate that CETP plays a role in abnormalities of lipoprotein metabolism in patients with chronic HCV infection.     

Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency

Six homozygous, 10 heterozygous and 8 unaffected subjects in a CETP deficient family confirmed by CETP gene analysis were studied to characterize serum lipoproteins separated by ultracentrifugation, and to examine the relations between CETP levels and lipoprotein lipid concentration and composition. The serum CETP levels were measured by radioimmunoassay using ¹²⁵I-labeled monoclonal antibodies (TP2). The serum CETP levels in the homozygotes were undetectable and those in the heterozygotes were significantly lower than those in the unaffected subjects (1.5 ± 0.1 vs. 2.2 ± 0.5 μg/ml, P < 0.01). In the HDL fraction, esterified cholesterol (EC) levels in the homozygotes were significantly increased (P < 0.01), and those in the heterozygotes were slightly increased (n.s.), in comparison with those in the unaffected and the normolipidemic controls. The EC levels in the IDL fractions were lower in the homozygotes than in the normolipidemic controls. The EC/triglyceride (TG) molar ratios in IDL, the fraction obtained from the homo- and heterozygotes, were lower than those from the unaffected subjects (P < 0.01 and < 0.01, respectively), and the EC/TG ratios in the HDL fraction obtained from the homo- and heterozygotes were higher than those from the unaffected subjects (P < 0.01 and n.s., respectively). Linear regression analysis showed that positive correlates of the serum CETP levels in all subjects were: IDL-EC (r = 0.463), HDL-TG (r = 0.603) and VLDL- and IDL-EC/TG ratio (r = 0.698 and and 0.843). When the homozygotes were excluded from the analysis, the EC/TG ratios in VLDL IDL were still positively correlated with the serum CETP levels (r = 0.677 and 0.676). Inverse correlates of the serum CETP levels in all subjects were: HDL-EC (r = −0.783) and HDL-EC/TG ratio (r = −0.739). These results suggested that the decreased CETP concentration decreased IDL-cholesterol and increased HDL-cholesterol levels through reducing transport of EC from HDL to IDL, and produced an anti-atherogenic plasma lipoprotein pattern.     

Phospholipid and cholesteryl ester transfer are increased in lipoprotein lipase deficiency

OBJECTIVES: Phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) are key enzymes in lipoprotein metabolism by mediating the transfer and exchange of phospholipids (PL) and neutral lipids between lipoproteins. Lipoprotein lipase (LPL) deficiency is associated with low HDL-cholesterol (HDL-C) levels in both, the homozygous and heterozygous state. In the present study we set out to investigate the role of lipid transfer proteins, which are known to strongly determine HDL-C levels, in LPL deficiency. DESIGN/SUBJECTS: Phospholipid acceptor and donor properties of lipoproteins, PLTP activity, CETP mass, activity and cholesteryl ester (CE) transfer were determined in two homozygous and six heterozygous LPL-deficient subjects and in 10 healthy, normolipidaemic controls, respectively. RESULTS: The HDL isolated from LPL-deficient subjects showed strongly increased PL-acceptance when compared with controls (homozygotes versus heterozygotes versus control: 26.46 +/- 15.26 vs. 3.41 +/- 1.61 vs. 1.89 +/- 0.33 micromol mL-1 h-1/micromol mL-1 PL; all P < 0.05). Phospholipid transfer from apolipoprotein B containing lipoproteins was increased in heterozygotes when compared with controls (46.66 +/- 23.3 vs. 28.91 +/- 18.05 micromol mL-1 h-1/micromol mL-1 PL, P = 0.05). PLTP activity, however, was similar in LPL-deficient subjects and controls. CETP mass was highest in homozygotes, whilst enzyme activity was similar in LPL-deficient subjects and controls. CE transfer was highest in homozygotes (72.5 +/- 8.8%) and lowest in controls (28.7 +/- 5.2%, P < 0.01). CONCLUSIONS: In conclusion, PL and CE transfer are increased in LPL deficiency and thus, partly explain low HDL-levels in LPL-deficient subjects. Enhanced transfer seems rather to be the result of altered lipoprotein composition and concentration than altered enzyme activity. Our findings on mechanisms leading to low HDL-C levels might show another aspect in atherogenesis in LPL deficiency.     

A protective role of a cholesteryl ester transfer protein gene variant towards ischaemic stroke in Sardinians

OBJECTIVES: Cholesteryl ester transfer protein (CETP) plays a key role in the metabolism of high-density lipoprotein (HDL), a strong, inverse, independent risk factor for cardiovascular disease. We sought to investigate the relationship between a common variant of CETP gene, the Taq1 B polymorphism, that has been previously associated with CETP blood concentrations, and the risk of ischaemic stroke in a genetically homogenous population from the Sardinia island, Italy. This population has been previously shown to be a highly conservative sample. DESIGN: A total of 215 cases of ischaemic stroke and 236 controls were selected and characterized for the CETP Taq1 B polymorphism. Allele and genotype frequencies were compared amongst cases and controls. RESULTS: Age, hypertension and hypercholesterolaemia were independent risk factors for stroke in this cohort. We found that presence of the CETP Taq1 B2 allele was associated with a significantly decreased risk of ischaemic stroke when assuming a recessive mode of inheritance (OR 0.55, 95% CI = 0.34-0.90, P = 0.017). This result was confirmed by multivariate analysis, after adjustment for age, presence of hypertension and hypercholesterolaemia (OR 0.53, 95% CI = 0.32-0.88, P = 0.014). By performing separate analysis for gender we found that the effect was present in females but not in males, with a significant sex-CETP gene variant interaction for both recessive (P = 0.005) and additive (P = 0.029) modes of inheritance. CONCLUSIONS: Our data suggest that the Taq1 B2 allelic variant of the CETP gene may be associated, as a protective factor, with occurrence of ischaemic stroke. Further studies are needed to further elucidate the clinical implications of our finding.     

High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants

Cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are two HDL modifying proteins that have both pro- and anti-atherogenic properties. We hypothesized that CETP and HL synergistically affect HDL cholesterol and atherosclerotic risk. To test our hypothesis, we analysed the genotype frequencies of CETP Taq1B (rs708272) and LIPC-514C/T (rs1800588) polymorphisms in male coronary artery disease patients (CAD; n = 792) and non-symptomatic controls (n = 539). Cases and controls had similar allele frequencies, but the occurrence of the combined genotypes differed (p = 0.027). In CAD patients, 1.3% had the CETP-B2B2/LIPC-TT genotype, with only 0.2% in controls (p = 0.033). The presence of the CETP lowering B2 allele and the HL lowering LIPC-T allele synergistically increased HDL cholesterol from 0.87 ± 0.19 mmol/L in the B1B1/CC (n = 183) to 1.21 ± 0.25 mmol/L in the B2B2/TT carriers (n = 10). The B1B1/CC carriers had an increased CAD risk (OR 1.4; p = 0.025). Despite their high HDL cholesterol, the B2B2/TT individuals also had an increased CAD risk (OR 3.7; p = 0.033). In a 2-year follow up, the loss of coronary artery lumen diameter in these patients was higher than in all other patients combined (0.34 ± 0.70 versus 0.10 ± 0.29 mm; p = 0.044). We conclude that a high HDL cholesterol does not protect against coronary artery disease when associated with combined CETP- and HL-lowering gene variants.     

胆固醇酯转运蛋白抑制剂对动脉粥样硬化性心血管疾病影响的研究进展

大量临床流行病学资料证实血浆低密度脂蛋白胆固醇水平升高及高密度脂蛋白胆固醇水平降低均是动脉粥样硬化性心血管疾病的独立危险因素。在生理过程中抑制胆固醇酯转运蛋白可以升高血浆高密度脂蛋白胆固醇水平,理论上可能具有抗动脉粥样硬化的作用。然而迄今为止,调节胆固醇酯转运蛋白的动物模型和临床研究结果不尽一致,以抑制胆固醇酯转运蛋白为基础的相关药物治疗选择带来了不确定性。文章从胆固醇酯转运蛋白在脂质代谢中的生理作用、部分动物研究中与动脉粥样硬化的关系以及临床应用对动脉粥样硬化性心血管疾病的影响等方面的最新研究进展进行综述。     

Modulation of plasma cholesteryl ester transfer protein activity by unsaturated fatty acids in Tunisian type 2 diabetic women

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.     

Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk

Background

Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes.