In vivo metabolism of apolipoprotein E within the HDL subpopulations LpE,LpE:A-I,LpE:A-II and LpE:A-I:A-II

High-density lipoproteins can be separated into distinct particles based on their apolipoprotein content. In the present study, the in vivo metabolism of apoE within the apoE-containing HDL particles LpE, LpE:A-I, LpE:A-II and LpE:A-I:A-II was assessed in control subjects and in patients with abetalipoproteinemia (ABL), in whom HDL are the sole plasma lipoproteins. The metabolism of apoE within these HDL subspecies was investigated in three separate studies which differed by donor or recipient status: (1) particles purified from normolipidemic plasma and reassociated with 125I or 131I-labeled apoE injected into normolipidemic subjects (study 1); (2) particles purified from ABL plasma injected into normolipidemic subjects (study 2); and (3) particles purified from ABL plasma injected into ABL subjects (study 3). The plasma residence times (RT, hours) in study 1 were 14.3+/-2.9, 11.3+/-3.4, and 9.1+/-1.2 for apoE within LpE:A-I:A-II, LpE:A-II and LpE:A-I, respectively, while those in study 2 were 10.1+/-2.2, 9.7+/-2.4, 7.9+/-1.0 and 7.3+/-0.8 for apoE within LpE:A-I:A-II, LpE:A-II, LpE:A-I and LpE, respectively. In study 3, RTs for apoE within LpE:A-I:A-II and LpE were 8.7+/-0.9 and 6.8+/-0.9, respectively. In comparison, RT for apoA-I on LpA-I:A-II has been reported to be 124.1+/-5.5 h and that for apoA-I on LpA-I 105.8+/-6.2 h. Thus, apoE within the different apoE-containing HDL particles was metabolized rapidly and at a similar rate in control and ABL subjects. The plasma RT of apoE was longest when injected on LpE:A-I:A-II particles and shortest when injected on LpE. In summary, our data show that: (1) the plasma RT of apoE within HDL is approximately ten times shorter than that of apoA-I within HDL, and (2) apoE within HDL is metabolized at a slower rate when apoproteins A-I and A-II are present (LpE:A-I:A-II RT>LpE:A-II>LpE:A-I>LpE). These differences were related to the lipid and apolipoprotein composition of the HDL subspecies, and, in control subjects, to the transfer of apoE from HDL subspecies to apoB-containing lipoproteins as well.     

In vivo evidence for both lipolytic and nonlipolytic function of hepatic lipase in the metabolism of HDL

To investigate the in vivo role that hepatic lipase (HL) plays in HDL metabolism independently of its lipolytic function, recombinant adenovirus (rAdV) expressing native HL, catalytically inactive HL (HL-145G), and luciferase control was injected in HL-deficient mice. At day 4 after infusion of 2 x 10(8) plaque-forming units of rHL-AdV and rHL-145G-AdV, similar plasma concentrations were detected in postheparin plasma (HL=8.4+/-0.8 microg/mL and HL-145G=8.3+/-0.8 microg/mL). Mice expressing HL had significant reductions of cholesterol (-76%), phospholipids (PL; -68%), HDL cholesterol (-79%), apolipoprotein (apo) A-I (-45%), and apoA-II (-59%; P<0.05 for all), whereas mice expressing HL-145G decreased their cholesterol (-49%), PL (-40%), HDL cholesterol (-42%), and apoA-II (-89%; P<0.005 for all) but had no changes in apoA-I. The plasma kinetics of (125)I-labeled apoA-I HDL, (131)I-labeled apoA-II HDL, and [(3)H]cholesteryl ester (CE) HDL revealed that compared with mice expressing luciferase control (fractional catabolic rate [FCR] in d(-1): apoA-I HDL=1.3+/-0.1; apoA-II HDL=2.1+/-0; CE HDL=4.1+/-0.7), both HL and HL-145G enhanced the plasma clearance of CEs and apoA-II present in HDL (apoA-II HDL=5.6+/-0.5 and 4.4+/-0.2; CE HDL=9.3+/-0. 0 and 8.3+/-1.1, respectively), whereas the clearance of apoA-I HDL was enhanced in mice expressing HL (FCR=4.6+/-0.3) but not HL-145G (FCR=1.4+/-0.4). These combined findings demonstrate that both lipolytic and nonlipolytic functions of HL are important for HDL metabolism in vivo. Our study provides, for the first time, in vivo evidence for a role of HL in HDL metabolism independent of lipolysis and provides new insights into the role of HL in facilitating distinct metabolic pathways involved in the catabolism of apoA-I- versus apoA-II-containing HDL.     

Changes in plasma apo B, apo E, apo A-I, and apo A-IV concentrations in dogs consuming different atherogenic diets

To define the relationship between apoprotein levels and plasma cholesterol concentration in dogs, we measured the cholesterol, apo B, apo E, apo A-IV, and apo A-I levels in 6 dogs fed a synthetic diet (Diet I), and in 5 dogs fed dog chow supplemented with lard, cholesterol, bile salts, and propylthiouracil (Diet II). The diet-induced hypercholesterolemia exceeded 900 mg/dl in dogs fed Diet I and was accompanied by a 12-fold increase in apo B, a 30-fold increase in apo E, an 8-fold increase in apo A-IV, and a 1 1/2-fold increase in apo A-I. By contrast, the hypercholesterolemia averaged 1300 mg/dl in dogs fed Diet II and was accompanied by a 12-fold increase in apo B, an 11-fold increase in apo E, a 3-fold increase in apo A-IV, and a 5-fold decrease in apo A-I levels. When 3 of the Diet I dogs were switched to dog chow, their plasma cholesterol, apo B, and apo E levels dropped to 30% of their peak value within 7 days. The change in apo B and apo E levels was found to be highly correlated with the change in plasma cholesterol concentrations in each of the Diet I animals (r2 ranged from 0.92 to 0.99 for both apoproteins). A strong linear relationship was also observed between apo E and apo B (r2 ranged from 0.94 to 0.98), indicating that the plasma apo E to apo B ratio remained constant in these animals as the hypercholesterolemia progressed or regressed.     

Effect of overexpression of human apo A-I in C57BL/6 and C57BL/6 apo E-deficient mice on 2 lipoprotein-associated enzymes, platelet-activating factor acetylhydrolase and paraoxonase. Comparison of adenovirus-mediated human apo A-I gene transfer and human apo A-I transgenesis

Various mechanisms may contribute to the antiatherogenic potential of apolipoprotein A-I (apo A-I) and high density lipoproteins (HDLs). Therefore, the effect of adenovirus-mediated human apo A-I gene transfer or human apo A-I transgenesis on platelet-activating factor acetylhydrolase (PAF-AH) and arylesterase/paraoxonase (PON1) was studied in C57BL/6 and C57BL/6 apo E(-/-) mice. Human apo A-I transgenesis in C57BL/6 mice resulted in a 4.2-fold (P<0.0001) increase of PAF-AH and a 1.7-fold (P=0.0012) increase of PON1 activity. The apo E deficiency was associated with a 1.6-fold (P=0.008) lower PAF-AH and a 2.0-fold (P=0.012) lower PON1 activity. Human apo A-I transgenesis in C57BL/6 apo E(-/-)mice increased PAF-AH and PON1 activity by 2.1-fold (P=0.01) and 2.5-fold (P=0.029), respectively. After adenovirus-mediated gene transfer of human apo A-I into C57BL/6 apo E(-/-)mice, a strong correlation between human apo A-I plasma levels and PAF-AH activity was observed at day 6 (r=0.92, P<0.0001). However, PON1 activity failed to increase, probably as a result of cytokine-mediated inhibition of PON 1 expression. In conclusion, this study indicates that overexpression of human apo A-I increases HDL-associated PAF-AH activity. PON1 activity was also increased in human apo A-I transgenic mice, but not after human apo A-I gene transfer, a result that was probably related to cytokine production induced in the liver by the adenoviral vectors. Increased levels of these HDL-associated enzymes may contribute to the anti-inflammatory and antioxidative potential of HDL and thereby to the protection conferred by HDL against atherothrombosis.     

Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apo A-I(Zaragoza) (L144R)

We have recently reported a new apolipoprotein (apo) A-I variant (apo A-I(Zaragoza) L144R) in a Spanish family with HDL-C levels below the 5th percentile for age and sex and low apo A-I concentrations. All the apo A-I(Zaragoza) subjects were heterozygous and none of them showed evidence of coronary artery disease (CAD). Mean plasma HDL-C, apo A-I, and apo A-II levels were lower in apo A-I(Zaragoza) carriers as compared to control subjects (40, 60, and 50%, respectively). Lipid composition analysis revealed that apo A-I(Zaragoza) carriers had HDL particles with a higher percentage of HDL triglyceride and a lower percentage of HDL esterified cholesterol as compared to those of control subjects. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate of apo A-I(Zaragoza) carriers were normal. Apo A-I and apo A-II metabolic studies were performed on two heterozygous apo A-I(Zaragoza) carriers and on six control subjects. We used a primed constant infusion of [5,5,5-2H3]leucine and HDL apo A-I and apo A-II tracer/tracee ratios were determined by gas chromatography mass spectrometry and fitted to a monoexponential equation using SAAM II software. Both subjects carrying apo A-I(Zaragoza) variant showed mean apo A-I fractional catabolic rate (FCR) values more than two-fold higher than mean FCR values of their controls (0.470+/-0.0792 vs. 0.207+/-0.0635 x day(-1), respectively). Apo A-I secretion rate (SR) of apo A-I(Zaragoza) subjects was slightly increased compared with controls (17.32+/-0.226 vs. 12.76+/-3.918 mg x kg(-l) x day(-1), respectively). Apo A-II FCR was also markedly elevated in both subjects with apo A-I(Zaragoza) when compared with controls (0.366+/-0.1450 vs. 0.171+/-0.0333 x day(-1), respectively) and apo A-II SR was normal (2.31+/-0.517 vs. 2.1+/-0.684 mg x kg(-l) x day(-1), respectively). Our results show that the apo A-I(Zaragoza) variant results in heterozygosis in abnormal HDL particle composition and in enhanced catabolism of apo A-I and apo A-II without affecting significantly the secretion rates of these apolipoproteins and the LCAT activation.     

In vivo correlation of myocardial metabolism, perfusion, and mechanical function during increased cardiac work.

STUDY OBJECTIVE--The aim was to study the in vivo interaction and regulation of myocardial perfusion, metabolism, and pump function in an open chest canine model using a combination of potentially non-invasive and clinically useful techniques. DESIGN--To assess potential regulatory mechanisms and the interaction of myocardial perfusion, metabolism, and contractile function responses during changes in cardiac workload, noradrenaline (1 microgram.kg-1.min-1) was infused and hypoxia was produced by increasing the inspired ratio of nitrogen to oxygen to produce a PaO2 of 2.6-4.0 kPa in separate interventions. SUBJECTS--Nine mongrel dogs of either sex, age 2-5 years, weight 8.5(SD 2.2) kg, were studied in separate interventions. MEASUREMENTS AND MAIN RESULTS--Myocardial perfusion was determined using 2H nuclear magnetic resonance (NMR) measured washout of deuterium oxide from the left ventricle interpreted with a one component Kety-Schmidt exponential model. High energy phosphate bioenergetics were determined by 31P NMR measurements of the phosphocreatine/ATP ratio. Redox state was estimated by nicotinamide adenine dinucleotide fluorometry expressed as percent change from the baseline, normalised to maximum response measured at 100% inspired N2. Mechanical function was evaluated using heart rate X systolic blood pressure and oxygen consumption measurements. During both noradrenaline infusion and hypoxia, mechanical function increased significantly from control values: heart rate X systolic blood pressure = 1.9(SD 0.5), 3.6(0.1), and 2.6(0.4), respectively; oxygen consumption = 0.9(2), 1.6(0.1), and 1.2(0.6) ml.min-1.100 g-1. Myocardial perfusion increased to support the increased workloads, from 87(10) to 131(20), and from 60(12) to 182(14) ml.min-1.100 g-1, respectively. ADP, estimated by the phosphocreatine/ATP ratio, did not change during noradrenaline infusion [2.4(0.2) to 2.4(0.7)], but decreased during hypoxia [2.4(0.4) to 1.7(0.5)]. Redox state decreased during noradrenaline infusion, from 100% to 84(0.7)%, and increased during hypoxia, from 100% to 140(10)%. CONCLUSIONS--Similar changes in workload induced by different physiological stimuli are associated with different biochemical responses even though changes in perfusion are similar. The data suggest that myocardial function is regulated by different biochemical mechanisms under different physiological conditions, ie, there is probably no universal regulator of myocardial function. It is now possible to evaluate potential metabolic regulators of myocardial function in an in vivo animal model.     

Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction.

BACKGROUND. A large and consistent body of evidence supports the judgment that elevation of total plasma blood cholesterol is a cause of myocardial infarction (MI) and that high levels of low density lipoprotein (LDL) cholesterol have a positive relation and high levels of high density lipoprotein (HDL) cholesterol an inverse relation with MI. At present, however, the roles, if any, of the major subfractions of HDL, namely, HDL2 and HDL3, have not been clarified. In addition, the relation of plasma apolipoprotein concentrations to MI and whether they provide predictive information over and above their lipoprotein cholesterol associations is unknown. METHODS AND RESULTS. We evaluated these questions in a case-control study of patients hospitalized with a first MI and neighborhood controls of the same age and sex. Cases had significantly lower levels of total HDL (p less than 0.0001) as well as HDL2 (p less than 0.0001) and HDL3 (p less than 0.0001) cholesterol. These differences persisted after controlling for a large number of demographic, medical history, and behavioral risk factors and levels of other lipids. There were significant (p less than 0.0001) inverse dose-response relations with odds ratios for those in the highest quartile relative to those in the lowest of 0.15 for total HDL, 0.17 for HDL2, and 0.29 for HDL3 cholesterol levels. Levels of LDL and very low density lipoprotein cholesterol and triglycerides were also higher among cases than controls, but only for triglycerides was the difference statistically significant after adjustment for coronary risk factors and other lipids (p = 0.044). Apolipoproteins A-I and A-II were both significantly (p less than 0.0001) lower in cases, and differences remained even after adjustment for coronary risk factors and lipids. There were significant dose-response relations for both apolipoprotein A-I (p = 0.026) and A-II (p = 0.002). Neither apolipoprotein B nor E was significantly related to MI after adjustment for lipids and other coronary risk factors. When all four apolipoproteins were taken together, there was an increased level of prediction of MI over the information provided by the lipids and other coronary risk factors (p = 0.003), but this appeared present only for the individual apolipoproteins A-I (p = 0.027) and A-II (p = 0.011). CONCLUSIONS. These data indicate that both HDL2 and HDL3 cholesterol levels are significantly associated with MI. They also raise the possibility that apolipoprotein levels, especially A-I and A-II, may add importantly relevant information to determination of risk of MI.     

Lipases and HDL metabolism.

Plasma levels of high-density lipoprotein (HDL) cholesterol are strongly inversely associated with atherosclerotic cardiovascular disease, and overexpression of HDL proteins, such as apolipoprotein A-I in animals, reduces progression and even induces regression of atherosclerosis. Therefore, HDL metabolism is recognized as a potential target for therapeutic intervention of atherosclerotic vascular diseases. The antiatherogenic properties of HDL include promotion of cellular cholesterol efflux and reverse cholesterol transport, as well as antioxidant, anti-inflammatory and anticoagulant properties. The molecular regulation of HDL metabolism is not fully understood, but it is influenced by several extracellular lipases. Here, we focus on new developments and insights into the role of secreted lipases on HDL metabolism and their relationship to atherosclerosis.     

Separation of high density lipoprotein (HDL) using anti-apo A-I, apo A-II immuno-affinity chromatography to evaluate the effects of probucol]

An assessment has been made regarding the changes of the particles of lipoprotein A-I without A-II (Lp A-I) and lipoprotein A-I with A-II (LpA-I/A-II) which correspond to HDL subfraction isolated by the use of anti-apo A-I and A-II antibody affinity columns in order to quantitatively and qualitatively investigate the change of HDL caused by administration of probucol and pravastatin which are therapeutic drugs for hypercholesterolemia. Probucol caused significant decreases of HDL-cholesterol, plasma apo A-I/apo A-II ratio and particles larger in diameter than 10.4 nm. Comparing Lp A-I and A-I/A-II ratios with those in normolipidemic controls and the ratios before and after administration of probucol, the decrease of LpA-I ratio was found to be remarkable after prolonged administration of probucol, and it was presumed that the decrease of HDL cholesterol by prolonged administration reflects the decrease of LpA-I particles more than the decrease of LpA-I/A-II. On the other hand, no significant change was seen in HDL cholesterol, plasma apo A-I/apo A-II ratio or HDL particle size in the pravastatin group. It is considered essential to observe HDL from the aspect of apoprotein, which plays an important role in the metabolism of lipoprotein, in the assessment of the anti-atherogenic activity of HDL cholesterol in future. In other words, it is necessary to analyze the change of HDL from the aspect of Lp A-I and Lp A-I/AII and investigate their respective metabolisms and roles.     

Gemfibrozil increases both apo A-I and apo E concentrations. Comparison to other lipid regulators in cholesterol-fed rats

HDL cholesterol (HDL-C) was increased by gemfibrozil (+3.6-fold), fenofibrate (+1.3-fold) and ciprofibrate (+1.2-fold) but not clofibrate or bezafibrate when dosed PO at 50 mg/kg for 2 weeks in cholesterol-fed rats. Cholesterol in apo B-containing lipoproteins decreased with gemfibrozil (-76%), clofibrate (-12%) and ciprofibrate (-12%). Plasma apo B decreased to the greatest extent with gemfibrozil (-86%) followed by ciprofibrate (-47%), fenofibrate (-40%), clofibrate (-24%) and bezafibrate (-20%). Only gemfibrozil increased plasma apo E levels which are characteristically low in this rat model. Gemfibrozil, fenofibrate and ciprofibrate increased apo A-I concentrations. It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI (fenofibrate, ciprofibrate) or both apo E and A-I (gemfibrozil). It is hypothesized that drugs which alter the metabolism of both HDL peptides result in the greatest HDL-C elevation in the rat.     

High density lipoproteins, genetic polymorphism for apo A-I and coronary artery disease

HDL cholesterol and apolipoprotein A-I are associated with the development of coronary artery-disease (CAD). The presence of a PstI site polymorphism adjacent to the gene encoding apo A-I (known as P₂) has also been shown to be associated with CAD but this relationship is controversial. A case control study was conducted in an Australian population to re-examine whether the rare P₂ allele is associated with CAD. Data were derived from 159 cases of angiographically confirmed CAD and 99 healthy controls. The proportion of CAD cases carrying the P₂ allele did not differ significantly from controls (11% versus 9%). In a multiple logistic regression model controlling for the effects of age, country of birth, hypertension and hypotensive drugs, body mass index and lipid variables, the P₂ allele failed to predict significantly the presence of CAD (odds ratio 1.83; 95% confidence interval 0.65–5.19).     

Inflammation modulates human HDL composition and function in vivo

ObjectivesInflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans.Methods and resultsWe employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (?32.2 ± 9.3% at 24 h, p < 0.05) as well as small (?23.0 ± 5.1%, p < 0.01, at 24 h) and medium (?57.6 ± 8.0% at 16 h, p < 0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (～36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (?20.8 ± 3.4% at 24 h, p < 0.01) and cholesterol ester transfer protein mass (?22.2 ± 6.8% at 24 h, p < 0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models.ConclusionsThese data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.     

Effects of cross-link breakers,glycation inhibitors and insulin sensitisers on HDL function and the non-enzymatic glycation of apolipoprotein A-I

Aims/hypothesis Hyperglycaemia, a key feature of diabetes, is associated with non-enzymatic glycation of plasma proteins. We have shown previously that the reactive α-oxoaldehyde, methylglyoxal, non-enzymatically glycates apolipoprotein (Apo)A-I, the main apolipoprotein of HDL, and prevents it from activating lecithin:cholesterol acyltransferase (LCAT), the enzyme that generates almost all of the cholesteryl esters in plasma. This study investigates whether the glycation inhibitors aminoguanidine and pyridoxamine, the insulin sensitiser metformin and the cross-link breaker alagebrium can inhibit and/or reverse the methylglyoxal-mediated glycation of ApoA-I and whether these changes can preserve or restore the ability of ApoA-I to activate LCAT. Methods Inhibition of ApoA-I glycation was assessed by incubating aminoguanidine, pyridoxamine, metformin and alagebrium with mixtures of methylglyoxal and discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and ApoA-I, ([A-I]rHDL). Glycation was assessed as the modification of ApoA-I arginine, lysine and tryptophan residues, and by the extent of ApoA-I cross-linking. The reversal of ApoA-I glycation was investigated by pre-incubating discoidal (A-I)rHDL with methylglyoxal, then incubating the modified rHDL with aminoguanidine, pyridoxamine or alagebrium. Results Aminoguanidine, pyridoxamine, metformin and alagebrium all decreased the methylglyoxal-mediated glycation of the ApoA-I in discoidal rHDL and conserved the ability of the particles to act as substrates for LCAT. However, neither aminoguanidine, pyridoxamine nor alagebrium could reverse the glycation of ApoA-I or restore its ability to activate LCAT. Conclusions/interpretation Glycation inhibitors, insulin sensitisers and cross-link breakers are important for preserving normal HDL function in diabetes.     

Structure, function and amyloidogenic propensity of apolipoprotein A-I.

Apolipoprotein A-I, the major structural apolipoprotein of high-density lipoproteins, efficiently protects humans from cholesterol accumulation in tissues; however, it can cause systemic amyloidosis in the presence of peculiar amino acid replacements. The wild-type molecule also has an intrinsic tendency to generate amyloid fibrils that localise within the atherosclerotic plaques. The structure, folding and metabolism of normal apolipoprotein A-I are extremely complex and as yet not completely clarified, but their understanding appears essential for the elucidation of the amyloid transition.We reviewed present knowledge on the structure, function and amyloidogenic propensity of apolipoprotein A-I with the aim of highlighting the possible molecular mechanisms that might contribute to the pathogenesis of this disease. Important clues on apolipoprotein A-I amyloidogenesis may be obtained from classical comparative studies of the properties of the wild-type versus the amyloidogenic counterpart. Additionally, in the case of apoA-I, further insights on the molecular mechanisms underlying its amyloidogenic propensity may derive from comparative studies between amyloidogenic variants and other mutations associated with hypoalphalipoproteinemia without amyloidosis.     

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.     

Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I

The preferred extracellular acceptor of cell phospholipids and unesterified cholesterol in the process mediated by the ATP-binding cassette A1 (ABCA1) transporter is a monomolecular, prebeta-migrating, lipid-poor or lipid-free form of apolipoprotein (apo) A-I. This monomolecular form of apoA-I is quite distinct from the prebeta-migrating, discoidal high-density lipoprotein (HDL) that contains two or three molecules of apoA-I per particle and which are present as minor components of the HDL fraction in human plasma. The mechanism of the ABCA1-mediated efflux of phospholipid and cholesterol from cells has been studied extensively. In contrast, much less attention has been given to the origin and subsequent metabolism of the acceptor lipid-free/lipid-poor apoA-I. There is a substantial body of evidence from studies conducted in vitro that a monomolecular, lipid-free/lipid-poor form of apoA-I dissociates from HDL during the remodeling of HDLs by plasma factors such as cholesteryl ester transfer protein, hepatic lipase, and phospholipid transfer protein. The rate at which apoA-I dissociates from HDL is influenced by the phospholipid composition of the particles and by the presence of apoA-II. This review describes current knowledge regarding the formation, metabolism, and regulation of monomolecular, lipid-free/lipid-poor apoA-I in plasma.