Current understanding of the role of high-density lipoproteins in atherosclerosis and senescence

Numerous epidemiologic and interventional studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well documented HDL functions that may account for the antiatherogenic effects of this lipoprotein. The best recognized of these is the capacity of HDL to transport cholesterol from the periphery to the liver, and thereby prevent cholesterol deposition in the arterial wall. Further properties of HDL that may also be antiatherogenic include its potent anti oxidative and anti-inflammatory action. In addition, HDL seems to be involved in processes related to senescence at both the cellular and whole-organism level. Both protein components of HDL (such as apolipoprotein A-I) and its lipid components (such as, lysosphingolipids) appear to mediate the antiatherogenic and anti-aging effects of HDL. The purpose of this review is to summarize the novel functions of HDL that may protect from atherosclerosis and senescence.     

High density lipoproteins (HDL) and the oxidative hypothesis of atherosclerosis.

The oxidative hypothesis of atherosclerosis classically implies a central role for low density lipoprotein (LDL) oxidation. However, new antiatherogenic properties have been recognized for high density lipoproteins (HDL), apart from their ability to reverse cholesterol transport. Indeed, native HDL could protect LDL from oxidation, thereby minimizing the deleterious consequences of this process. Several mechanisms have been suggested to explain this protective role. Two HDL-associated enzymes, paraoxonase and PAF-acetylhydrolase, detoxify oxidized phospholipids produced by lipid peroxidation. In addition, HDL could reduce hydroperoxides to their corresponding hydroxides. It has also been suggested that HDL could inhibit oxidized LDL-induced transduction signals. However, in vivo HDL oxidation in the subendothelial space would favor the atherosclerotic process. Indeed, atherogenic properties of these oxidized HDL partly result from some loss of their cholesterol effluxing capacity and from an inactivation of the lecithin-cholesterol acyltransferase, which is a HDL-associated enzyme involved in reverse cholesterol transport. Finally, oxidized HDL could induce cholesterol accumulation in macrophages. Further in-depth investigation is needed to assess these antagonistic effects and their consequences for the atherosclerotic process.     

Determination of cholesterol and phospholipid concentrations in high-density lipoproteins by heparin-manganese chloride precipitation.

Cholesterol as well as phospholipids in high-density lipoproteins (HDL) have been measured in 60 serum samples after heparin-manganese chloride precipitation of the apolipoprotein B containing lipoproteins. The values obtained correlated well with values from ultracentrifugal separation (slope 1.11 for cholesterol, 0.92 for phospholipids). Furthermore, there was a significant correlation between the low-density lipoprotein (LDL) cholesterol estimated by the formula of Friedewald et al. and the ultracentrifugally separated LDL cholesterol (slope 1.02). By the additional determination of HDL phospholipids with a precipitation procedure, further information about the "antiatherogenic" is easily available.     

HDL dysfunction in diabetes: causes and possible treatments

HDL is known to be inversely correlated with cardiovascular disease due to its diverse antiatherogenic functions. These functions include cholesterol efflux and reverse cholesterol transport, antioxidative and anti-inflammatory activities. However, HDL has been shown to undergo a loss of function in several pathophysiological states, as in the acute phase response, obesity and chronic inflammatory diseases. Some of these diseases were also shown to be associated with increased risk for cardiovascular disease. One such disease that is associated with HDL dysfunction and accelerated atherosclerosis is diabetes mellitus, a disease in which the HDL particle undergoes diverse structural modifications that result in significant changes in its function. This review will summarize the changes that occur in HDL in diabetes mellitus and how these changes lead to HDL dysfunction. Possible treatments for HDL dysfunction are also briefly described.     

Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia

In mediating the transfer of cholesteryl esters (CE) from antiatherogenic high density lipoprotein (HDL) to proatherogenic apolipoprotein (apo)-B-containing lipoprotein particles (including very low density lipoprotein [VLDL], VLDL remnants, intermediate density lipoprotein [IDL], and low density lipoprotein [LDL]), the CE transfer protein (CETP) plays a critical role not only in the reverse cholesterol transport (RCT) pathway but also in the intravascular remodeling and recycling of HDL particles. Dyslipidemic states associated with premature atherosclerotic disease and high cardiovascular risk are characterized by a disequilibrium due to an excess of circulating concentrations of atherogenic lipoproteins relative to those of atheroprotective HDL, thereby favoring arterial cholesterol deposition and enhanced atherogenesis. In such states, CETP activity is elevated and contributes significantly to the cholesterol burden in atherogenic apoB-containing lipoproteins. In reducing the numbers of acceptor particles for HDL-derived CE, both statins (VLDL, VLDL remnants, IDL, and LDL) and fibrates (primarily VLDL and VLDL remnants) act to attenuate potentially proatherogenic CETP activity in dyslipidemic states; simultaneously, CE are preferentially retained in HDL and thereby contribute to elevation in HDL-cholesterol content.Mutations in the CETP gene associated with CETP deficiency are characterized by high HDL-cholesterol levels (>60 mg/dL) and reduced cardiovascular risk. Such findings are consistent with studies of pharmacologically mediated inhibition of CETP in the rabbit, which argue strongly in favor of CETP inhibition as a valid therapeutic approach to delay atherogenesis. Consequently, new organic inhibitors of CETP are under development and present a potent tool for elevation of HDL in dyslipidemias involving low HDL levels and premature coronary artery disease, such as the dyslipidemia of type II diabetes and the metabolic syndrome. The results of clinical trials to evaluate the impact of CETP inhibition on premature atherosclerosis are eagerly awaited.     

Effect of alcohol on lipids and lipoproteins in relation to atherosclerosis

Several studies indicate that light-to-moderate alcohol consumption is associated with a low prevalence of coronary heart disease. An increase in high-density lipoprotein (HDL) cholesterol is associated with alcohol intake and appears to account for approximately half of alcohol's cardioprotective effect. In addition to changes in the concentration and composition of lipoproteins, alcohol consumption may alter the activities of plasma proteins and enzymes involved in lipoprotein metabolism: cholesteryl ester transfer protein, phospholipid transfer protein, lecithin:cholesterol acyltransferase, lipoprotein lipase, hepatic lipase, paraoxonase-1 and phospholipases. Alcohol intake also results in modifications of lipoprotein particles: low sialic acid content in apolipoprotein components of lipoprotein particles (e.g., HDL apo E and apo J) and acetaldehyde modification of apolipoproteins. In addition, "abnormal" lipids, phosphatidylethanol, and fatty acid ethyl esters formed in the presence of ethanol are associated with lipoproteins in plasma. The effects of lipoproteins on the vascular wall cells (endothelial cells, smooth muscle cells, and monocyte/macrophages) may be modulated by ethanol and the alterations further enhanced by modified lipids. The present review discusses the effects of alcohol on lipoproteins in cholesterol transport, as well as the novel effects of lipoproteins on vascular wall cells.     

HDL-c is a powerful lipid predictor of cardiovascular diseases

Relationship between HDL‐c and cardiovascular diseases: Beyond the role of low‐density lipoprotein cholesterol (LDL‐c) in the development of atherosclerosis, growing evidence suggest that high‐density lipoprotein cholesterol (HDL‐c) is a powerful predictor of cardiovascular disease. Indeed, epidemiological, mechanistic and intervention studies suggest that low HDL‐c is a major cardiovascular risk factor and that increasing HDL‐c plasma levels may be beneficial, particularly in patients with low HDL‐c levels. The inverse association between HDL‐c concentrations and cardiovascular risk is continuous without threshold value. Thus, any categorical definition of low HDL‐c is arbitrary. Protective effects of HDL: HDL particles are highly heterogeneous in structure and intravascular metabolism. Antiatherogenic properties of HDL include its role in the reverse cholesterol transfer, besides its antioxidant, anti‐inflammatory and antiapoptotic activities. What should clinicians do?: From a practical point of view, HDL‐c should be systematically measured to assess the cardiovascular risk in patients. The first step to consider in subjects with low HDL‐c is to look for specific causes and give advice to change inappropriate lifestyle components associated with low HDL‐c, such as smoking, lack of physical exercise and overweight. Patients with very low HDL‐c need a thorough evaluation by specialist physicians. Statins are associated with a modest increase of HDL‐c (5%) while fibrates and nicotinic acid increase HDL‐c by 10% and 20% respectively.     

ABCA1: regulation,trafficking and association with heteromeric proteins

HDL metabolism is crucial in maintaining cellular cholesterol and phospholipid homeostasis and prevention of atherosclerosis progression. Recent work identified the ATP-binding cassette transporter A1 (ABCA1) as the major regulator of plasma high density lipoprotein (HDL) cholesterol responsible for the removal of excess cholesterol from peripheral cells and tissues. Here we discuss some novel aspects of the ABCA1 network: 1) the cellular pathways involved in cholesterol and phospholipid efflux, 2) regulation of ABCA1, 3) sulfonylurea receptor 1 (SUR1)- or cystic fibrosis transmembrane conductance regulator (CFTR)-like function of ABCA1, 4) interaction of the ABCA1 C-terminus with beta2-syntrophin, 5) ABCA1 modulation of the Rho GTPase Cdc42, 6) localization of ABCA1 in plasma membrane microdomains and intracellular sites, 7) differential effects of prebeta-HDL precursors on ABCA1 mediated alpha-HDL particle formation and 8) ABCA1 in platelets and its relation to phosphatidylserine-flippase activity. A complex regulatory network and additional antiatherogenic features that may depend on the composition of prebeta-HDL precursor particles are believed to coordinate ABCA1 function in reverse cholesterol and phospholipid transport. Distinct prebeta-HDL ligand-specific receptor-clusters are involved that may modulate specific signaling pathways with varying outcomes related to prebeta-HDL particle composition, the cell-type and the cellular response status.     

High density lipoprotein cholesterol concentrations in physically active and sedentary spinal cord injured patients

Individuals with traumatic spinal cord injury (SCI) are extremely inactive yet little is known about the long-term consequences of chronic inactivity. Current research investigated the concentrations of high density lipoprotein cholesterol (HDLc) and its subfractions HDL2 and HDL3 in 66 extremely sedentary SCI admissions to a rehabilitation center. High density lipoprotein cholesterol is a primary risk factor for cardiovascular disease with decreased levels associated with increased cardiovascular risk. The concentrations of HDLc observed in the SCI sedentary population were compared with 22 olympic caliber wheelchair athletes (SCI athletes) and 126 able-bodied controls. Total HDLc, HDL2, and HDL3 was significantly lower in the male SCI sedentary population (34.2 mg/dl, 8.9 mg/dl, 25.3 mg/dl) than the male SCI athletes (42.7 mg/dl, 13.9 mg/dl, 28.8 mg/dl) or male able-bodied control populations (47.1mg/dl, 11.3mg/dl, 35.8 mg/dl). A similar pattern emerged for the female subjects. The reduction in HDLc seen in the SCI sedentary would predict over a 60% increased risk of heart attack compared to nondisabled controls. The primary difference between the two SCI groups was the level of physical activity, suggesting that this may be an important parameter for elevating total HDLc and HDL2, and presumably decreasing the risk for coronary heart disease. Therefore, physical activity positively affects total HDL and the supposedly antiatherogenic subfraction HDL2 in the SCI patient.     

Comparison of cholesterol-lowering regimens

Drug therapy should be reserved for patients with marked total cholesterol elevation not amenable to dietary measures. While current guidelines suggest that bile acid sequestrants, such as cholestyramine and colestipol, are first-line drugs for the treatment of hypercholesterolemia, recent studies suggest that lovastatin is a safe, more potent alternative. Gemfibrozil reduces the serum triglyceride level and raises the high-density lipoprotein (HDL) cholesterol level, but has only a moderate effect on the serum cholesterol level. Nicotinic acid lowers serum low-density lipoprotein (LDL) cholesterol and triglyceride levels and raises serum HDL levels, but its use is limited because of troublesome side effects, notably a flushing reaction. Probucol lowers both serum LDL and HDL levels and is a second-line agent for the treatment of hypercholesterolemia.     

HDL metabolism in hypertriglyceridemic states: an overview.

Reduced plasma high-density lipoprotein (HDL) cholesterol levels have been recognized as a highly significant independent risk factor for atherosclerotic cardiovascular disease. HDL levels are also inversely related to plasma triglyceride levels and there is a dynamic interaction between HDL and triglyceride (TG) rich lipoproteins in vivo. The mechanisms underlying the lowering of HDL in hypertriglyceridemic states have not been fully elucidated, but there is evidence to suggest that triglyceride enrichment of HDL, a common metabolic consequence of hypertriglyceridemia, may play an important role in this process. There is accumulating evidence to suggest that the primary mechanisms leading to reduced plasma HDL cholesterol levels and HDL particle number in hypertriglyceridemic states may be due to any one or a combination of the following possibilities: (1) small HDL particles, which are the product of the intravascular lipolysis of triglyceride-enriched HDL, may be cleared more rapidly from the circulation, (2) triglyceride-enriched HDL may be intrinsically more unstable in the circulation, with apo A-I loosely bound, (3) the lipolytic process itself of triglyceride-enriched HDL may lower HDL particle number by causing apo A-I to be shed from the HDL particles and cleared from the circulation, (4) a dysfunctional lipoprotein lipase or reduced LPL activity may contribute to the lowering of HDL levels by reducing the availability of surface constituents of triglyceride-rich lipoproteins that are necessary for the formation of nascent HDL particles. This review summarizes the evidence that triglyceride-enrichment of HDL is an important factor determining the rate at which HDL is catabolized, a mechanism which could explain, at least in part, the reduced plasma HDL cholesterol levels and particle number frequently observed in hypertriglyceridemic states.     

Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus

Dyslipidaemia, hallmarked by low HDL cholesterol and high plasma triglycerides, is a feature of insulin resistance and type 2 diabetes mellitus. These lipoprotein abnormalities represent major cardiovascular risk factors in these conditions. Among other factors, lipoprotein lipase (LPL), hepatic lipase (HL), lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) play an important role in an abnormal HDL metabolism in insulin resistance and type 2 diabetes mellitus. LPL hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. In insulin resistant states, a decreased post-heparin plasma LPL activity contributes to a low HDL cholesterol, whereas an increased activity of HL reduces HDL particle size by hydrolysing its triglycerides and phospholipids. High HL activity coincides with low HDL cholesterol. The esterification of free cholesterol by LCAT increases HDL particle size. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins. This cholesteryl ester transfer process results in lower HDL cholesterol and indirectly decreases HDL size. Plasma cholesterol esterification is unaltered or increased, whereas cholesteryl ester transfer is enhanced in type 2 diabetes mellitus, abnormalities which are probably related to the degree of hypertriglyceridaemia. It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain. Since the cholesteryl ester transfer process between lipoproteins provides a metabolic intermediate between low HDL cholesterol and high plasma triglycerides, hypertriglyceridaemia-associated accelerated transfer of cholesteryl ester out of HDL may be pathogenetically involved in the development of cardiovascular disease in insulin resistance and type 2 diabetes mellitus.     

Effects of a new alpha 1-blocker, bunazosin hydrochloride, on plasma lipid components in hypertensive patients with hypercholesterolemia

Oral bunazosin hydrochloride, a new alpha 1-blocker, for 12 weeks was given to ten outpatients diagnosed as having essential hypertension associated with hypercholesterolemia. High-density lipoprotein (HDL) triglyceride, HDL3 cholesterol, and apolipoprotein E levels were significantly decreased by bunazosin treatment. The decrease in HDL triglycerides was a result of the decrease in HDL3 triglyceride levels. There were no significant changes in the other components. The ratio of cholesterol to triglycerides in the low-density lipoprotein (LDL) and HDL fractions was increased significantly after bunazosin treatment. Furthermore, the ratio of HDL2 cholesterol to HDL3 cholesterol after bunazosin treatment was significantly higher than before treatment. The results suggest that the catabolism of triglycerides in lipoprotein and the reduction in tissue cholesterol increase, and that bunazosin hydrochloride does not adversely affect the lipid component in hypertensive patients with hypercholesterolemia.     

Abnormal high density lipoproteins in cerebrotendinous xanthomatosis.

The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). Abnormalities in the HDL may contribute to their increased atherogenesis and excessive deposits of tissue sterols in the presence of low or low-normal concentrations of plasma cholesterol (165 +/- 25 mg/dl) and low density lipoproteins (LDL). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The abnormalities in lipoprotein distribution profile and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.     

Effects of chronic ethanol intake on mobilization and excretion of cholesterol in baboons.

To investigate the effects of chronic ethanol administration on the mobilization and excretion of cholesterol, turnover and balance studies were carried out in baboons pair-fed cholesterol-free diets containing 50% of energy either as ethanol or as additional carbohydrate for several years. Ethanol feeding increased free cholesterol in all plasma lipoprotein fractions, and esterified cholesterol in very low density lipoprotein, intermediate density lipoprotein, and high density lipoprotein (HDL). The major increase occurred in HDL, mainly as esterified cholesterol. The latter was associated with decreased transfer of esterified cholesterol from HDL to low density lipoprotein. By contrast, the smaller increase in HDL-free cholesterol was associated with increased turnover in the plasma, increased splanchnic uptake, and increased fecal excretion of plasma cholesterol, mainly as neutral steroids. Cholesterol extraction predominated over release in the splanchnic vascular bed, suggesting that the excess of cholesterol excreted in the feces originated in extrasplanchnic tissues. Thus, these findings indicate that alcohol consumption favors mobilization of tissue free cholesterol for hepatic removal and excretion. By contrast the increase in HDL-cholesterol (mainly esterified) appears to be a poor indicator of cholesterol mobilization.     

Lipid modification in type 2 diabetes: the role of LDL and HDL

Patients with type 2 diabetes feature important modification of both low density lipoprotein (LDL) and high density lipoprotein particles which are likely to play an important role in the development of atherosclerosis. Although plasma LDL cholesterol level is usually normal in type 2 diabetic patients, LDLs show a significant increase in their plasma residence time which may promote cholesterol deposition in the arterial wall. Moreover, important qualitative abnormalities of LDLs, potentially atherogenic, are observed in type 2 diabetic patients: small dense, triglyceride-rich, LDL particles (known as subclass B), oxidized LDL and glycated LDL. All these qualitative modification of LDLs amplify the atherosclerotic process.
Plasma high density lipoprotein (HDL) cholesterol is decreased in type 2 diabetes related to increased catabolism of HDL particles. One of the mechanism responsible for increased catabolism of HDLs is hypertriglyceridemia, promoting through cholesteryl ester transfer protein (CETP) the transfer of triglycerides (TG) to HDL leading to the formation of TG-rich HDLs which are very good substrates for hepatic lipase, enzyme in charge of HDLs catabolism. The reduction in plasma adiponectin level, observed in type 2 diabetes may be another mechanism involved in the diminution of HDL cholesterol. Furthermore, qualitative abnormalities of HDLs are described in type 2 diabetes: enrichment in triglycerides and glycation, which may impair HDL-mediated cholesterol efflux and reverse cholesterol transport. In addition to their role in reverse cholesterol transport, HDLs usually show antioxidative, anti-inflammatory, anti-thrombotic and endothelium-dependent vasorelaxant effects. It has been shown that HDLs from patients with type 2 diabetes have a significant reduction in their antioxidative and endothelium-dependent vasorelaxant properties.     

Immunochemical detection of circulating oxidized high-density lipoprotein with antioxidized apolipoprotein A-I monoclonal antibody

The oxidative susceptibility of high-density lipoprotein (HDL) may play a role in its antiatherogenic effects. In an effort to determine circulating levels of oxidized HDL in the bloodstream, we produced a monoclonal antibody (mAb), 3C11, specific to oxidized apolipoprotein A-I and developed an enzyme-linked immunosorbent assay (ELISA) for oxidized HDL that incorporates the mAb. The examination of oxidized forms of several lipoproteins showed that the ELISA had a high specificity for oxidized HDL and did not react appreciably with native, acetylated, or malondialdehyde-modified HDL or with the other lipoproteins and their oxidized forms. Using the ELISA, we detected oxidized HDL in human serum samples and determined serum levels of oxidized HDL in 40 healthy volunteers. The mean serum concentration of oxidized HDL was 4.65 +/- 2.65 U/dL (mean +/- SD; range 1.47-12.81 U/dL). Further analysis showed no correlation between serum concentrations of oxidized HDL and those of six serum markers: HDL, apolipoprotein A-I, oxidized low-density lipoprotein, C-reactive protein, thiobarbituric acid-reactive substances, and serum iron. The ELISA provides a method for measuring oxidized HDL in the circulation, and this determination may elucidate the clinical significance of HDL oxidation in human beings.     

Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters.

Endotoxin alters the metabolism of lipoproteins, including that of high density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) facilitates exchange of HDL cholesterol for very low density lipoprotein (VLDL) triglyceride, leading to catabolism of HDL. We investigated the effects of endotoxin and cytokines on CETP in Syrian hamsters. Endotoxin induced a rapid and progressive decrease in serum CETP levels, by 48 h CETP had decreased to < 20% of control levels. Endotoxin also decreased CETP mRNA and protein levels in adipose tissue, heart, and muscle, the tissues with highest levels of CETP mRNA, providing a plausible mechanism for the endotoxin-induced decrease in circulating CETP. Dexamethasone did not mimic the effects of endotoxin on CETP, but the combination of tumor necrosis factor and interleukin-1 did, indicating that these cytokines may in part mediate the effects of endotoxin on CETP. The endotoxin-induced decrease in CETP may help maintain HDL cholesterol levels during infection and inflammation when increased triglyceride levels could drive the exchange of HDL cholesteryl ester for VLDL triglyceride. Maintaining circulating HDL may be important because HDL protects against the toxic effects of endotoxin and provides cholesterol for peripheral cells involved in the immune response and tissue repair.     

ABCA1: regulation,trafficking and association with heteromeric proteins

HDL metabolism is crucial in maintaining cellular cholesterol and phospholipid homeostasis and prevention of atherosclerosis progression. Recent work identified the ATP-binding cassette transporter A1 (ABCA1) as the major regulator of plasma high density lipoprotein (HDL) cholesterol responsible for the removal of excess cholesterol from peripheral cells and tissues. Here we discuss some novel aspects of the ABCA1 network: 1) the cellular pathways involved in cholesterol and phospholipid efflux, 2) regulation of ABCA1, 3) sulfonylurea receptor 1 (SUR1)- or cystic fibrosis transmembrane conductance regulator (CFTR)-like function of ABCA1, 4) interaction of the ABCA1 C-terminus with &#103 2-syntrophin, 5) ABCA1 modulation of the Rho GTPase Cdc42, 6) localization of ABCA1 in plasma membrane microdomains and intracellular sites, 7) differential effects of pre &#103 -HDL precursors on ABCA1 mediated &#102 -HDL particle formation and 8) ABCA1 in platelets and its relation to phosphatidylserine-flippase activity. A complex regulatory network and additional antiatherogenic features that may depend on the composition of pre &#103 -HDL precursor particles are believed to coordinate ABCA1 function in reverse cholesterol and phospholipid transport. Distinct pre &#103 -HDL ligand-specific receptor-clusters are involved that may modulate specific signaling pathways with varying outcomes related to pre &#103 -HDL particle composition, the cell-type and the cellular response status.