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High-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure.

Extracellular vesicles such as exosomes are now recognized as key players in intercellular communication. Their role is influenced by the specific repertoires of proteins and lipids, which are enriched when they are generated as intraluminal vesicles (ILVs) in multivesicular endosomes. Here we report that a key component of small extracellular vesicles, the tetraspanin CD63, sorts cholesterol to ILVs, generating a pool that can be mobilized by the NPC1/2 complex, and exported via exosomes to recipient cells. In the absence of CD63, cholesterol is retrieved from the endosomes by actin-dependent vesicular transport, placing CD63 and cholesterol at the centre of a balance between inward and outward budding of endomembranes. These results establish CD63 as a lipid-sorting mechanism within endosomes, and show that ILVs and exosomes are alternative providers of cholesterol.

Background: In patients with rheumatoid arthritis (RA), qualitative alterations of low and high-density lipoproteins (LDL and HDL, respectively) might partially explain their increased cardiovascular risk. Tocilizumab has been associated with an increase in lipids, including triglyceride (TG) and cholesterol levels. The aim of this study is to evaluate the effect of tocilizumab on certain LDL and HDL characteristics (oxidized LDL levels, HDL-associated enzymes, chemical composition of both total HDL and HDL3c subpopulation, and their capacity to promote cellular cholesterol efflux) at baseline and 3 months after the start of treatment in patients with RA. Methods: Twenty-eight RA patients (ACR/EULAR 2010 criteria) with indication of treatment with tocilizumab were included in the present study. Clinical assessment [Health assessment questionnaire (HAQ)], disease activity score 28 (DAS28), high-sensitivity C reactive protein (hsCRP) concentration, lipid profile, and lipoprotein (a) [Lp(a)] levels were evaluated in all patients at baseline and after 3 months of treatment with tocilizumab. Lipoprotein characteristics were evaluated through the levels of oxidized LDL (OxLDL), the activity of paraoxonase (PON) 1, the composition of total HDL and small, dense HDL3c subpopulation, and their ability to promote cellular cholesterol efflux. Results: After 3 months of treatment with tocilizumab, HAQ (− 23%, p< 0.05), DAS28 (− 49%, p< 0.001), and hsCRP (− 94%, p< 0.01) levels decreased significantly. Total cholesterol (TC), LDL-C, non-HDL-C, and apo B levels showed a significant increase after treatment (TC: + 7.0%, p< 0.01; LDL-C: + 10%, p< 0.01; non-HDL-C: + 9.9%, p< 0.01; and apo B: + 9.6%, p< 0.05). Decreases in Lp(a) and OxLDL levels were also observed after treatment [Lp(a): − 50%, p< 0.01; and oxLDL: − 5.4%, p< 0.05]. The latter was in accordance with the increment detected in PON activity. No changes were observed in HDL capacity to promote cholesterol efflux (p> 0.05) in the whole group. Conclusions: Treatment with tocilizumab reduced hsCRP levels and displayed positive effects on certain lipoprotein-related parameters, such as a potent decrease inLp(a) and a reduction in OxLDL levels. Moreover, HDL capacity to promote cellular cholesterol efflux was maintained after 3 months of treatment.

Background Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk.Methods To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase.Results When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (−45%) and type 2 diabetes (–25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (−20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [3H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis.Conclusions Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.

Despite decades of therapeutic advances, myocardial infarction remains a leading cause of death worldwide. Recent studies have identified HDLs (high-density lipoproteins) as a potential candidate for mitigating coronary ischemia/reperfusion injury via a broad spectrum of signaling pathways. HDL ligands, such as S1P (sphingosine-1-phosphate), Apo (apolipoprotein) A-I, clusterin, and miRNA, may influence the opening of the mitochondrial channel, insulin sensitivity, and production of vascular autacoids, such as NO, prostacyclin, and endothelin-1. In parallel, antioxidant activity and sequestration of oxidized molecules provided by HDL can attenuate the oxidative stress that triggers ischemia/reperfusion. Nevertheless, during myocardial infarction, oxidation and the capture of oxidized and proinflammatory molecules generate large phenotypic and functional changes in HDL, potentially limiting its beneficial properties. In this review, new findings from cellular and animal models, as well as from clinical studies, will be discussed to describe the cardioprotective benefits of HDL on myocardial infarction. Furthermore, mechanisms by which HDL modulates cardiac function and potential strategies to mitigate postmyocardial infarction risk damage by HDL will be detailed throughout the review.

Apolipoprotein B-containing lipoproteins and low-density lipoprotein play a key role in atherosclerotic vascular disease. Modified forms of low-density lipoprotein drive inflammation, an integral aspect of plaque progression. High-density lipoprotein particles are equipped to protect low-density lipoprotein from enzymatic and nonenzymatic modification. Under normal conditions, high-density lipoproteins facilitate cholesterol efflux from tissues, preventing its accumulation with deleterious consequences. However, the high-density lipoprotein particles characteristic of dyslipidemic states associated with premature atherosclerosis are typically dysfunctional as a result of alteration in their metabolism and consequently their structure and composition. Such an effect indirectly enhances low-density lipoprotein atherogenicity.

The functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, P< 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3-fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, P< 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8-fold (P< 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation.

Uptake of low-density lipoprotein (LDL) particles by macrophages represents a key step in the development of atherosclerotic plaques, leading to the foam cell formation. Chemical modification of LDL is however necessary to induce this process. Proatherogenic LDL modifications include aggregation, enzymatic digestion and oxidation. LDL oxidation by one-electron (free radicals) and two-electron oxidants dramatically increases LDL affinity to macrophage scavenger receptors, leading to rapid LDL uptake and fatty streak formation.

APOC3 is produced mainly by the liver and intestine and approximately half of plasma APOC3 associates with HDL. Though it was believed that APOC3 associates with HDL by simple binding to preexisting particles, recent data support that biogenesis of APOC3-containing HDL (APOC3-HDL) requires Abca1. Moreover, APOC3-HDL contributes to plasma triglyceride homeostasis by preventing APOC3 association with triglyceride-rich lipoproteins. Interestingly, APOC3-HDL also shows positive correlation with the morbidly obese phenotype. However, the roles of APOC3 in HDL functionality and adipose tissue metabolic activity remain unknown. Therefore, here we investigated the direct effects of APOC3 expression on HDL structure and function, as well as white adipose tissue (WAT) and brown adipose tissue (BAT) metabolic activity. C57BL/6 mice were infected with an adenovirus expressing human APOC3 or a recombinant attenuated control adenovirus expressing green fluorescent protein and blood and tissue samples were collected at 5 days postinfection. HDL was then analyzed for its apolipoprotein and lipid composition and particle functionality. Additionally, purified mitochondria from BAT and WAT were analyzed for uncoupling protein 1, cytochrome c (Cytc), and Cytc oxidase subunit 4 protein levels as an indirect measure of their metabolic activity. Serum metabolomic analysis was performed by NMR. Combined, our data show that APOC3 modulates HDL structure and function, while it selectively promotes BAT metabolic activation.

Increased lipid peroxidation and elevated oxidative stress represent well-established characteristics of Alzheimer’s disease (AD). Amyloid-β (Aβ) peptide, a major component of amyloid plaques, can strongly influence oxidative processes. In aggregated form, Aβ has prooxidative properties, whereas in monomeric form it functions as an antioxidant. The antioxidative properties of monomeric Aβ are related to its ability to chelate transition metal ions, which are potent catalysts of oxidation. Aβ possesses an amphiphilic structure, associates with lipoproteins in vivo and may therefore function as a preventive antioxidant which protects lipoproteins from oxidation by transition metal ions. Increased production of Aβ in response to elevated oxidative stress has been documented in a number of in vitro studies, implying that production of monomeric Aβ as a lipoprotein antioxidant can be abnormally increased in response to elevated oxidative stress in aging. Subsequent accumulation of Aβ-metal aggregates, production of reactive oxygen species and toxic action to neuronal cells may represent a gain-of-function transformation and form temporal sequence of events in the development of AD.

Large-scale epidemiological studies firmly established the association between low plasma levels of high-density lipoprotein-cholesterol (HDL-C) and elevated risk of cardiovascular disease. This relationship is thought to reflect the key biological function of HDL, which involves reverse cholesterol transport from the arterial wall to the liver for further excretion from the body. Other aspects of the cardioprotective HDL functionality include antioxidative, anti-inflammatory, anti-apoptotic, anti-thrombotic, vasodilatory, anti-infectious and antidiabetic activities. Over the last decades, wide interest in HDL as an athero- and cardioprotective particle has resulted in the development of HDL-C raising as a therapeutic approach to reduce cardiovascular risk. Several strategies to increase circulating HDL-C concentrations were developed that primarily included use of niacin and fibrates as potent HDL-C raising agents. In the statin era, inhibition of cholesteryl ester transfer protein, infusion of artificially reconstituted HDL and administration of apolipoprotein A-I mimetics were established as novel approaches to raise HDL-C. More recently, other strategies targeting HDL metabolism, such as upregulation of apolipoprotein A-I production by the liver, were added to the list of HDL therapeutics. This review summarises current knowledge of novel HDL-targeting therapies and discusses perspectives of their use.

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (−41%) and LDL-cholesterol (−38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3.

In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality also appears to be very important for atheroprotection. Analysis of various clinical paradigms suggests that the lipid and apolipoprotein composition of HDL defines its size, shape, and functions and may determine its beneficial effects on human health. Previously, we reported that like apolipoprotein A-I (Apoa1), apolipoprotein E (Apoe) is also capable of promoting the de novobiogenesis of HDL with the participation of ATP binding cassette A lipid transporter member 1 (Abca1) and plasma enzyme lecithin:cholesterol acyltransferase (Lcat), in a manner independent of a functional Apoa1. Here, we performed a comparative analysis of the functions of these HDL subpopulations. Specifically, Apoe and Apoa1 double-deficient (Apoe–/–× Apoa1–/–) mice were infected with APOA1-or APOE3-expressing adenoviruses, and APOA1-containing HDL (APOA1-HDL) and APOE3-containing HDL (APOE3-HDL), respectively, were isolated and analyzed by biochemical and physicochemical methods. Western blot and lipidomic analyses indicated significant differences in the apolipoprotein and lipid composition of the two HDL species. Moreover APOE3-HDL presented a markedly reduced antioxidant potential and Abcg1-mediated cholesterol efflux capacity. Surprisingly, APOE3-HDL but not APOA1-HDL attenuated LPS-induced production of TNFα in RAW264.7 cells, suggesting that the anti-inflammatory effects of APOA1 are dependent on APOE expression. Taken together, our data indicate that APOA1 and APOE3 recruit different apolipoproteins and lipids on the HDL particle, leading to structurally and functionally distinct HDL subpopulations. The distinct role of these two apolipoproteins in the modulation of HDL functionality may pave the way toward the development of novel pharmaceuticals that aim to improve HDL functionality.

HDL protects against atherosclerosis through multiple mechanisms that include amelioration of endothelial dysfunction, removal of excess cholesterol from macrophages, and antioxidative, anti-inflammatory, and antiapoptotic effectsUnder particular circumstances, HDL loses its atheroprotective properties, resulting in the formation of dysfunctional HDL particlesDysfunctional HDL particles increase proinflammatory signalling and reduce the efflux of cholesterol from macrophages by the ATP-binding cassette transporter A1In prospective studies, myeloperoxidase-mediated oxidation of particular residues on apolipoprotein A-I creates a dysfunctional HDL particle that is associated with an increased incidence of cardiovascular events

To evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 ± 9 mg/dl), low apoA-I (79 ± 24 mg/dl), normal LDL-cholesterol (132 ± 25 mg/dl), and elevated TG (130 ± 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to −25%, P< 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to −48%, P< 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.

Plasma high density lipoproteins (HDL) are small, dense, protein-rich particles compared with other lipoprotein classes; roughly half of total HDL mass is accounted for by lipid components. Phospholipids predominate in the HDL lipidome, accounting for 40–60% of total lipid, with lesser proportions of cholesteryl esters (30–40%), triglycerides (5–12%), and free cholesterol (5–10%). Lipidomic approaches have provided initial insights into the HDL lipidome with identification of over 200 individual molecular lipids species in normolipidemic HDL. Plasma HDL particles, however, reveal high levels of structural, compositional, and functional heterogeneity. Establishing direct relationships between HDL structure, composition, and atheroprotective functions bears the potential to identify clinically relevant HDL subpopulations. Furthermore, development of HDL-based therapies designed to target beneficial subspecies within the circulating HDL pool can be facilitated using this approach. HDL lipidomics can equally contribute to the identification of biomarkers of both normal and deficient HDL functionality, which may prove useful as biomarkers of cardiovascular risk. However, numerous technical issues remain to be addressed in order to make such developments possible. With all technical questions resolved, quantitative analysis of the molecular components of the HDL lipidome will contribute to expand our knowledge of cardiovascular and metabolic diseases.

Numerous epidemiological studies have demonstrated that light to moderate alcohol consumption is associated with reduced risk of cardiovascular disease (CVD). The purpose of this review is to discuss the potential CV benefit of alcohol consumption with a particular focus on the findings of publications appearing within the past 2 years.

Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (–62%) and apoAI (–16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ∼1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ∼1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (–50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (–53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix.

Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (−62%) and apoAI (−16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ∼1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ∼1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (−50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (−53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix.

Oxidative stress, an emerging risk factor for premature atherosclerosis and cardiovascular disease, mediates the formation of proinflammatory, pro-atherogenic oxidized low-density lipoprotein (oxLDL) in the arterial intima. Circulating HDL particles, and particularly small, dense, protein-rich HDL3, may provide potent protection of LDL in vivofrom oxidative damage by free radicals in the arterial intima, resulting in the inhibition of the generation of proinflammatory oxidized lipids, primarily lipid hydroperoxides (LOOH) but also short-chain oxidized phospholipids (oxPL). HDL-mediated inactivation of LOOH involves initial transfer of phospholipid hydroperoxides (PLOOH) from LDL to HDL3, which is governed by the rigidity of the surface monolayer of HDL, and subsequent reduction of PLOOH by redox-active Met residues of apolipoprotein A-I (apoA-I) with the formation of phospholipid hydroxides (PLOH) and methionine sulphoxides. HDL-associated enzymes may in turn contribute to the hydrolytic inactivation of short-chain oxPL. Mounting evidence suggests that the integrated antioxidative activity of HDL appear to be defective in atherogenic dyslipidaemias involving low HDL-cholesterol levels; anomalies in the proteome and lipidome of HDL particles in dyslipidaemic patients may underlie such functional deficiency. Pharmacological normalization of HDL metabolism concomitantly with correction of circulating levels, composition and biological activities of HDL particles, with enrichment in apoA-I and reduction in HDL surface rigidity, may constitute an efficacious therapeutic approach to attenuate atherosclerosis in dyslipidaemic patients at high cardiovascular risk.

The premature termination of the torcetrapib trial in December 2006 was widely publicized. A year on, Anatol Kontush, Maryse Guérin and M John Chapman revisit cholesteryl ester transfer protein inhibition as a potential therapeutic target and review recent developments in HDL-raising therapy with a focus on torcetrapib trials.

Background: Oxidative stress represents a key event in the pathogenesis of Alzheimer's disease (AD). Low circulating concentrations of vitamin E, quantitatively the major lipophilic antioxidant in the brain, are frequently observed in AD patients, suggesting that supplementation with vitamin E may delay the development of AD. Objectives: To assess the value of therapeutic use of vitamin E in AD. Method: Search of the PubMed and Medline online libraries for relevant English-language publications between 1966 and 2007. Results and conclusions: Supplementation of AD patients with vitamin E increases its levels in biological fluids and decreases their susceptibility to oxidative stress. However, clinical interventional and observational studies demonstrated contradicting results regarding the benefit of vitamin E in AD. Available data do not provide any clear evidence that vitamin E beneficially influences AD and are not sufficient to recommend vitamin E for primary or secondary prevention of AD. The future of vitamin E supplementation in AD should be therefore regarded with caution.

High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.

ABSTRACTObjective:The objective of this study was to identify key determinants of high-density lipoprotein-cholesterol (HDL-C) level, including subclinical inflammation and insulin resistance, and to determine the prevalence of a low HDL-C phenotype in dyslipidaemic patients at high cardiovascular risk.Methods:In a cross-sectional study, we assessed the prevalence of low HDL‐C phenotypes in 14 667 dyslipidaemic patients attending our specialised lipid clinic and evaluated the potential relationships between HDL‐C level and 16 clinical and biological parameters.Results:In univariate analysis, women exhibited higher plasma concentrations of HDL‐C as compared with men. Levels of triglycerides, fasting blood glucose, uric acid, waist circumference, body mass index, high sensitivity C-reactive protein (hs‐CRP), insulin resistance (as HOMA‐IR index) and smoking were all negatively correlated with HDL‐C, whereas age was positively correlated with HDL‐C levels. Moderate drinkers (10–30 g/day) displayed higher HDL‐C concentrations as compared with abstinent subjects; in contrast, consumption of more than 30 g alcohol/day was associated with a further non-significant elevation of HDL‐C levels as compared to moderate drinkers. Multivariate analysis identified eight independent correlates of HDL‐C. Age, sex and TG accounted for 37% of variability in HDL‐C; modifiable factors including waist circumference, alcohol consumption and smoking, in addition to HOMA‐IR and hs‐CRP, accounted for an additional 5% of the variability in HDL‐C. Using a cut-off of 40 mg/dL (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women, 33% and 28% of men and women displayed low levels of HDL‐C.Conclusion:Eight independent determinants of HDL‐C account for 41% of variability in HDL‐C in our dyslipidaemic population. Three of them, i.e. age, sex and degree of triglyceridaemia accounted for more than one third of such variability. The high prevalence of low HDL‐C phenotypes in dyslipidaemic patients at elevated cardiovascular risk emphasises the need for both lifestyle and pharmacological strategies of intervention to raise HDL‐C.

Small, dense HDL possesses potent antioxidative activity but this is compromised under conditions of atherogenic dyslipidemia. The raising of HDL cholesterol levels might, however, improve functionality. In this review, Kontush and Chapman explore the mechanisms behind the antiatherogenic effects of small HDL, and the possible roles of these particles as therapeutic targets.

Amyloid‐β (Aβ) has for a long time been thought to play a central role in the pathogenesis of Alzheimer disease (AD). Analysis of available data indicates that Aβ possesses properties of a metal‐binding apolipoprotein influencing lipid transport and metabolism. Protection of lipoproteins from oxidation by transition metals, synaptic activity and role in the acute phase response represent plausible physiological functions of Aβ. However, these important biochemical qualities which may critically influence the development of AD, have been largely ignored by mainstream AD researchers, making Aβ appear to be a “black sheep” in a “good apolipoprotein” family. New studies are needed to shed further light on the physiological role of Aβ in lipid metabolism in the brain.

Newborn infants are susceptible to a range of problems attributed to excessive production of free radicals. Because of a higher content of antioxidants, above all bilirubin, and a lower content of oxidizable lipids, newborn plasma should be better protected against oxidation than adult plasma. To test this hypothesis, we measured the susceptibility of plasma to in vitro oxidation in microsamples (7 µL) from 57 healthy newborns and 18 adults. Heparin plasma was diluted 150-fold and oxidized by 50 µM Cu2+. Oxidation was monitored as an increase in sample absorbance at 234 nm. Plasma oxidizability was found to be significantly lower in newborns than in adults. Accordingly, the level of bilirubin, an important antioxidant, was significantly higher, and the level of polyunsaturated fatty acids, a major substrate of lipid peroxidation, was significantly lower in newborn plasma. In addition, plasma oxidizability correlated positively with the level of polyunsaturated fatty acids and negatively with that of bilirubin. These data indicate that plasma is better protected against oxidative stress in newborns than in adults, owing to its higher content of antioxidants like bilirubin and its lower content of oxidizable lipids.

Newborn infants are susceptible to a range of problems attributed to excessive production of free radicals. Because of a higher content of antioxidants, above all bilirubin, and a lower content of oxidizable lipids, newborn plasma should be better protected against oxidation than adult plasma. To test this hypothesis, we measured the susceptibility of plasma to in vitrooxidation in microsamples (7 L) from 57 healthy newborns and 18 adults. Heparin plasma was diluted 150-fold and oxidized by 50 M Cu2. Oxidation was monitored as an increase in sample absorbance at 234 nm. Plasma oxidizability was found to be significantly lower in newborns than in adults. Accordingly, the level of bilirubin, an important antioxidant, was significantly higher, and the level of polyunsaturated fatty acids, a major substrate of lipid peroxidation, was significantly lower in newborn plasma. In addition, plasma oxidizability correlated positively with the level of polyunsaturated fatty acids and negatively with that of bilirubin. These data indicate that plasma is better protected against oxidative stress in newborns than in adults, owing to its higher content of antioxidants like bilirubin and its lower content of oxidizable lipids.

Imbalances of oxidative homeostasis and lipid peroxidation have been revealed as important factors involved in neurodegenerative disorders such as Alzheimer's disease. The brains of patients with Alzheimer's disease contain increased levels of lipid-peroxidation products such as 4-hydroxy-2-nonenal or acrolein, and enhanced lipid peroxidation can also be detected in cerebrospinal fluid and plasma from such patients. Recent research revealed that the interplay of transition metals, amyloid-β peptide and lipid peroxidation might be responsible for increased oxidative stress and cell damage in this disease. In particular, the contrasting roles of amyloid-β peptide, as a possible transition metal-chelating antioxidant for lipoproteins and a pro-oxidant when aggregated in brain tissue, has been the focus of discussion recently. In this context, lipid peroxidation has to be seen as an important part of the pathophysiological cascade in Alzheimer's disease, and its measurement in body fluids might serve as a therapy control for Alzheimer's disease and other neurodegenerative diseases.

Oxidative Prozesse sind sowohl an der Alterung als auch verschiedenen degenerativen Erkrankungen beteiligt. In den letzten Jahren ist insbesondere die Rolle der Oxidation von Lipoproteinen geringer Dichte bei der Entstehung der Artherosklerose und der koronaren Herzkrankheit deutlich geworden. Dazu wurde die Lipoproteinoxidation im Plasma untersucht. Wir haben uns für die Rolle der Lipoproteinoxidation bei der Alzheimer Demenz interessiert und haben die Methoden zur Bestimmung der Oxidierbarkeit von Lipoproteinen weiterentwickelt, um Messungen im Liquor cerebrospinalis von Alzheimerpatienten durchzuführen. Ausserdem sind die wichtigsten lipophilen und hydrophilen Antioxidantien, α-Tocopherol (Vitamin E) und Ascorbat (Vitamin C), und der Gehalt an mehrfach-ungesättigten Fettsäuren bestimmt worden. Bei Alzheimerpatienten findet sich gegenüber Kontrollen eine erhöhte Lipoproteinoxidation sowohl im Liquor als auch im Plasma. Die Konzentrationen der antioxidantiven Vitamine sind dagegen erniedrigt, was auf erhöhten oxidativen Stress bei dieser Erkrankung hinweist. In einer Pilotstudie konnte die in vitro Lipoproteinoxidation im Liquor von Alzheimerpatienten durch die Gabe von Vitamin E und C verzögert werden. Zusammenfassend zeigen die Ergebnisse, dass eine erhöhte Lipoproteinoxidation auch bei der Alzheimer Krankheit eine wichtige Rolle spielen könnte, und sie bilden eine mögliche Grundlage zur Behandlung dieser Erkrankung mit Antioxidantien. Die klinische Wirksamkeit eines solchen Ansatzes muss durch entsprechende Langzeitstudien geprüft werden. Oxidative processes are involved in aging as well as the pathogenesis of different degenerative diseases. In the last few years the role of low density lipoprotein oxidation in the development of artherosclerosis and coronary heart disease has become evident. Lipoprotein oxidation in plasma is used as a marker for disease progression. We were interested in the role of lipoprotein oxidation in Alzheimer‘s disease. For this purpose we developed methods to determine the in vitro oxidizability of cerebrospinal fluid and plasma lipoproteins of Alzheimer patients. In addition we measured the lipophilic and hydrophillic antioxidants, α-tocopherol (vitamin E) and ascorbate (vitamin C). Cerebrospinal fluid and plasma lipoprotein oxidation was found to be increased in Alzheimer‘s patients compared to controls and a corresponding decrease of antioxidant vitamins was found. In a pilot study, in vitro lipoprotein oxidation in cerebrospinal fluid of Alzheimer patients could be delayed by vitamin E and C supplementation. In conclusion these data show that increased lipoprotein oxidation could play an important role in Alzheimer‘s disease and possibly provide a rationale for the treatment of this disease with antioxidant drugs. The clinical effect of this therapeutical approach remains to be proved in long-term studies.

Elevated production of amyloid-β (Aβ) as a preventive antioxidant for brain lipoproteins under the action of increased oxidative stress in aging is postulated to represent a major event in the development of Alzheimer’s disease (AD). Increase in Aβ production is followed by chelation of transition metal ions by Aβ, accumulation of Aβ-metal lipoprotein aggregates, production of reactive oxygen species and neurotoxicity. Chelation of copper by Aβ is proposed to be a most important part of this pathway, because Aβ binds copper stronger than other transition metals and because copper is a more efficient catalyst of oxidation than other metals. This amyloid-binds-copper (ABC) model does not remove Aβ peptide from its central place in our current thinking of AD, but rather places additional factors in the center of discussion. Most importantly, they embrace pathological mechanisms known to develop in aging (which is the major risk factor for AD), such as increased production of reactive oxygen species by mitochondria, that are positioned upstream relative to the generation of Aβ.

1. Increased production of Aβ in a form of lipoprotein antioxidant under the action of increased oxidative stress in aging with subsequent chelation of transition metal ions by Aβ, accumulation of toxic Aβ–metal lipoprotein complexes, production of reactive oxygen species, and neurotoxicity are reviewed and postulated to form the temporal sequence of events in the development of Alzheimer's disease (AD). 2. Since (i) Aβ binds copper stronger than iron and other transition metals, and (ii) copper is a more efficient catalyst of oxidation than other transition metals, chelation of copper by Aβ is proposed to be a most important part of this pathway. 3. Whereas this amyloid-binds-copper (ABC) model does not remove Aβ peptide from its central place in our current thinking of AD, it places additional factors in the center of discussion. 4. Most importantly, they embrace pathological mechanisms known to develop in aging (which is the most important risk factor for AD), such as increased production of reactive oxygen species by mitochondria, that can be positioned upstream relative to the generation of Aβ.

Amyloid-β (Aβ) peptide, a major constituent of senile plaques and a hallmark of Alzheimer's disease (AD), is normally secreted by neurons and can be found in low concentrations in cerebrospinal fluid (CSF) and plasma where it is associated with lipoproteins. However, the physiological role of Aβ secretion remains unknown. We measured the resistance to in vitro oxidation of CSF obtained from 20 control subjects and 30 patients with AD, and correlated it with CSF levels of antioxidants, lipids and Aβ. We found that the oxidative resistance, expressed as a duration of the oxidation lag-phase, was directly related to CSF levels of Aβ1-40, Aβ1-42 and ascorbate and inversely to levels of fatty acids. These data suggest that, besides ascorbate, Aβ is another major physiological antioxidant for CSF lipoproteins.

The sign–alternating electric field in rectangular impulses has been used to eliminate linear electrophoresis and to study nonlinear electrophoresis in water at strong fields. We found out that the particle drift velocity could change its direction with the growth of the strength of the field. This new phenomenon has obtained its explanation in the framework of the Debye–Hückel theory of strong electrolyte where we consider a particle as a “heavy” effective ion and take into account all relevant nonlinear effects, grounding ourselves on basic physics. With the help of our theory we have succeeded in good fitting of our experimental data on black oil and Al2O3particles in distilled water using reasonable values for the basic parameters such as the Debye screening length.