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.     

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.     

Apolipoprotein A-II and adiponectin as determinants of very low-density lipoprotein apolipoprotein B-100 metabolism in nonobese men

Data from cellular systems and transgenic animal models suggest a role of apolipoprotein (apo) A-II in the regulation of very low-density lipoprotein (VLDL) metabolism. However, the precise mechanism whereby apoA-II regulates VLDL metabolism remains to be elucidated in humans. In this study, we examined the associations between the kinetics of high-density lipoprotein (HDL)-apoA-II and VLDL-apoB-100 kinetics, and plasma adiponectin concentrations. The kinetics of HDL-apoA-II and VLDL-apoB-100 were measured in 37 nonobese men using stable isotope techniques. Plasma adiponectin concentration was measured using immunoassays. Total plasma apoA-II concentration was positively associated with HDL-apoA-II production rate (PR) (r = 0.734, P < .01); both were positively associated with plasma triglyceride concentration (r = 0.360 and 0.369, respectively) and VLDL-apoB-100 PR (r = 0.406 and 0.427, respectively), and inversely associated with plasma adiponectin concentration (r = −0.449 and −0.375, respectively). Plasma adiponectin was inversely associated with plasma triglyceride concentration (r = −0.327), VLDL-apoB-100 concentration (r = −0.337), and VLDL-apoB-100 PR (r = −0.373). In multiple regression models including waist circumference and plasma insulin, plasma adiponectin concentration was an independent determinant of total plasma apoA-II concentration (β-coefficient = −0.508, P = .001) and HDL-apoA-II PR (β-coefficient = −0.374, P = .03). Conversely, total plasma apoA-II concentration (β-coefficient = 0.348, P = .047) and HDL-apoA-II PR (β-coefficient = −0.350, P = .035) were both independent determinants of VLDL-apoB-100 PR. However, these associations were not independent of plasma adiponectin. Variation in HDL apoA-II production, and hence total plasma apoA-II concentration, may exert a major effect on VLDL-apoB-100 production. Plasma adiponectin may also contribute to the variation in VLDL-apoB-100 production partly by regulating apoA-II transport.     

LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial

OBJECTIVE: We tested the hypothesis that concentrations of LpA-I and/or LpA-I:A-II HDL subclasses are significantly associated with CHD prevalence and recurrent cardiovascular events. METHODS: LpA-I levels were determined by differential electroimmunoassay in male participants with (n = 169) and without CHD (n = 850) from the Framingham Offspring Study (FOS) and in male participants with CHD from the placebo arm of the Veterans Affairs HDL Intervention Trial (VA-HIT) (n = 741). Data were analyzed cross-sectionally (FOS) and prospectively (VA-HIT) and were adjusted for established lipid and non-lipid CHD risk factors. RESULTS: We observed slightly but significantly higher LpA-I levels in CHD cases compared to all or to HDL-C-matched controls and slightly but significantly higher LpA-I:A-II levels in CHD cases compared to HDL-C-matched controls it the FOS. Neither LpA-I nor LpA-I:A-II levels were significantly different between groups with and without recurrent cardiovascular events in the VA-HIT. No significant differences were observed in LpA-I and LpA-I:A-II levels in low HDL-C (< or = 40 mg/dl) subjects with CHD (VA-HIT, n = 711) and without CHD (FOS, n = 373). Plasma LpA-I concentration had a positive correlation with the large LpA-I HDL particle (alpha-1) but no correlation with the small LpA-I HDL particle (prebeta-1). LpA-I:A-II concentration had a positive correlation with the large (alpha-2) and an inverse correlation with the small (alpha-3) LpA-I:A-II HDL particles. CONCLUSION: Our data do not support the hypothesis that CHD prevalence (FOS) or recurrence of cardiovascular events (VA-HIT) are associated with significant reductions in the concentrations of LpA-I and/or LpA-I:A-II HDL subclasses.     

Apolipoprotein E polymorphism and atherosclerosis

The relationship between apolipoprotein (apo) E and vascular disease has been the subject of a considerable amount of research. However, this relationship is far from clearly defined. This deficiency appears to be due to a multitude of factors. Among these are differences in ethnicity, age (and possibly gender), diagnostic criteria, and environmental factors (eg, diet and smoking) that have contributed to the contradictory findings. Several diseases and their treatment may also influence this relationship. There are also documented interactions between apo E genotypes and other genes or vascular risk factors. One possible clinically relevant application of identifying the apo E genotype could be to assess the response to a particular drug treatment. It may also be that apo E polymorphism will become a good predictor of vascular death (eg, from myocardial infarction or stroke) rather than an indicator of the risk of developing vascular disease but without an acute ischemic event. More research is required to define the place of apo E genotyping in the management of vascular disease in its various forms. Whatever the future brings, the evaluation of apo E genotypes will need to be rapid, cheap, and technically undemanding before this investigation becomes widely available and clinically relevant.     

HDL biogenesis and functions: Role of HDL quality and quantity in atherosclerosis

Coronary heart disease (CHD) is a leading cause of death in western societies. In the last few decades, a number of epidemiological studies have shown that a disproportion between atheroprotective and atherogenic lipoproteins in plasma is one of the most important contributors towards atherosclerosis and CHD. Thus, based on the classical view, reduced HDL cholesterol levels independently predict one's risk factor for developing cardiovascular disease, while elevated HDL levels protect from atherosclerosis. However, more recent studies have suggested that the relationship between HDL and cardiovascular risk is more complex and extends beyond the levels of HDL in plasma. These studies challenge the existing view on HDL and cardiovascular risk and trigger a discussion as to whether low HDL is a causal effect for the development of heart disease. In this article we provide a review of the current literature on the biogenesis of HDL and its proposed functions in atheroprotection. In addition, we discuss the significance of both HDL quality and quantity in assessing cardiovascular risk.     

HDL metabolism and CETP inhibition

High density lipoprotein-cholesterol (HDL-C) concentration in the blood is independently and inversely associated with an increased risk of coronary heart disease. Some of the cholesterol-lowering drugs (niacin, fibrates, and statins) incidentally raise HDL-C. These drugs are not effective in causing major changes in HDL-C. Since the discovery of human genetic cholesteryl ester transfer protein (CETP) deficiency in a Japanese population with high levels of HDL-C and apolipoprotein A-I, CETP inhibition has become a novel strategy for raising HDL-C in humans. Mice, a species naturally lacking CETP, were transduced with the human CETP gene, which resulted in dose-related reductions in HDL-C. Rabbits, a species with naturally high levels of CETP, were fed a synthetic CETP inhibitor, JTT-705, leading to both a 90% increase in HDL-C and a 70% reduction in aortic atherosclerotic lesion area. Human intervention trials with a new potent and selective CETP inhibitor, torcetrapib, have taken place. In a phase I multidose trial, HDL-C increased by 91% with torcetrapib 120 mg twice daily. A phase II trial conducted with multiple combinations of torcetrapib and atorvastatin showed that the combination was well tolerated and doses 30 mg and higher of torcetrapib caused 8.3-40.2% changes from baseline HDL-C across the dose range of atorvastatin at 12 weeks. Recently the phase III clinical trial ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) was prematurely terminated because of an increase in mortality in the torcetrapib/atorvastatin treatment arm compared with atorvastatin used alone. In companion studies no improvement in carotid or coronary atherosclerosis could be detected in patients treated with the torcetrapib/atorvastatin combination despite favorable changes in both low density lipoprotein (LDL)- and HDL-cholesterol levels. The future for CETP inhibition with drug therapy is now unclear, and must include a closer look at CETP inhibitor's effects on blood pressure and HDL itself. Accordingly, it was recently shown in 2 double-blind, placebo-controlled, randomized, phase I studies with the CETP inhibitor anacetrapib in healthy individuals and in patients with dyslipidemias that the drug increased HDL and reduced LDL, while having no effect on blood pressure.     

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.     

High-density lipoprotein metabolism and progression of atherosclerosis: new insights from the HDL Atherosclerosis Treatment Study

PURPOSE OF REVIEW: The purpose of this review is to summarize the current understanding of the potentially antiatherogenic properties of high-density lipoprotein related to its different components. RECENT FINDINGS: Recent findings on the role of the different high-density lipoprotein subspecies in reverse cholesterol transport, inflammation, endothelial dysfunction, and low-density lipoprotein oxidation are covered. Special emphasis is put on the heterogeneity of high-density lipoprotein and functional changes related to specific high-density lipoprotein particles with the potential therapeutic alterations of high-density lipoprotein metabolism. SUMMARY: The diverse action of high-density lipoprotein observed could be explained by the heterogeneity of high-density lipoprotein particles with completely different composition and properties. The modification of specific high-density lipoprotein subpopulations to reach the maximum atheroprotective effects under various pathologic conditions bears great potential in lipid research.     

HDL metabolism in diabetes

Based on the data reviewed, it is necessary to conclude that diabetes is associated with profound changes in HDL metabolism. However, once we go beyond this simple generalization, it is apparent that the relationship between diabetes and HDL metabolism is not a simple one. A good deal of the complication evolves from the fact that IDDM and NIDDM seem to affect HDL metabolism quite differently, with the only apparent similarity the fact that plasma HDL-cholesterol concentration can be low in untreated patients with either IDDM or NIDDM. Thus, in patients with IDDM the primary event seems to be related to the insulin-deficient state, which results in a decrease in HDL turnover rate and resultant decline in plasma HDL-cholesterol concentration. In contrast, HDL turnover appears to be accelerated, not reduced in patients with NIDDM, and the low plasma HDL-cholesterol concentration is a consequence of the increased turnover rate. In addition, patients with NIDDM are not absolutely insulin deficient, and available evidence suggests that the higher the plasma insulin level, the lower the plasma HDL-cholesterol concentration in these patients. The differences noted above in the effect of IDDM and NIDDM on HDL metabolism are of great interest, and, unfortunately, not very well understood. There is, however, one additional difference, which may be of paramount clinical importance. For reasons not totally clear, plasma HDL-cholesterol concentrations in patients with IDDM treated with insulin are not lower than normal, and even tend to be higher than these values in a nondiabetic population. Possibly as a result of this phenomenon, there is no evidence that changes in plasma HDL-cholesterol concentration play a role in the development of macrovascular complications in IDDM. Although it is apparent from the considerations discussed in this review that a great deal more needs to be learned about the effect of insulin deficiency on HDL metabolism, changes in HDL metabolism do not appear to be clinically important in patients with IDDM. Unfortunately, this does not appear to be the situation in patients with NIDDM. Plasma HDL-cholesterol concentrations are lower than normal in patients with NIDDM, and this finding seems to be related to increased morbidity and mortality from CAD. Furthermore, there is no form of anti-diabetic treatment, irrespective of how effective it has been in achieving glycemic control, that has been shown to substantially increase plasma HDL-cholesterol level. Indeed, it has been difficult to demonstrate a consistent effect of any therapeutic approach on plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 400 WORDS)