脂蛋白(a)合成的调节

脂蛋白(a) ［ LP(a)］是一种与低密度脂蛋白(LDL)结构极其相似的脂蛋白,它由LDL脂质核心、载脂蛋白B100(apoB100)及特异性的成分载脂蛋白(a)［ apo(a)］组成. 大量的研究表明,高LP(a)是动脉粥样硬化独立的危险因素.而LP(a)在血浆中的水平及致病能力取决于其合成的速率及其颗粒的大小. 因此, 如何抑制LP(a)合成,进而从源头减少LP(a) 的血浆水平,对动脉粥样硬化的防治具有重要的意义.本文就当前关于影响LP(a)合成的环节及相关机制进行综述, 从而为降LP(a)药物的研究提供新的视角.     

载脂蛋白(a)单克隆抗体的制备及其性能研究

载脂蛋白(a)简称 apo(a),是脂蛋白(a)(Lp(a))中特征性蛋白成分,分子量在400—700kD,apo(a)以二硫键与低密度脂蛋白(LDL)的载脂蛋白 B100相连构成 Lp(a),分子量在1 200—1 500kD。近年来国内外学者认为 Lp(a)和 apo(a)是研究动脉粥样硬化危险因素的重要指标。我们为了探索脂质代谢紊乱引起的心血管系统疾病,进行了apo(a)的单克隆抗体研究。apo(a)提取的脂蛋白 Lp(a)经密度为     

降脂蛋白(a)研究

脂蛋白(a)[Lp(a)]是由载脂蛋白(a)(apo(a))与载脂蛋白B100(apoB100)通过共价键连接的脂蛋白。高血浆水平Lp(a)是心血管疾病的独立风险因子,Lp(a)的血浆水平主要受遗传因素调控,主要有LPA[lipoprotein,Lp(a)]基因的三环结构域kringle IV/2拷贝数和单核苷酸多态性(SNP)。欧洲动脉粥样硬化协会(EAS)和美国心脏病协会(AHA)建议对于高Lp(a)的人群应当考虑降高Lp(a)的治疗。目前已有多种降高Lp(a)的药物和方法,如血浆分离置换法、雌激素治疗、反义核苷酸治疗、类法尼醇X核内受体(farnesoid X receptor,FXR)激动治疗等,但应用于临床的降高Lp(a)的药物和方法依然缺乏。本文拟就降Lp(a)的药物和方法进展情况进行综述。     

睡眠呼吸暂停综合征患者血脂水平的研究

目的:了解阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者血浆脂质代谢情况。方法:分别检测健康对照组、睡眠呼吸暂停综合征患者组甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、载脂蛋白A、载脂蛋白B、脂蛋白a、载脂蛋白E含量。进行统计学对比及分析。结果:睡眠呼吸暂停综合征患者的甘油三酯、总胆固醇、高密度脂蛋白、总胆固醇/高密度脂蛋白、载脂蛋白A、载脂蛋白B及载脂蛋白E与健康对照组比较有显著差异,且与其睡眠监测指标有明显相关。结论:OSAHS可导致血浆脂质代谢紊乱,与动脉粥样硬化发生及发展的存在重要的相关性,是独立于年龄、体重、饮食、遗传等原因的冠心病、高血压、脑卒中等心脑血管疾病的发病因素之一。因此,提高对OSAHS的警惕是非常重要的。     

脂蛋白(a)的分离纯化及其抗血清的制备

脂蛋白(a)简称Lp(a),是血清中一种具特殊结构、抗原成分和生理功能的脂蛋白,近年来国外学者高度重视Lp(a)的研究并确定为动脉粥样硬化危险因素的良好指标,为了探索有关动脉粥样硬化防治的新领域,我们进行了Lp(a)的分离纯化及其抗血清的制备。     

脂代谢的测定对老年2型糖尿病患者临床意义

目的探讨老年2型糖尿病与血脂、载脂蛋白、脂蛋白(a)之间的关系及其临床测定的意义。方法对97例老年2型糖尿病患者及65例老年对照组进行了血清总胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白AI(ApoAI)、载脂蛋白B(ApoB)及脂蛋白(a)[Lp(a)]的测定。结果老年2型糖尿病患者血清TC、TG、LDL-C、ApoB及Lp(a)水平均显著高于老年对照组。而血清HDL-C和ApoAI水平老年2型糖尿病组显著低于老年对照组。结论老年2型糖尿病患者由于体内胰岛素相对不足及胰岛素抵抗,使血脂、载脂蛋白、脂蛋白浓度和组成成分发生变化及功能发生异常,从而促进动脉粥样硬化,并伴随着血管并发症的发生。因此,在对老年糖尿病并发症的预防和控制上,应在控制血糖的基础上减少脂肪的摄入,以降低高脂血症的发生,从而降低血管并发症的发生。     

脂蛋白与冠心病

冠心病绝大多数由动脉粥样硬化引起,而动脉粥样硬化的形成与消退均与血浆脂蛋白有密切关系。近年上述两者的关系已不断得到阐明,不仅血浆低密度脂蛋白浓度的增高可引起动脉粥样斑块的形成,且高密度脂蛋白浓度的降低亦与动脉粥样斑块的产生有关。此外,低密度脂蛋白(LDL)受体缺陷已被认为是家族性高胆固醇血症的原因。本文以脂蛋白为中心就血脂与脂蛋白的关系、高脂蛋白血症,动脉粥样硬化病变的预防,动脉粥样斑块的消退等四个方面探讨了动脉粥样硬化的发病原理与冠心病的防治问题。     

载脂蛋白C3-高脂血症与内皮细胞功能障碍的重要分子

载脂蛋白C3(APOC3)是一个多功能蛋白质,与甘油三酯(TG)水平成正相关关系,是预测冠心病(CAD)发生发展的一个独立风险因子。近年来的研究表明,它不仅可调节富甘油三酯脂蛋白(TRL)代谢,而且是内皮功能的一个重要调节者,它可以同时诱导内皮功能紊乱和脂质代谢紊乱,从而参加诱发动脉粥样硬化(AS)、增加发生CAD的风险以及其它相关疾病。APOC3基因多态性也与疾病发生密切相关。     

脂蛋白酯酶与动脉粥样硬化

脂蛋白酯酶(1ipopmtein lipase,LPL)是调节脂蛋白代谢的一种关键酶,如具有水解血浆脂蛋白中三酰甘油的作用等．体内LPL减少会导致血三酰甘油升高和高密度脂蛋白胆固醇降低,增加患动脉粥样硬化的危险．通过提高LPL的活性可以抑制动脉粥样硬化的发生发展．已有的研究说明NO-1886促进心肌和脂肪组织LPL mRNA表达,提高心肌、脂肪组织、骨骼肌和血液中LPL活性,因而改善脂蛋白代谢,抑制动脉粥样硬化．     

基因修饰小鼠在脂代谢紊乱与动脉粥样硬化研究中的新进展

近十余年来,载脂蛋白(ApoE)与低密度脂蛋白(LDL)受体 (LDLr)基因敲除小鼠已成为研究脂代谢和动脉粥样硬化最为常用的模型.在这两种小鼠模型基础上,通过与不同的转基因、基因敲除小鼠杂交,产生了多种脂代谢紊乱和动脉粥样硬化小鼠模型,为发现调控血浆脂蛋白以及动脉粥样硬化发生的机制,创造了有利条件.此外,新的严重高甘油三酯血症小鼠模型也制备成功,本文笔者研究组研究了其中的脂蛋白脂酶缺陷模型与代谢性疾病的关系,得到了许多有意义的结果.而利用不同转基因和去基因小鼠作为供体, 以及ApoE或LDL受体缺陷小鼠作为接受体的骨髓移植技术,则大大丰富了人们对于巨噬细胞中不同基因在动脉粥样硬化发生、发展和消退过程中作用的认识.动脉粥样硬化的易损斑块形成是近年来的一个研究热点,应用小鼠模型进行模拟也取得了一定的成功.然而,小鼠与人类在脂代谢和动脉粥样硬化中存在很大的种系差异,本文对此也予以评述.     

Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity

PURPOSE OF REVIEW: Lipoprotein(a) is a structurally and functionally unique lipoprotein consisting of the glycoprotein apolipoprotein(a) covalently linked to LDL. Lipoprotein(a) is assembled extracellularly by a two-step mechanism, still incompletely understood, in which initial non-covalent interactions between apolipoprotein(a) and apolipoprotein B precede specific disulfide bond formation. Elevated concentrations of plasma lipoprotein(a) are a risk factor for a variety of vascular diseases, including coronary heart disease, ischaemic stroke and venous thrombosis. Whereas many pathogenic mechanisms have been proposed for lipoprotein(a), it remains to be conclusively demonstrated which mechanisms are relevant to human disease. RECENT FINDINGS: Structural and functional studies have verified that apolipoprotein(a) kringle 4 types 6-8 contain lysine binding sites of a weaker affinity for lysine analogues than kringle 4 type 10. Recent evidence has conclusively shown a role for kringle 4 types 7 and 8 in lipoprotein(a) assembly. Moreover, apolipoprotein(a) has been shown to undergo a conformational change, from a closed to an open form, which accelerates the rate of covalent lipoprotein(a) assembly. Functional studies in vitro have identified the domains in apolipoprotein(a) that mediate its inhibitory effects on fibrin clot lysis, binding to fibrin and other biological substrates, and pro-inflammatory and anti-angiogenic properties. SUMMARY: Extensive structure-function studies of apolipoprotein(a) have begun to yield important insights into the domains in apolipoprotein(a) that mediate lipoprotein(a) assembly and the pathogenic effects of this lipoprotein. Continued investigations of these relationships will contribute critically to unravelling the many outstanding questions about lipoprotein(a) metabolism and pathophysiology.     

Apolipoproteins and atherosclerosis. Apolipoprotein E and apolipoprotein(a) as candidate genes of premature development of atherosclerosis

Apolipoprotein E (apoE) is a plasma lipoprotein which plays a basic role in the degradation of particles rich in cholesterol and triglycerides. It is able to bind to LDL receptors, but also to receptors for chylomicron remnants. There are three major apoE isoforms, E2, E3, and E4. Their role in lipoprotein metabolism is related to their affinity for receptors. Allele E3 is predominant and apoE3 affects metabolism of lipoproteins in a standard way. When compared to allele E3, allele E2 is associated with lower LDL levels, whereas allele E4 with higher LDL levels. This has an impact on the progression of atherosclerosis. Allele E2 exhibits a protective role, whereas allele E4 is associated with a high risk factor. Lipoprotein(a) [Lp(a)] is a plasma lipoprotein, consisting of apolipoprotein(a), linked by a covalent bond with the LDL particle. Increased Lp(a) levels are associated with an increased incidence of diseases based on atherosclerosis, namely the ischemic heart disease. Another effect of Lp(a) is its competition with plasminogen, resulting in a decrease of fibrinolysis and thrombogenic activity. ApoE and Lp(a) are independent risk factors for premature development of atherosclerosis and therefore can be considered as candidate genes of premature atherosclerosis.     

Isolation and partial characterization of the lipoprotein families A and A-I from high-density lipoproteins of human serum

Procedures for the isolation of two lipoprotein fractions from plasma high-density lipoproteins (HDL), characterized by apolipoprotein A-I and apolipoprotein A-I together with apolipoprotein A-II, have been elaborated. Apolipoprotein A-I was identified as the protein moiety of one of these fractions (lipoprotein A-I) with polyacrylamide gel electrophoresis (at basic and acidic pH, as well as in the presence of sodium dodecyl sulphate), immuno-double-diffusion, and amino acid analysis. Apolipoproteins A-I and A-II were identified as the protein moiety of the other fraction (lipoprotein A) with polyacrylamide gel electrophoresis (basic and acidic pH) and immuno-double-diffusion. Lipoprotein A-I consisted of spherical particles with a diameter similar to that of HDL as judged from negative strains in the transmission electron microscope. The diameter was estimated to be 8.7 nm from gel chromatography. Lipoprotein A-I migrated in the HDL position on crossed immunoelectrophoresis. On iso-electric focusing lipoprotein A-I appeared as multiple bands in the pH range 5.05-5.55. Lipoprotein A-I had the density of an HDL-2 fraction (rho: 1.063-1.105). Lipoprotein A consisted of spherical particles with a diameter similar to that of HDL, as judged from negative strains in the transmission electron microscope. The diameter was estimated to be 7.9 nm from gel chromatography. The molar ratio between the A-I and A-II polypeptides was estimated to 1.3:1 with electroimmunoassay and calculations from the amino acid compositions. Lipoprotein A migrated in the position of HDL on crossed immuno-electrophoresis. On iso-electric focusing lipoprotein A appeared as one major and two minor bands in the pH range 5.10-5.30. Lipoprotein A had the hydrated density of an HDL-2 fraction.     

Morphology and structure of lipoproteins revealed by an optimized negative-staining protocol of electron microscopy

Plasma lipoprotein levels are predictors of risk for coronary artery disease. Lipoprotein structure-function relationships provide important clues that help identify the role of lipoproteins in cardiovascular disease. The compositional and conformational heterogeneity of lipoproteins are major barriers to the identification of their structures, as discovered using traditional approaches. Although electron microscopy (EM) is an alternative approach, conventional negative staining (NS) produces rouleau artifacts. In a previous study of apolipoprotein (apo)E4-containing reconstituted HDL (rHDL) particles, we optimized the NS method in a way that eliminated rouleaux. Here we report that phosphotungstic acid at high buffer salt concentrations plays a key role in rouleau formation. We also validate our protocol for analyzing the major plasma lipoprotein classes HDL, LDL, IDL, and VLDL, as well as homogeneously prepared apoA-I-containing rHDL. High-contrast EM images revealed morphology and detailed structures of lipoproteins, especially apoA-I-containing rHDL, that are amenable to three-dimensional reconstruction by single-particle analysis and electron tomography.     

Lipoprotein(a): biology and clinical importance

Lipoprotein(a) [Lp(a)] is a unique lipoprotein that has emerged as an independent risk factor for developing vascular disease. Plasma Lp(a) levels above the common cut-off level of 300 mg/L place individuals at risk of developing heart disease particularly if combined with other lipid and thrombogenic risk factors. Studies in humans have shown Lp(a) levels to be hugely variable and under strict genetic control, largely by the apolipoprotein(a) [apo(a)] gene. In general, Lp(a) levels have proven difficult to manipulate, although some factors have been identified that can influence levels. Research has shown that Lp(a) has a high affinity for the arterial wall and displays many athero-thrombogenic properties. While a definite function for Lp(a) has not been identified, the last two decades of research have provided much information on the biology and clinical importance of Lp(a).     

Lipoprotein(a): still an enigma?

PURPOSE OF REVIEW: Lipoprotein(a) belongs to the class of the most atherogenic lipoproteins. Despite intensive research - in the last year more than 80 papers have been published on this topic - information is still lacking on the physiological function of lipoprotein(a) and the site of its catabolism. Important advances have been made in the knowledge of these points, which may have some therapeutic implications. RECENT FINDINGS: The association of high lipoprotein(a) values with an increase in risk for coronary events has been documented in further prospective studies. This increased risk may relate to recent findings that apolipoprotein(a) is produced in situ within the vessel wall. In addition, lipoprotein(a) binds and inactivates the tissue factor pathway inhibitor and induces plasminogen activator inhibitor type 2 expression in monocytes. A new antisense oligonucleotide strategy has been proposed which efficiently inhibits apolipoprotein(a) expression in vitro and in vivo. Apolipoprotein(a), however, suppresses angiogenesis and thus may interfere with the infiltration of tumor cells. Finally, the enzymatic activity leading to the formation of apolipoprotein(a) fragments in plasma and their catabolism have been further elucidated. SUMMARY: We are still far away from understanding the pathways involved in lipoprotein(a) catabolism, and the physiological function of this lipoprotein. Recent findings, however, provide new insight into pathomechanisms in patients with increased lipoprotein(a) related to hemostasis, which may serve as a basis for designing new treatment strategies.     

Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size

Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given.     

Lipoprotein(a): intrigues and insights.

Lipoprotein(a) is an atherogenic, cholesterol ester-rich lipoprotein of unknown physiological function. The unusual species distribution of lipoprotein(a) and the extreme polymorphic nature of its distinguishing apolipoprotein component, apolipoprotein(a), have provided unique challenges for the investigation of its biochemistry, genetics, metabolism and atherogenicity. Some fundamental questions regarding this enigmatic lipoprotein have escaped elucidation, as will be highlighted in this review.