High-density lipoprotein cholesterol levels as a marker of reverse cholesterol transport

Dramatic advances have been made over the last decade in understanding the role of low-density lipoprotein (LDL) in atherosclerotic cardiovascular diseases and how to manage elevated levels of LDL cholesterol. Understanding the role of high-density lipoprotein (HDL) and how to intervene therapeutically in HDL action offers the possibility of even greater benefits. Epidemiologic studies have shown a strong inverse relation between HDL cholesterol and the risk of coronary artery disease (CAD). Whereas several subfractions of HDL can be identified, none convincingly offers better predictive value than total HDL cholesterol. Apolipoprotein A-I, the major apolipoprotein of HDL, also is inversely related to atherosclerotic risk. Unfortunately, measurements of HDL cholesterol or apolipoprotein A-I are considerably less precise and less accurate than measurements of total or LDL cholesterol. The biologic phenomena responsible for these epidemiologic relations are not yet clear. Moreover, several apparently contradictory observations and puzzling exceptions to the simplistic inverse relation of HDL cholesterol to CAD suggested by epidemiologic studies have created considerable confusion. The current confusion is not likely to be resolved until HDL metabolism and the cellular and molecular events responsible for the apparent protective effects of HDL are better understood. One current hypothesis that could explain the protective effects of HDL is that it mediates reverse cholesterol transport, the process by which cholesterol is removed from sites of deposition and delivered to the liver for excretion. From the standpoint of current therapy, each intervention that changes HDL cholesterol levels must be evaluated individually, on its own merit, in light of its effect on atherosclerosis and coronary events rather than on alterations in HDL cholesterol levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

High-density lipoproteins and endothelial function

Elevated plasma levels of HDL cholesterol or apolipoprotein A-I, the major protein moiety of HDL particles, are protective against coronary artery disease. HDL particles remove cholesterol from peripheral cells and transfer it to the liver for bile acid synthesis. The interaction between lipoproteins is not mediated through simple contact between 2 phospholipid membranes but involves specific protein-receptor interactions, charged phospholipid-phospholipid contact, and activation of cellular signaling pathways. These lead to regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell proliferation, and cellular cholesterol homeostasis.     

High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport

High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol from cells of the arterial wall to the liver and steroidogenic organs. Enhancement of cholesterol efflux and of reverse cholesterol transport (RCT) is considered an important target for antiatherosclerotic drug therapy. Levels and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. In vitro experiments as well as genetic family and population studies and investigation of transgenic animal models have revealed that HDL cholesterol plasma levels do not necessarily reflect the efficacy and antiatherogenicity of RCT. Instead, the concentration of HDL subclasses, the mobilization of cellular lipids for efflux, and the kinetics of HDL metabolism are important determinants of RCT and the risk of atherosclerosis.     

Role of high density lipoproteins (HDL) in reverse cholesterol transport

The atheromatous risk is negatively correlated with the plasma concentration of HDL cholesterol. This might be due to the role of HDL in the reverse cholesterol transport. In the first stage, free cholesterol molecules from peripheral cells are taken up by HDL through a receptor-dependent mechanism. In HDL, the esterification of cholesterol is catalysed by the lecithin: cholesterol acyl transferase. The progressive accumulation of cholesterol esters leads to the formation of HDL2. Through the action of cholesterol ester transfer protein, HDL2 become enriched in triglycerides and transfer cholesterol esters to LDL. Finally, cholesterol may be taken up by the liver through two routes which are: the receptor-mediated LDL endocytosis and the direct uptake of cholesterol esters which occurs during the degradation of HDL2 by hepatic lipase.     

A new framework for reverse cholesterol transport: non-biliary contributions to reverse cholesterol transport

Reduction of low-density lipoprotein-cholesterol through statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Major efforts are now focused on therapies that augment high-density lipoprotein (HDL)-mediated reverse cholesterol transport (RCT), and ultimately increase the fecal disposal of cholesterol. The process of RCT has long been thought to simply involve HDL-media...     

Acceleration of reverse cholesterol transport

A low level of high-density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease. Levels of HDL cholesterol and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. Reverse transport of cholesterol from cells of the arterial wall to the liver is an important mechanism by which HDL exerts its anti-atherogenic properties. Enhancement of reverse cholesterol transport is considered as a potential target for anti-atherosclerotic drug therapy. It is suggested, however, that the serum level of HDL cholesterol does not necessarily reflect the efficacy of reverse cholesterol transport.     

High-density lipoprotein cholesterol in male alcoholics with and without severe liver disease

In a study of 26 male alcoholics, the subgroup without severe liver disease showed significant elevation in high-density lipoprotein cholesterol (HDL) in the immediate post-intoxication period; HDL levels decreased to control levels after one to two weeks of abstinence. Those patients with advanced liver disease failed to show this ethanol-induced rise in HDL. We were not able to correlate these observations with any variation in sex hormone levels, nutritional indices, age or quantity of alcohol intake. We concluded that ethanol consumption in alcoholics is associated with an increase in HDL levels, which is offset by the development of alcoholic liver disease.     

Vascular inflammation and impaired reverse cholesterol transport and lipid metabolism in obese children and adolescents

Background and aimsChildhood obesity is associated to complications such as insulin resistance and dyslipidemia. High density lipoproteins (HDL) constitute the only lipoprotein fraction with ateroprotective properties. The aim of the present study was to analyze inflammatory markers, carbohydrate metabolism, lipid profile and HDL functionality in obese children and adolescents compared to healthy controls.Methods and resultsTwenty obese children and adolescents (Body mass index z score >3.0) (9–15 years old) and 20 age and sex similar controls were included in the study. Triglyceride (TG), total cholesterol (TC), HDL-C, LDL-C, apolipoproteins (apo) A-I and B, glucose and insulin levels were quantified. Lipid indexes and HOMA-IR were calculated. Cholesterol efflux (CEC), lipoprotein associated phospholipase A₂ (Lp-PLA₂), lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein, plus paraoxonase and arylesterase (ARE) activities were evaluated. Obese children and adolescents showed significantly higher TG [69 (45–95) vs 96 (76–121); p < 0.05], non-HDL-C [99 ± 34 vs 128 ± 26; p < 0.01], TC/HDL-C [2.8 ± 0.6 vs 4.7 ± 1.5; p < 0.01], TG/HDL-C [1.1 (1.0–1.8) vs 2,2 (1.4–3.2); p < 0.01], and HOMA-IR [1.5 (1.1–1.9) vs. 2.6 (2.0–4.5); p < 0.01] values, plus Lp-PLA₂ activity [8.3 ± 1.9 vs 7.1 ± 1.7 umol/ml.h; p < 0,05] in addition to lower HDL-C [57 ± 10 vs 39 ± 9; p < 0.01], apo A-I [143 ± 25 vs 125 ± 19; p < 0.05], and CEC [6.4 (5.1–6.8) vs. 7.8 (5.7–9.5); p < 0.01] plus LCAT [12.6 ± 3.3 vs 18.7 ± 2.6; p < 0.05] and ARE [96 ± 19 vs. 110 ± 19; p < 0.05] activities. Lp-PLA₂ activity correlated with LDL-C (r = 0.72,p < 0.01), non-HDL-C (r = 0.76,p < 0.01), and apo B (r = 0.60,p < 0.01). LCAT activity correlated with triglycerides (r = ?0.78,p < 0.01), HDL-C (r = 0.64,p < 0.01), and apo A-I (r = 0.62, p < 0.05). ARE activity correlated with HDL-C (r = 0.32,p < 0.05) and apoA-I (r = 0.43,p < 0.01). CEC was negatively associated with BMI z-score (r = ?0.36,p < 0.05), and triglycerides (r = ?0.28,p < 0.05), and positively with LCAT activity (r = 0.65,p < 0.05). In multivariate analysis, BMI z-score was the only parameter significantly associated to CEC (r2 = 0.43, beta = ?0.38, p < 0.05).ConclusionThe obese group showed alterations in carbohydrate and lipid metabolism, which were associated to the presence of vascular specific inflammation and impairment of HDL atheroprotective capacity. These children and adolescents would present qualitative alterations in their lipoproteins which would determine higher risk of suffering premature cardiovascular disease.     

同型半胱氨酸对高密度脂蛋白逆转运和抗氧化功能的影响

目的探讨同型半胱氨酸(Hcy)对HDL逆转运和抗炎抗氧化功能的影响。方法选择顺德第一人民医院住院患者120例,根据血Hcy水平,将患者分为正常对照组60例和高Hcy组60例,记录患者的人口学特点和检测血液生化指标,同时测定患者血卵磷脂胆固醇酰基转移酶(LCAT)和胆固醇酯转运蛋白(CETP)水平,患者HDL颗粒中的对氧磷酶1(PON1)、髓过氧化物酶(MPO)活性以及脂质过氧化物(LPO)含量。结果与正常对照组比较,高Hcy组患者血LCAT[(925.6±127.0)U/mg vs(1015.3±131.1)U/mg,P=0.000]、CETP[(26.3±4.1)μg/mg vs(34.6±5.0)μg/mg,P=0.000]和PON1[(213.4±71.4)U/ml vs(416.5±85.1)U/ml,P=0.000]活性显著降低,MPO[(4.8±1.9)U/L vs(3.3±1.5)U/L,P=0.000]活性和LPO[(0.93±0.08)U/L vs(0.83±0.09)U/L,P=0.000]含量显著升高。结论高Hcy通过降低血LCAT、CETP浓度,降低HDL胆固醇逆转运功能,并通过降低HDL颗粒中PON1活性,升高HDL颗粒中MPO活性,导致HDL颗粒中LPO含量升高,从而降低HDL的抗炎抗氧化功能。     

Long-term ethanol consumption impairs reverse cholesterol transport function of high-density lipoproteins by depleting high-density lipoprotein sphingomyelin both in rats and in humans

Moderate alcohol consumption has been linked to lower incidence of coronary artery disease due to increased plasma high-density lipoprotein (HDL), whereas heavy drinking has the opposite effect. Because of the crucial role of HDL in reverse cholesterol transport and positive correlation of HDL sphingomyelin (SM) content with cholesterol efflux, we have compared HDL SM content with its reverse cholesterol transport capacity both in rats fed ethanol on long-term basis and alcoholic individuals. In rats, SM HDL content was decreased in the ethanol group (-15.4%, P < .01) with a concomitant efflux decrease (-21.0%, P < .01) compared to that in controls. Similarly, HDL from the ethanol group, when compared with HDL from the control group, exhibited 13.8% (P < .05) less cholesterol uptake with control-group hepatocytes and 35.0% (P < .05) less cholesterol uptake with ethanol-group hepatocytes. Conversely, hepatocytes from the ethanol group, when compared with hepatocytes from the control group, exhibited 31.0% (P < .01) less cholesterol uptake with control-group HDL and 48.0% (P < .01) less with ethanol-group HDL. In humans, SM content in plasma HDL was also decreased in chronically alcoholic individuals without liver disease (-51.5%, P < .01) and in chronically alcoholic individuals with liver disease (-51.3%, P < .01), compared with nondrinkers. Concomitantly, in alcoholic individuals without liver disease, both efflux and uptake were decreased by 83.0% and 54.0% (P < .01), respectively, and in chronically alcoholic individuals with liver disease by 84.0% and 61.0% (P < .01), respectively, compared with nondrinkers. Based on these findings, we conclude that long-term ethanol consumption significantly impairs not only cholesterol efflux function of HDL by decreasing its SM content but also cholesterol uptake by affecting presumably hepatocyte receptors for HDL.     

Molecular regulation of macrophage reverse cholesterol transport

PURPOSE OF REVIEW: Macrophage reverse cholesterol transport is one of the key mechanisms mediating the protective effects of high-density lipoproteins on atherosclerosis. This review focuses on the recent developments in our understanding of molecular mechanisms of macrophage reverse transport and regulators that play important roles during this process. RECENT FINDINGS: Macrophage reverse cholesterol transport is promoted by apolipoprotein A-I overexpression and reduced in the setting of apolipoprotein A-I deficiency. A liver X receptor agonist markedly increases macrophage reverse cholesterol transport. ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 are liver X receptor-responsive macrophage genes that promote cholesterol efflux to lipid-free apolipoprotein A-I and mature high-density lipoprotein, respectively. The direct roles of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 in macrophage reverse cholesterol transport in vivo remain unclear. Therapeutically promoting macrophage reverse cholesterol transport has been recognized as one of the promising means to prevent atherosclerosis. SUMMARY: Increasing evidence has suggested that ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 are involved in macrophage reverse cholesterol transport. In-depth understanding of the molecular mechanisms will enable us to develop new therapeutic means to protect against atherosclerosis.     

Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation

To test the hypothesis that apolipoprotein A-I (apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol (HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I-/- mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor-/-/apobec-/- (LA) mice to generate LA mice with apoA-I+/+, apoA-I+/-, and apoA-I-/- genotypes. There were no major differences in the amounts of non-HDL-C and HDL-C in the plasma between different apoA-I genotypes. A significant inverse relationship was observed, however, between apoA-I gene dose and atherosclerosis in both female and male mice. Compared with LA-apoA-I+/+ mice, serum from LA-apoA-I-/- mice had a significantly reduced capacity to function as an acceptor of ABCA1- and SR-BI-mediated cellular cholesterol efflux, and also had markedly reduced lecithin cholesterol acyltransferase activity. In addition, LA-apoA-I-/- mice had significantly reduced macrophage-derived cholesterol esterification and reverse cholesterol transport in vivo. There was significantly reduced plasma paraoxonase (PON-1) activity, impaired HDL vascular antiinflammatory function, and increased basal levels of monocyte chemotactic protein-1 in the plasma of LA-apoA-I-/- mice compared with LA-apoA-I+/+ mice. In LA-apoA-I-/- mice, there was also greater induction of some, but not all, inflammatory cytokines and chemokines in response to intraperitoneal injection of lipopolysaccharide than in LA-apoA-I+/+ mice. We conclude that apoA-I inhibits atherosclerosis by promoting both macrophage reverse cholesterol transport and HDL antiinflammatory function, and that these anti-atherogenic functions of apoA-I are largely independent of the plasma level of HDL-C in this mouse model.     

Scavenger receptor type BI potentiates reverse cholesterol transport system by removing cholesterol ester from HDL

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Subsequently, cholesterol ester (CE) on HDL in humans is transported to apolipoprotein B-containing lipoproteins by cholesteryl ester transfer protein (CETP). CETP deficiency, which is common in the Japanese population, leads to a marked increase in HDL-cholesterol levels due to impaired CE transport from HDL to LDL. It has been reported that the HDL observed in CETP deficiency is an atherogenic lipoprotein, as it contains a large amount of CE. Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free cholesterol between HDL and cells. In the present study, the interaction between SR-BI and CE-rich HDL from CETP-deficient patient was studied in order to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport. When CE-rich HDL was added to the medium of SR-BI-transfected CHO (SR-BI CHO) cells, more CE accumulated in SR-BI CHO cells compared to control HDL. In contrast, the amount of cholesterol efflux from SR-BI CHO cells into HDL was almost the same between the two HDLs. Therefore, when CE-rich HDL was added to the medium of SR-BI CHO cells, the intracellular CE content increased significantly. Moreover, the particle size of HDL in CETP-deficient patient decreased significantly when the HDL was added to the medium of SR-BI CHO cells, and this HDL showed an increment of CE efflux from foam cells. These results indicate that SR-BI reduces the cholesterol content and size of the CE-rich HDL from CETP deficiency, which ultimately activate reverse cholesterol transport system.     

炎症调控胆固醇逆向转运的机制研究

胆固醇逆向转运(RCT)是促进细胞内胆固醇流出并转运至肝脏进行代谢的过程,其功能异常在动脉粥样硬化(As)的发生发展中起着关键作用。糖尿病、肥胖等慢性代谢性炎症疾病促进As的进展,而体内炎症、脂肪因子参与调控RCT是其重要的调控机制之一。本期专题收集的研究论文和综述探讨了糖基化终末产物Nε-羧甲基赖氨酸、核因子κB(NF-κB)、脂肪因子Visfatin等对细胞内胆固醇流出及介导RCT中关键蛋白三磷酸腺苷结合盒转运体A1、Sortilin、酯酰辅酶A:胆固醇酰基转移酶(ACAT)等表达的影响,从不同角度阐释慢性代谢性炎症疾病调控RCT和心血管疾病发生发展的分子机制。