载脂蛋白A功能研究进展

载脂蛋白（Apo）能与血浆脂质结合并形成脂蛋白，是决定脂蛋白结构、功能和代谢的核心组分。ApoA是最重要的Apo，其对脂质代谢的作用机制及与心血管疾病之间的关系一直是研究的热点。近年研究表明，ApoA在氧化应激和炎症调节、老化、淀粉样变性、肺纤维化、肿瘤中也有重要作用。本文就ApoA功能的最新研究进展进行综述。     

干预载脂蛋白AⅠ表达的研究进展

大量的临床流行病学研究已经表明,高密度脂蛋白(HDL)水平与心血管疾病风险呈负相关。载脂蛋白AⅠ(Apo AⅠ)是HDL中的主要功能蛋白,其含量约占HDL的70%左右。寡脂的Apo AⅠ是ATP结合盒转运子A1(ABCA1)介导的巨噬细胞胆固醇流出的主要接受体,能够介导巨噬细胞中游离胆固醇的外流,启动胆固醇逆转运(RCT)过程,并在肝外组织清除过多胆固醇。大量的动物实验也已证实即使HDL保持正常水平,Apo AⅠ的缺乏也可导致动脉粥样硬化病变加重,过表达人Apo AⅠ基因抑制动脉粥样硬化早期脂纹的产生,因此调控Apo AⅠ基因表达对动脉粥样化及其他心血管疾病具有重要意义。本文拟就干预Apo AⅠ基因表达调控机制及诱导和抑制Apo AⅠ表达的相关因素进行综述。     

疾病状态下高密度脂蛋白的功能缺陷

在炎症、脂质紊乱以及代谢性疾病中,高密度脂蛋白(HDL)抗动脉粥样硬化特性会受到影响。这种功能的损伤反映在HDL的组成、代谢及相关的生物学活性上。HDL的功能缺陷会影响血管内HDL代谢,使胆固醇逆转运、抗炎及抗氧化能力下降。HDL功能缺陷和浓度降低的共同作用,加速了动脉粥样硬化的发生。对HDL功能异常的检测有助于进一步了解动脉粥样硬化发生的机制,针对HDL功能和数量的治疗有希望在未来成为抗动脉粥样硬化治疗的新靶点。     

以ABCA1为靶点防治动脉粥样硬化

动脉粥样硬化(atherosclerosis,As)是一个多因素参与的复杂疾病,其中血管壁胆固醇蓄积和炎症反应是其发生发展的两个关键环节,而两者又相互促进。三磷酸腺苷结合盒转运体A1(ATP binding cassette transporterA1,ABCA1)是一种膜整合蛋白,通过与载脂蛋白AⅠ(apoAⅠ)结合,促进细胞内胆固醇流出并抑制血管壁炎症反应。人类ABCA1基因突变导致血浆高密度脂蛋白(HDL)水平降低,并增加心血管疾病的风险。ABCA1基因敲除动物不仅表现出低的血浆HDL水平,还表现出胰腺β细胞功能紊乱、体内促炎状态和As斑块的形成。多种促As的炎症因子和代谢产物可能通过下调ABCA1的表达,从而促进As相关心血管疾病的发展。因此,ABCA1有望成为心血管疾病和糖尿病新的治疗靶标和研究方向。     

载脂蛋白A5调控机制的研究进展

血脂异常其实质是脂蛋白和载脂蛋白(Apo)的异常,对致动脉粥样硬化来说脂蛋白的作用更甚于胆固醇。20年前鉴定了已知在血脂代谢中起重要作用大多数载脂蛋白(Apo)中的9个(ApoA1,ApoA2,ApoA4,ApoB48,ApoB100,ApoC1,ApoC2,ApoC3和ApoE)是与脂蛋白调节最相关的。在2001年通过蛋白组学技术鉴定的一个新的载脂蛋白家族成员载脂蛋白A5(ApoA5)〔1,2〕。因为它的血浆浓度大约只是其他Apo(如ApoA1和ApoA2)的千分之一〔3,4〕,所以ApoA5的关联性和功能不能直接充分的被发现。最近研究发现ApoA5降低甘油三酯(TG)是通过脂蛋白脂肪酶(LPL)的…     

高密度脂蛋白颗粒大小与青年冠心病无症状性心肌缺血的关系

目的 探讨高密度脂蛋白(HDL)颗粒大小与青年冠心病无症状性心肌缺血(SMI)的相关性。方法 共纳入469例青年冠心病患者,其中无症状性心肌缺血组194例(SMI组,n=194),有症状性心肌缺血组275例(non-SMI组,n=275)。收集患者的一般资料,检测血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDLC)、载脂蛋白A1(ApoA1)水平及相关生化指标。计算HDL颗粒大小的量化指标HDLC/ApoA1,以及相关脂质参数TC/HDLC、non-HDLC、TG/HDLC、LDLC/HDLC。应用多因素Logistic回归分析明确HDL颗粒大小(HDLC/ApoA1)与青年冠心病SMI发生的关系。结果 与non-SMI组比较,SMI组患者血清TC、尿酸、LDLC、LDLC/HDLC、TC/HDLC、non-HDL水平偏低,HDLC、ApoA1、HDLC/ApoA1值更大(均P＜0.05)。相关分析结果显示,HDL颗粒大小(HDLC/ApoA1)与Gensini积分呈负相关(r=－0.405,P＜0.05)。多因素分析显示,HDL颗粒大小(HDLC/ApoA1)是青年冠心病患者SMI的独立预测因子(OR=0.697,95%CI:0.233~0.910,P=0.007)。受试者工作特征曲线显示,以0.36为HDL颗粒大小(HDLC/ApoA1)临界值预测青年冠心病SMI发生的灵敏度为92.1%,特异度为75.5%。结论 HDL颗粒大小(HDLC/ApoA1)与青年冠心病SMI患者冠状动脉病变严重程度呈负相关,对青年冠心病SMI具有较强的预测价值。     

microRNA对ABCA1调控的研究进展

microRNA(miRNA)对许多生物学过程具有微调作用,ATP结合盒转运体A1(ABCA1)是调节高密度脂蛋白(HDL)代谢和功能的关键蛋白。目前已发现多种miRNA可抑制ABCA1表达,进而抑制胆固醇流出,降低血清HDL水平。而沉默miRNA或抑制其表达则无法抑制胆固醇流出,血清HDL水平无改变。目前对miRNA调控ABCA1表达进行了大量研究,有望带来治疗技术的革新,在调节脂代谢和抗动脉粥样硬化领域具有广阔前景。     

载脂蛋白与动脉粥样硬化的关系

动脉粥样硬化与脂质(尤其是载脂蛋白)代谢异常有关。目前已知载脂蛋白(Apo)有8种,本文拟浅述ApoA、ApoB与动脉粥样硬化的关系。一、ApoA 已有研究表明,血浆ApoA-Ⅰ含量与动脉粥样硬化呈负相关。ApoA-Ⅰ是体内抗动脉粥样硬化的因素之一,其和高密度脂蛋白(HDL)可将周围组织细胞的游离胆固醇酯化,并转运到肝脏进一步代谢,以防外周组织的脂质沉积和粥样硬化。ApoA-Ⅰ和磷脂结合可加强上述作用,有助于细胞内胆固醇     

膜转运蛋白三磷酸腺苷结合盒转运体A1的表达调控与信号传导

<正>动脉硬化性心血管疾病(atherosclerotic cardiovascular disease,CVD)是最常见的死亡原因。高密度脂蛋白(High density lipoprotein,HDL)主要通过转运动脉巨噬细胞多余的胆固醇到肝脏代谢来预防CVD。这个途径的第1步称为胆固醇逆转运,由整合膜蛋白——三磷酸腺苷结合盒转运体A1(ATP-binding cassette transporter A1,ABCA1)介导。ABCA1转运细胞的胆固醇和磷脂到乏脂载脂蛋白     

人血浆高密度脂蛋白亚类分布与动脉粥样硬化

高密度脂蛋白(HDL)是一类不均一的脂蛋白,各种HDL亚类具有不同而又相关的代谢功能.血浆脂质和载脂蛋白含量变化会影响HDL亚类分布.高甘油三酯血症、高胆固醇血症、特别是混合型高脂血症患者血浆HDL颗粒变小,而且随着血浆甘油三酯、总胆固醇含量的升高,上述变化会更加明显.提示HDL成熟代谢受阻,胆固醇逆向转运减弱.不同的载脂蛋白在HDL合成及代谢中起着各不相同的作用.当血浆apoAⅠ含量增加时,所有的HDL亚类均增加,且大颗粒的HDL2b增加最为明显.ApoAⅡ具有双重功能,有使小颗粒HDL3b、HDL3a以及大颗粒的HDL2b同时增加的作用.血浆apoB100、CⅡ以及CⅢ在HDL组装中具有协同作用,apoAⅠ对抗上述载脂蛋白引起HDL颗粒变小的作用.此外,糖尿病和冠心病患者血浆HDL颗粒呈变小趋势.使用他汀治疗的冠心病患者血浆HDL亚类分布的改善滞后于血浆脂质水平的正常化,表明HDL亚类图谱分析有助于冠心病患者的风险分层.     

绝经后女性冠心病性激素与血脂,载脂蛋白的关系

测定３６例绝经后女性冠心病病人和２４例对照者的血清雌二醇（Ｅ２）、睾酮（Ｔ）、总胆固醇（ＴＣ）、甘油三酯（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Ｂ１００（ＡｐｏＢ１００）水平。结果显示：ＣＨＤ组Ｅ２、ＨＤＬ－Ｃ、ＡｐｏＡⅠ显著低于对照组。ＴＣ、ＴＧ、ＬＤＬ－Ｃ、ＡｐｏＢ１００显著高于对照组。Ｅ２和Ｔ与ＡｐｏＡⅠ呈显著正相关。表明绝经后女性ＣＨＤ存在性激素环境失衡，Ｅ２水平不足，引起血脂、脂蛋白代谢紊乱，支持Ｅ２对女性ＣＨＤ有直接保护作用。     

Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux

OBJECTIVE: Elevated levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease. The anti-atherosclerotic function of HDL is mainly ascribed to its role in reverse cholesterol transport, and requires the integrity of HDL structure. Experimental evidence suggests that the ability of HDL to promote removal of excess cholesterol from peripheral cells is impaired upon oxidation. On the other hand, tyrosylation of HDL enhances its protective function, suggesting that not all forms of modified lipoprotein may be atherogenic. In the present study we investigated the effect of a mild oxidation of HDL(3) on its function as cholesterol acceptor. METHODS AND RESULTS: A mild oxidative stress (induced by 15 min exposure of HDL(3) to 1 microM Cu(++) or to 15-lipoxygenase) caused the formation of pre-beta-migrating particles. Compared to native lipoprotein, mildly modified HDL(3) induced a significant ATP-binding cassette transporter 1 (ABCA1)-mediated increase of cholesterol and phospholipids efflux from J774 macrophages. This effect was abolished by an inhibitor of ABCA1-mediated lipid efflux (glyburide) and was absent in Tangier fibroblasts. CONCLUSIONS: A mild oxidative modification of HDL(3) may improve its function as cholesterol acceptor, increasing ABCA1-mediated lipid efflux from macrophages, a process that may reduce foam cell formation.     

Modulation of lipoprotein plasma concentrations during long-term anti-TNF therapy in patients with active rheumatoid arthritis

OBJECTIVE: Durable blockade of tumour necrosis factor-alpha (TNF-alpha) in patients with rheumatoid arthritis (RA) suppresses disease activity and its progression. Cardiovascular diseases are 1.5-2-fold more frequent in RA patients than in the general population. Although TNF-alpha has well-established effects on lipid metabolism, the long-term effects of TNF-alpha blockade on lipid pattern are still unclear. In the present study, we investigated the effects of 1-year therapy with anti-TNF on the lipid profile of RA patients. METHODS: Disease activity (DAS28) and plasma lipoproteins concentrations (total, HDL and LDL-cholesterol, triglycerides, ApoA, ApoB) were assessed in 55 RA patients and 55 controls. The whole RA group was followed up for 6 months, and 31 of the patients were followed up for 1 year. RESULTS: In RA patients, DAS28 decreased after 2 weeks from the start of therapy (p<0.001) and remained low during the entire study duration. Short-term effects of anti-TNF on plasma lipid concentrations seemed beneficial and anti-atherogenic. However, these changes did not persist: plasma concentrations of total and LDL-cholesterol and the atherogenic index increased after 6 months and 1 year from the start of therapy. During therapy, the changes in disease activity and inflammatory status were inversely correlated with changes in plasma total and HDL cholesterol levels and positively correlated with the variation of atherogenic index. CONCLUSION: We conclude that one-year therapy with infliximab is likely to lead to a more pro-atherogenic pattern of the plasma lipids concentrations. However, the overall impact of these changes on the cardiovascular risk is more complex, considering the strong anti-inflammatory effects of anti-TNF drugs.     

A systematic review of the effect of TNF-α antagonists on lipid profiles in patients with rheumatoid arthritis

Atherosclerosis plays a key role in cardiovascular disease in patients with rheumatoid arthritis (RA). Although therapy with TNF-α antagonists has resulted in dramatic improvement in the prognosis of RA, its effects on circulatory lipids are unclear. We conducted a systematic review of the literature to summarize the available evidence on lipid profile modification in patients with RA treated with TNF-α antagonists, with extensive searches in PubMed, the Cochrane Collaboration database (Central), and SCOPUS. Twenty-four observational studies met the inclusion criteria; 12 included only patients with RA treated with infliximab and three, patients with RA treated with adalimumab. The other nine included a mix of patients with various rheumatic diseases, or receiving one of several TNF-α antagonists. Eleven studies found a statistically significant increase in total cholesterol (TC) and high-density lipoprotein (HDL); six of 20 found significant increases in triglycerides (TG). Four of 13 studies found a statistical increase in low-density lipoprotein. No major changes were observed for ApoB/ApoA1 ratios. A small trend to increased TC was observed in patients receiving TNF-α antagonists, mostly due to an increase in HDL. There was a small trend to increased TG, and no changes in ApoB/ApoA1 ratio. The clinical impact of these findings is unclear, and further studies are needed to clarify the role of these lipid changes on cardiovascular morbidity in RA.     

Effect of ABCA1 mutations on risk for myocardial infarction

The adenosine triphosphate-binding cassette A1 (ABCA1) gene codes for a cellular phospholipid and cholesterol transporter that mediates the initial and essential step in high-density lipoprotein (HDL) biogenesis: the formation of nascent HDL particles. Mutations at the ABCA1 gene locus cause severe familial HDL deficiency and, in the homozygous form, cause Tangier disease. Several studies have investigated the influence of ABCA1 variation on lipid metabolism and coronary heart disease, but they have resulted in controversial and inconsistent results. Genetic variability at the ABCA1 gene has also been associated with increased risk of myocardial infarction. In one study, this association was independent of HDL cholesterol levels, raising the possibility that the measurement of HDL cholesterol levels may not provide adequate information on the functional roles of HDL particles. Nevertheless, genomic screening for complex diseases, such as coronary heart disease, and HDL deficiency in particular, may not add additional information to that gained from conventional global cardiovascular risk stratification.     

High-density lipoprotein and atherosclerosis: Roles of lipid transporters

Various previous studies have found a negative cor-relation between the risk of cardiovascular events and serum high-density lipoprotein(HDL) cholesterol levels. The reverse cholesterol transport, a pathway of choles-terol from peripheral tissue to liver which has several potent antiatherogenic properties. For instance, the particles of HDL mediate to transport cholesterol from cells in arterial tissues, particularly from atherosclerotic plaques, to the liver. Both ATP-binding cassette trans-porters(ABC) A1 and ABCG1 are membrane cholesterol transporters and have been implicated in mediating cholesterol effluxes from cells in the presence of HDL and apolipoprotein A-I, a major protein constituent of HDL. Previous studies demonstrated that ABCA1 and ABCG1 or the interaction between ABCA1 and ABCG1 exerted antiatherosclerotic effects. As a therapeutic approach for increasing HDL cholesterol levels, much focus has been placed on increasing HDL cholesterol levels as well as enhancing HDL biochemical functions. HDL therapies that use injections of reconstituted HDL, apoA-I mimetics, or full-length apoA-I have shown dramatic effectiveness. In particular, a novel apoA-I mi-metic peptide, Fukuoka University ApoA-I Mimetic Pep-tide, effectively removes cholesterol via specific ABCA1 and other transporters, such as ABCG1, and has an an-tiatherosclerotic effect by enhancing the biological func-tions of HDL without changing circulating HDL choles-terol levels. Thus, HDL-targeting therapy has significant atheroprotective potential, as it uses lipid transporter-targeting agents, and may prove to be a therapeutic tool for atherosclerotic cardiovascular diseases.     

Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations

BACKGROUND: A syndrome of lipodystrophy, associated with hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia and peripheral insulin resistance has been reported in protease inhibitor (PI)-treated HIV-infected patients. Because lipid metabolism, fat mass distribution and insulin resistance are partly regulated by steroid hormones, we questioned whether lipodystrophy is related to hormonal perturbations. OBJECTIVE: To evaluate serum lipid and steroid hormone concentrations in HIV-positive men on highly active antiretroviral therapy (HAART) in order to determine whether dyslipidaemia, peripheral loss of fatty tissue and central fat accumulation are related to steroid hormone modifications. DESIGN: A cross-sectional study. METHODS: Thirty-seven HIV-1-positive men on HAART, 23 of whom had symptoms of lipodystrophy, according to a subjective clinical score of lipodystrophy (SCSL), were tested. Serum concentrations of cholesterol, triglycerides and their subclasses, apolipoproteins and steroid hormones, including cortisol, dehydroepiandrosterone (DHEA), DHEA sulphate, androstenedione, testosterone and dihydrotestosterone were measured. RESULTS: Serum cholesterol, very low density lipoprotein (VLDL) cholesterol, triglycerides, VLDL triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) triglycerides, apolipoprotein B (ApoB) and atherogenic ratios of cholesterol:HDL cholesterol, LDL cholesterol:HDL cholesterol and ApoB:apolipoprotein A1 (ApoA1) were significantly increased in lipodystrophy-positive compared with lipodystrophy-negative men. The serum cortisol level was similar in lipodystrophy-positive versus lipodystrophy-negative men, but was elevated compared with controls. Serum DHEA was significantly lower in lipodystrophy-positive versus lipodystrophy-negative men and, consequently, the cortisol:DHEA ratio was increased in lipodystrophy-positive patients. A positive correlation was found between the cortisol:DHEA ratio and increased levels of atherogenic lipids. In addition, the SCSL was positively correlated with dyslipidaemia and the cortisol:DHEA ratio. CONCLUSION: This study demonstrates an association between the cortisol:DHEA ratio, lipid alterations and lipodystrophy. This syndrome might result from an imbalance between peripheral lipolysis and lipogenesis, both regulated by cortisol and DHEA.     

2型糖尿病患者脂质代谢改变的临床意义

对２７６例２例糖尿病（ＮＩＤＤＭ）患者的甘油三酯（ＴＧ）,总胆固醇（ＴＣ）,载脂蛋白Ａ１和Ｂ（ＡｐｏＡ１,ＡｐｏＢ）,高密度脂蛋白（ＨＤＬ）,低密度脂蛋白（ＬＤＬ）脂蛋白（ａ）（Ｌｐ（ａ）进行了检测,并与１８９例正常人（对照组）作对照,结果ＮＩＤＤＭ组ＴＧ,ＴＣ,ＡｐｏＢ,ＬＤＬ,Ｌｐ（ａ）,明显高于对照组（Ｐ〈０．０１）,ＨＤＬ明显低于对照组（Ｐ〈０．０１）,两组ＡｐｏＡ１无显著差异（Ｐ〉０．０     

New insights into the regulation of HDL metabolism and reverse cholesterol transport

The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.