胆固醇酯转运蛋白限制片长多态性与冠心病

胆固醇酯转运蛋白促进脂蛋白中各种中性脂质的转运和交换,调节高密度脂蛋白代谢,在胆固醇逆向转运中起关键作用。胆固醇酯转运蛋白基因在第1内含子上具有限制片长多态性,其等位基因为B1和B2,等位基因B1与血浆胆固醇酯转运蛋白水平升高,活性增强,高密度脂蛋白水平降低密切相关,在冠心病的发生发展过程中具重要意义。     

垂体性侏儒症患儿血脂及载脂蛋白A1,B水平

对25例垂体性侏儒儿的血胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-C),低密度脂蛋白(LDL-C)、载脂蛋白A_1(Apo A_1)、载脂蛋白(Apo B)等进行了测定,并与相应健康儿作了比较;与此同时,还着重观察了基因重组人生长激素(hGH)治疗3个月后对患儿上述指标的影响。结果表明:(1)患儿组TC、TG、LDL-C和Apo B值均明显高于对照组(P分别<0.01、<0.05、<0.01和<0.01);其中TC值高于正常值上限者14例,占56％;TG升高者2例,占8％;Apo B升高者13例,占52％;而Apo　A_1水平较对照组明显降低(P<0.01)。(2)hGH治疗3个月后随访,患儿组的TC,LDL-C和Apo B水平较治疗前明显下降(P分别<0.05,<0.01和<0.01);而TG和Apo A_1水平皆有不同程度的上升(P<0.01)。提示垂体性侏儒儿存在着不同程度的脂质代谢紊乱,而生长激素缺乏是其主要原因之一。     

胆固醇酯转运蛋白在动脉粥样硬化中的作用

胆固醇酯转运蛋白介导血浆高密度脂蛋白、低密度脂蛋白和极低密度脂蛋白之间胆固醇酯、磷脂和甘油三酯的转运,直接关联各种脂蛋白分子的组成、大小和浓度,在胆固醇的逆向转运中起关键作用,与动脉粥样硬化的发生发展密切相关。胆固醇酯转运蛋白基因有多种突变,基因突变者胆固醇酯转运蛋白浓度和活性发生改变,并伴有高密度脂蛋白胆固醇水平升高等显著的脂代谢异常。雌激素对胆固醇酯转运蛋白水平也有调节作用。胆固醇酯转运蛋白在小颗粒致密的B型低密度脂蛋白形成中起重要作用,大而轻的A型低密度脂蛋白在高甘油三酯的条件下,经胆固醇酯转运蛋白介导极低密度脂蛋白中甘油三酯与低密度脂蛋白中胆固醇酯交换,导致典型的A型低密度脂蛋白变成强致病性的B型低密度脂蛋白。     

胆固醇酯转运蛋白TaqIB基因多态性对脂蛋白水平的影响

胆固醇酯转运蛋白 (CETP)介导高密度脂蛋白(HDL)中的胆固醇酯与低密度脂蛋白 (LDL)及极低密度脂蛋白 (VLDL)中的甘油三酯等量交换 ,在胆固醇逆向转运中起关键作用 ,调节各种脂蛋白颗粒大小和脂质组成 ,与动脉粥样硬化的发生和发展密切相关。CETP在多个位点有基因多态性 ,目前研究较多的是CETP基因第 1内含子限制性片段多态性 ,根据是否有TaqI作用位点划分等位基因B1和B2 ,由此测定 3种CETP基因型B1B1、B1B2、B2B2[1] 。研究表明 ,CETP TaqIB多态性是一普遍存在于白种人群中的遗传学变异 ,等位基因B2与血浆高密度脂蛋白胆…     

血清脂蛋白及载脂蛋白测定在高血压病患者中的临床意义

本文选择高血压病患者206例,测定血清脂蛋白及载脂蛋白含量,发现总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL—c)及载脂蛋白B_(100)(ApoB_(100))明显高于对照组(P<0.01);高密度脂蛋白胆固醇(HDL—C)、亚组HDL_2—C及Apo A_1明显低于对照组。结果表明,LDL—C及Apo B_(100)增高;HDL—C及Apo A_1降低是高血压病患者心血管动脉粥样硬化疾病的易患因子,尤其对冠心病(CHD)的发生与发展影响就更为明显。     

胆固醇逆向转运与动脉粥样硬化的转基因动物研究进展

肝外组织获得的胆固醇通过胆固醇逆向转运(reverse cholesterol transport,RCT)回到肝脏排出体内。RCT起始于肝外组织细胞内胆固醇的流出,以胆固醇从肝脏分泌和粪便中排出体外结束。数个关键蛋白如三磷酸腺苷结合盒转运体A1/G1(adenotriphos binding cassette transporter A1/G1,ABCA1/G1)、卵磷脂胆固醇酰基转移酶(lecithin:cholesterolacyltransfer,LCAT)、胆固醇酯转移蛋白(cholesterol ester transfer protein,CETP)和B类Ⅰ型清道夫受体(scavenger receptor B1,SR-B1)参与了这个过程。本文综述RCT在心血管疾病中作用的转基因动物实验研究。这些动物和实验室资料对临床现象的解释和临床调查的未来方向可能有用。     

高密度脂蛋白的代谢相关基因表达产物与动脉粥样硬化

高密度脂蛋白胆固醇水平降低是动脉粥样硬化性心脏病独立和重要的危险因素。血浆高密度脂蛋白胆固醇水平不仅决定于它的生成速率,更重要的是取决于它的代谢水平。一系列的基因及其相关产物参与了高密度脂蛋白参与的胆固醇逆向转运过程,包括与升高血浆高密度脂蛋白胆固醇水平的基因及其产物如三磷酸腺苷结合盒转运A1、磷脂酰胆碱胆固醇酰基转移酶、磷脂转运蛋白和脂蛋白脂酶等,以及降低血浆高密度脂蛋白胆固醇水平的基因和产物如清道夫受体B1、胆固醇酯转运蛋白、肝脂肪酶和内皮细胞脂肪酶等。而高密度脂蛋白代谢与动脉粥样硬化的关系也是多方面的,不能仅由血浆高密度脂蛋白胆固醇水平来明确推断对动脉粥样硬化的影响,降低血浆高密度脂蛋白胆固醇水平与动脉粥样硬化有一定的关联但不是必然的联系。     

高脂血症人群血清胆固醇酯转运蛋白的水平

目的分析不同高脂血症人群血清胆固醇酯转运蛋白水平及其对血浆各脂蛋白间脂质转运的调节作用。方法脂蛋白电泳结合酶显色法分别检测血清各脂蛋白中的甘油三酯含量;酶联免疫吸附试验测定血清胆固醇酯转运蛋白和氧化型低密度脂蛋白水平;分析胆固醇酯转运蛋白与脂质水平间的相关性。结果高甘油三酯组、高胆固醇组、混合组和对照组中胆固醇酯转运蛋白水平分别为1.89±1.32、2.37±1.30、2.33±1.73和1.58±1.00 mg/L,与对照组比较,高甘油三酯组变化无显著性(P>0.05),高胆固醇组(P<0.01)和混合组均升高(P<0.05)。高脂血症人群高密度脂蛋白中胆固醇/甘油三酯比值降低;高甘油三酯组和混合组低密度脂蛋白中甘油三酯/胆固醇比值升高,高胆固醇组无差别,其中高甘油三酯组变化程度最大,混合组次之,高胆固醇组最小;且胆固醇酯转运蛋白水平与上述比值相关。高脂血症人群血清氧化型低密度脂蛋白水平升高,与低密度脂蛋白中甘油三酯/胆固醇比值高度呈正相关。结论高脂血症人群胆固醇酯转运蛋白水平升高,促进了脂蛋白间脂质转运,使高密度脂蛋白和低密度脂蛋白脂质组成发生变化,促进了动脉粥样硬化的发生和发展。     

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。     

胆固醇酯转移蛋白与动脉粥样硬化

胆固醇酯转移蛋白由于介导胆固醇的逆向转运过程 ,其与动脉粥样硬化的关系受到重视。本文对胆固醇酯转移蛋白的生化特性、基因结构、在脂代谢中的作用及其与动脉粥样硬化关系的近期研究结果等方面进行了综述。     

Apolipoprotein A-II,HDL metabolism and atherosclerosis

Apolipoprotein (Apo) A-I and apo A-II are the major apolipoproteins of HDL. It is clearly demonstrated that there are inverse relationships between HDL-cholesterol and apo A-I plasma levels and the risk of coronary heart disease (CHD) in the general population. On the other hand, it is still not clearly demonstrated whether apo A-II plasma levels are associated with CHD risk. A recent prospective epidemiological (PRIME) study suggests that Lp A-I (HDL containing apo A-I but not apo A-II) and Lp A-I:A-II (HDL containing apo A-I and apo A-II) were both reduced in survivors of myocardial infarction, suggesting that both particles are risk markers of CHD. Apo A-II and Lp A-I:A-II plasma levels should be rather related to apo A-II production rate than to apo A-II catabolism. Mice transgenic for both human apo A-I and apo A-II are less protected against atherosclerosis development than mice transgenic for human apo A-I only, but the results of the effects of trangenesis of human apo A-II (in the absence of a co-transgenesis of human apo A-I) are controversial. It is highly suggested that HDL reduce CHD risk by promoting the transfer of peripherical free cholesterol to the liver through the so-called 'reverse cholesterol transfer'. Apo A-II modulates different steps of HDL metabolism and therefore probably alters reverse cholesterol transport. Nevertheless, some effects of apo A-II on intermediate HDL metabolism might improve reverse cholesterol transport and might reduce atherosclerosis development while some other effects might be deleterious. In different in vitro models of cell cultures, Lp A-I:A-II induce either a lower or a similar cellular cholesterol efflux (the first step of reverse cholesterol transport) than Lp A-I. Results depend on numerous factors such as cultured cell types and experimental conditions. Furthermore, the effects of apo A-II on HDL metabolism, beyond cellular cholesterol efflux, are also complex and controversial: apo A-II may inhibit lecithin-cholesterol acyltransferase (LCAT) (potential deleterious effect) and cholesteryl-ester-transfer protein (CETP) (potential beneficial effect) activities, but may increase the hepatic lipase (HL) activity (potential beneficial effect). Apo A-II may also inhibit the hepatic cholesteryl uptake from HDL (potential deleterious effect) probably through the SR-BI depending pathway. Therefore, in terms of atherogenesis, apo A-II alters the intermediate HDL metabolism in opposing ways by increasing (LCAT, SR-BI) or decreasing (HL, CETP) the atherogenicity of lipid metabolism. Effects of apo A-II on atherogenesis are controversial in humans and in transgenic animals and probably depend on the complex effects of apo A-II on these different intermediate metabolic steps which are in weak equilibrium with each other and which can be modified by both endogenous and environmental factors. It can be suggested that apo A-II is not a strong determinant of lipid metabolism, but is rather a modulator of reverse cholesterol transport.     

对Ⅱ型糖尿病患者血清载脂蛋白AI与B测定值的评价

采用逐步回归及多变量逐步判别分析,对56例Ⅱ型糖尿病并发动脉粥样硬化、冠心病患者的ApoAI、ApoB、Tch、TG、HDL-C、HDL_2-C、HDL_3-C等血生化指标进行分析。多变量判别结果,DM-A组优选指标男性组是ApoAI/ApoB;女性组是ApoAI/ApoB、TG、HDL_2-C,男、女混合组为ApoAI/ApoB、TG、ApoB、HDL_2-G。三组中优选值都有ApoAI/ApoB,且P值最小,可作为糖尿病并发冠心病、动脉硬化症的一项有意义的预测指标。     

乐瓦停治疗原发性和继发性高脂血症的临床观察

本文报道乐瓦停(Lovastatin)对伴有高脂血症的陈旧性心肌梗塞(OMI)、非胰岛素依赖型糖尿病(NIDDM)及肾病综合征(NS)三组患者34例的降血脂疗效。结果显示,与治疗前比,服安慰剂4周,各组血脂均无明显变化;服乐瓦停4周,各组血脂均有明显改善,继续服药,疗效稳定。服乐瓦停12周,TC降34.1%(P<0.001),LDL-C降43.6%(P<0.001),TC/HDL-C降35.6%(P<0.001),TG降30.8%(P<0.01),OMI组及NIDDM组ApoB都明显下降(P<0.01—0.001),Apo A Ⅰ/Apo B比值都明显上升(P<0.01—0.001);三组Apo A-Ⅰ、HDL-C及NS组的Apo B及Apo A-Ⅰ/Apo B比值均未见明显变化(P>0.05)。疗程中,乐瓦停与环磷酰胺或雷公藤合用的2例SGPT均明显升高,停药后迅速回降。本文未见其它重要副作用。     

Association between insulin resistance and apolipoprotein B in normoglycemic Koreans

BACKGROUND: Insulin resistance (IR) is associated with a significant increase in the risk of coronary artery disease (CAD). The serum apolipoprotein B and Apo A1/Apo B ratio are important markers of CAD. The aim of this study was to assess the association of the serum Apo B and Apo A1/Apo B ratio, with insulin resistance in apparently healthy normoglycemic Koreans. METHODS: From the individuals that participated in medical screening at the health promotion center of Kangbuk Samsung Hospital, between January and December 2002, a total of 7427 participants (4356 men, 3071 women) were enrolled in this study. All participants had no personal histories of diabetes, with normal fasting glucose levels. The clinical characteristics and biochemical parameters of the subjects were assessed. RESULTS: The Apo B, total cholesterol/high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C)/high-density lipoprotein-cholesterol showed positive correlations with metabolic syndrome and insulin resistance (p<0.001). The Apo A1, Apo A1/Apo B, LDL/Apo B and HDL/Apo A1 showed negative correlations with metabolic syndrome and insulin resistance (p<0.001). CONCLUSION: These data suggest that insulin resistance may be associated with the serum Apo B and Apo A1/Apo B ratio in non-diabetic, normoglycemic subjects. Thus, further study may be needed to determine whether medical intervention is inevitable or not in these type of subjects.     

Effect of nephropathy on the composition of apolipoprotein-containing particles in NIDDM

We investigated the effect of nephropathy on the composition of apolipoprotein-containing particles in non-obese NIDDM patients with normocholesterolemia. Sixty-seven normal control subjects (group A), 48 NIDDM patients without nephropathy (group B) and 36 NIDDM patients with nephropathy (group C) were studied. Apolipoprotein AI or B100 containing particles (Apo AI or Apo B100) were isolated by immunoaffinity columns prepared with monoclonal antibodies. The total cholesterol (CH), esterified cholesterol (EC) and free cholesterol (FC) content in these particles was analyzed. Both the EC/FC ratio levels in Apo AI and in Apo B100 in group C were significantly higher than those in group A or B. Both the CH in Apo AI/apolipoprotein AI ratio and in Apo B100/apolipoprotein B100 ratio levels in group C were significantly lower than those in group A or B. The insulin resistance index showed significant positive correlation with the EC/FC ratio levels in Apo AI and in Apo B100, and showed significant negative correlation with the CH levels in Apo AI/apolipoprotein AI ratio and the CH levels in Apo B100/apolipoprotein B100 ratio levels in group C. Those compositional changes of lipoproteins in NIDDM patients with nephropathy may reflect partial insulin resistance and deteriorating atherosclerosis.     

Effect of moderate alcohol consumption on parameters of reverse cholesterol transport in postmenopausal women

BACKGROUND: Alcohol consumption is associated with increased high-density lipoprotein (HDL) cholesterol levels. One of the main antiatherogenic functions of HDL is reverse cholesterol transport. Three early steps of reverse cholesterol transport are (1) cellular cholesterol efflux, (2) plasma cholesterol esterification (EST), and (3) cholesteryl ester transfer (CET) to apolipoprotein B-containing lipoproteins. Our previous study in healthy middle-aged men showed that moderate alcohol consumption increases cellular cholesterol efflux and EST. This study investigated the effect of moderate alcohol consumption on three early steps of reverse cholesterol transport in postmenopausal women. METHODS: In a randomized crossover study, 18 postmenopausal women--all apparently healthy, non-smoking, and moderate alcohol drinkers--consumed white wine or white grape juice with evening dinner during 2 successive periods of 3 weeks. During the white wine period, alcohol intake equaled 24 g/day. At the end of each of the two experimental periods, blood samples were collected. RESULTS: Three weeks of alcohol consumption increased serum HDL cholesterol levels (5.0%; p < 0.05), serum HDL phospholipid levels (5.8%; p < 0.05), and the ex vivo cellular cholesterol efflux capacity of plasma, measured with Fu5AH cells (3.4%; p < 0.05). Plasma EST and CET did not change. CONCLUSIONS: Moderate alcohol intake increases serum HDL cholesterol level and stimulates cellular cholesterol efflux in postmenopausal women. Moderate alcohol consumption does not seem to affect two other early steps of reverse cholesterol transport at this level of alcohol intake. Our data suggest that the relative protection of moderate alcohol consumption against cardiovascular disease in postmenopausal women may involve the stimulation of reverse cholesterol transport through increased HDL.     

Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia. Effects on apolipoprotein AI-containing lipoprotein particles

In order to investigate the effect of Probucol therapy on reverse cholesterol transport, apo AI-containing lipoprotein particles were isolated and characterized, and their cholesterol effluxing capacity and LCAT activity were assayed in four familial hypercholesterolemia patients before and after 12 weeks of Probucol therapy. Four major subpopulations of apo A-containing lipoprotein particles are separated before and after drug treatment; LpAI, LpAI:AII, LpAIV, LpAI:AIV:AII. Probucol reduces both total plasma and LDL-cholesterol (-17 and -14%, respectively). Apo B decreases slightly (-7.6%). Plasma HDL-cholesterol and apo AI decrease by 36.6 and 34.7%. LpA-I showed a marked decrease (-46%). Moreover, plasma LCAT and CETP activities were markedly increased under Probucol treatment. Analysis of lipoprotein particles showed that Probucol induces a decrease of protein content and an increase of cholesterol and triglycerides contents. Interestingly, Probucol induces an enhancement of LCAT activity in LpAI (4.5-fold). This drug induces a trend toward greater cholesterol efflux from cholesterol-preloaded adipose cells promoted by Lp AI and Lp AIV but not by Lp AI:AII. This study confirms the hypothesis, in addition to the lowering LDL-cholesterol levels and antioxidant effects of Probucol, that HDL reduction was not an atherogenic change in HDL system but may cause an antiatherogenic action by accelerating cholesterol transport through HDL system, promoting reverse cholesterol transport from peripheral tissues.     

PARADOXICAL EFFECTS OF THE ANTI-ANDROGEN CYPROTERONE ACETATE ON LIPID AND LIPOPROTEIN METABOLISM

The effects on fasting serum lipids of the potent anti-androgen, cyproterone acetate (CA) and the oestrogen, ethinyl oestradiol (EO) given both alone and in combination were examined in women acting as their own controls. Cyproterone acetate alone caused significant reductions in total cholesterol, high density lipoprotein subfraction 2 cholesterol (HDL2) and low density lipoprotein cholesterol (LDL). Ethinyl oestradiol alone significantly increased triglycerides, HDL and HDL2 and reduced LDL, and there was also a significant increase in the HDL/LDL and HDL2/LDL ratios. The two steroids were administered in combination according to a reverse sequential regime. The 28-day treatment cycle thus included Phase A during which both drugs were given followed by Phase B when EO alone was given. Triglycerides rose significantly in Phases A and B to the same extent as for the group taking EO alone. High density lipoprotein cholesterol was unchanged but HDL2 was reduced in both phases and this effect could not be overcome by increasing the dose of oestrogen. Low density lipoprotein cholesterol fell and the HDL/LDL ratio rose during the two Phases and these changes were significant during Phase A. The effects of EO demonstrated in this study are consistent with previous reports. Cyproterone acetate, however, has properties conventionally ascribed to both synthetic androgens (e.g. lowering of HDL2) and oestrogens (e.g. lowering of LDL). The limitations of the terms androgenic and oestrogenic activity in relation to their conventional associations with changes in lipid and lipoprotein levels are discussed.     

中国人非胰岛素依赖型糖尿病发病机制的分子遗传学研究

485例上海和美国旧金山中国人中6个基因(或基因区)的限制性内切酶片段长度多态性(RFLP)与非胰岛素依赖型糖尿病(NIDDM)的关联情况研究见到:(1)胰岛素受体(INSR)、载脂蛋白B(Apo B)、载脂蛋白A1(Apo A1)3个基因与中国人NIDDM发病有一定关联;(2)RFLP频率有明显的种族间差异,而且同一种民族在不同地区人群中亦有差异;(3)RFLP摹因型对糖尿病的临床表现型有影响,糖尿病与非糖尿病的肥胖在病因学上并不相同,尚见到NIDDM伴脂质代谢紊乱。