Academic literature on the topic 'High density lipoproteins'

High-density lipoproteins are regarded as “good guys” but not always. Situations involving high-density lipoproteins are discussed and medication results are considered. Clinicians usually consider high-density lipoprotein cholesterol. Nicotinic acid is the best available medication to elevate high-density lipoprotein cholesterol and this appears beneficial for cardiovascular risk. The major problem with nicotinic acid is that many patients do not tolerate the associated flushing. Laropiprant decreases this flushing and has an approval in Europe but not in the United States. The most potent medications for increasing high-density lipoprotein cholesterol are cholesteryl ester transfer protein inhibitors. The initial drug in this class, torcetrapib, was eliminated by excess cardiovascular problems. Two newer cholesteryl ester transfer protein inhibitors, R1658 and anacetrapib, initially appear promising. High-density lipoprotein cholesterol may play an important role in improving cardiovascular risk in the 60% of patients who do not receive cardiovascular mortality/morbidity benefit from low-density lipoproteins reduction by statins.

Abstract We assessed the distribution of alpha-tocopherol in serum lipoprotein samples after separating the lipoprotein fractions by either sequential ultracentrifugation or selective precipitation with sodium phosphotungstate-magnesium chloride reagent. alpha-Tocopherol concentrations were determined by reversed-phase high-performance liquid chromatography. After ultracentrifugation, we found that in men, low- and very-low-density serum lipoproteins (LDL-VLDL) contained 53.6% of alpha-tocopherol vs 46.4% in high-density lipoproteins (HDL). In women, serum LDL-VLDL contained 45.6% alpha-tocopherol after ultracentrifugation vs 54.4% in HDL. After selective precipitation, the proportions of alpha-tocopherol in men were 56.1% in LDL-VLDL vs 43.9% in HDL, and in women, 45.4% in LDL-VLDL vs 54.6% in HDL. After selective precipitation, alpha-tocopherol recovery from whole lipoprotein fractions was 97% to 100% vs 80% after ultracentrifugation, thus allowing more accurate alpha-tocopherol quantification than after separation by ultracentrifugation.

The article provides a review of the literature on the effect of excess and deficiency of high-density lipoprotein cholesterol on the prevention and treatment of cardiovascular pathology. Information about high-density lipoproteins structure, function, antiatherogenic role and the prospect of using various high-density lipoproteins subclasses in the pharmacotherapy of dyslipidemic conditions are also described. It is proven that a lowered level of such cholesterol is a predictor of cardiovascular disease. At the same time, many observations confirm the correlation between elevated high-density lipoprotein levels and mortality from myocardial infarction and other acute cardiovascular conditions. In large studies, the use of cholesterol ester transfer protein inhibitors and other drugs increased the level of high-density lipoprotein, but the unreduced risk of cardiovascular disease confirms the lack of positive results from the use as a therapeutic target. In addition, it was found that the composition of high-density lipoprotein cholesterol protein differs in healthy and diseased people: it becomes dysfunctional, losing its antioxidant and anti-inflammatory properties in diseased individuals. The atheroprotective activity of properly functioning high-density lipoprotein cholesterol is often impaired in clinical situations associated with oxidative stress. In these cases, high-density lipoproteins can have some changes, and even if the quantity is within the normal range, the quality is no longer the same. Thus, it is necessary to identify a better therapeutic target than high-density lipoprotein cholesterol levels, as there is currently insufficient clinical trial data to recommend targeted high-density lipoprotein therapy.

Lipoprotein mimetics were designed to recreate one or several functions of lipoproteins in context of cardiovascular disease; however, the current applications are much broader. Here we discuss the design principles, mechanisms of action, indications and efficacy of lipoprotein mimetics.

CONTEXT: Plasma phospholipid transfer protein mediates the transfer of phospholipids from triglyceride-rich lipoproteins, very low density lipoproteins and low density lipoproteins to high density lipoproteins, a process that is also efficient between high density lipoprotein particles. It promotes a net movement of phospholipids, thereby generating small lipid-poor apolipoprotein AI that contains particles and subfractions that are good acceptors for cell cholesterol efflux. CASE REPORT: We measured the activity of plasma phospholipid transfer protein in two cholestatic patients, assuming that changes in activity would occur in serum that was positive for lipoprotein X. Both patients presented severe hypercholesterolemia, high levels of low density lipoprotein cholesterol and, in one case, low levels of high density lipoprotein cholesterol and high levels of phospholipid serum. The phospholipid transfer activity was close to the lower limit of the reference interval. To our knowledge, this is the first time such results have been presented. We propose that phospholipid transfer protein activity becomes reduced under cholestasis conditions because of changes in the chemical composition of high density lipoproteins, such as an increase in phospholipids content. Also, lipoprotein X, which is rich in phospholipids, could compete with high density lipoproteins as a substrate for phospholipid transfer protein.

Chapter 1 provides an overview of the structure, composition, metabolism and clinical significance of the plasma lipoproteins, and specifically focuses on high density lipoprotein (HDL), and its major subfractions (HDL2 and HDL3). Chapter 2 describes the development and validation of a rapid ultracentrifugation method for the isolation of HDL2 and HDL3. This facilitated the examination of HDL subfractions in a variety of contexts, and lead to the discovery of a novel pro-oxidant effect of HDL on the oxidation ofvery low density lipoprotein (VLDL). Chapter 3 explores the role which HDL subfractions may play in endothelial dysfunction, by examining their effect on human coronary artery endothelial cells. Overall, native HDLs reduced the expression of pro-inflammatory molecules; in the oxidised state, HDLs promoted the release ofpro-inflammatory molecules. Chapter 4 describes the involvement of lecithin:cholesterol acyltransferase in lipoprotein oxidation and atherosclerosis. This work identified a duplicitous effect of LCAT during oxidation ofApo B-containing lipoproteins; it acted as a pro-oxidant during VLDL oxidation, but as an antioxidant during oxidation oflow density lipoprotein (LDL). Chapter 5 reports the effect of metfonnin and pioglitazone on the composition and oxidation of HDLz and HDL3, in a group of obese and overweight men. Results demonstrated that pioglitazone exhibited a broader range of effects on HDL subfractions, particularly by increasing the HDLz-to-HDL3 ratio - a change associated with improved reverse cholesterol transport. Chapter 6 presented a clinical case study on inherited cholesterol ester transfer protein (CETP) deficiency. HDL isolated from the proband had an abnormal composition and oxidation profile. Moreover, HDLisolated from the proband had a reduced pro-oxidant effect towards VLDL, confinning the participation ofCETP in this novel reaction ofHDL. Chapter 7 provides a general discussion, and concluding remarks, for the main body of the thesis, including suggestions for future work.

Hepatic lipase (HL) plays a pivotal role in the catabolism of apolipoprotein (apo)B-containing lipoproteins and high density lipoprotein (HDL) particles through its reported catalytic and non-catalytic extracellular functions. The current study tested the hypothesis that HL expression might impair formation and secretion of hepatic derived very low density lipoproteins (VLDL) and apoA-I (nascent HDL). Stable or transient expression of human HL (hHL) in McA-RH7777 cells resulted in decreased incorporation of [3H]glycerol into cell-associated and secreted (VLDL-associated) 3H-triacylglcyerol (TAG) relative to control cells. Stable expression of catalytically-inactive hHL (hHLSG) also resulted in decreased secretion of VLDL-associated 3H-TAG whereas cell-associated 3H-TAG levels were unchanged. Expression of hHL or hHLSG increased cell-associated 35S-apoB100 with relatively no change in secreted 35S-apoB100. Importantly, hHL or hHLSG expression resulted in reduced 3H-TAG associated with the microsomal lumen lipid droplets (LLD), and increased relative expression of ApoB and genes involved in lipogenesis and fatty acyl oxidation. Transient expression of hHL in HL-null primary hepatocytes, mediated by adenoviral gene transfer, resulted in decreased steady-state levels of cell-associated and secreted apoA-I and reduced rates of synthesis and secretion of 35S-apoA-I. HL-null hepatocytes exhibited increased levels of secreted 35S-apoA-I relative to wildtype hepatocytes while cell-associated 35S-apoA-I levels were normal. Transient expression of a hHL chimera (hHLmt), in which the C-terminus of hHL was replaced with mouse HL sequences, exerted an inhibitory effect on apoA-I production similar to that of hHL even though hHLmt was secreted less effectively than hHL with impaired exit from the endoplasmic reticulum (ER) as compared with hHL. In contrast, stable expression of hHL in McA-RH7777 cells resulted in a dose-dependent increase in cell-associated and secreted 35S-apoA-I levels. These studies demonstrate that hHL has an intracellular (but non-catalytic) role in reducing the content of the LLD and ultimately the buoyancy of secreted VLDL particles, and that the N-terminal sequences of ER-residing hHL directly or indirectly modulates the production and secretion of apoA-I (nascent HDL) from hepatocytes.

Reduced high-density lipoprotein cholesterol (HDL-C) concentrations are a major risk factor for cardiovascular disease. Intense interest recently has been in identifying the genetic factors that contribute to an aberrant HDL-C phenotype. Finding genetic factors associated with low HDL-C concentrations in New Zealanders was the major aim of this study, with a similar analysis aimed at finding factors associated with high HDL-C concentrations included. The study began with an investigation of a New Zealand family with HDL-C deficiency. The proband had virtually no HDL-C, and was homozygous for an R1068H mutation in the ABCA1 gene. Nineteen relatives were recruited into the study, and an analysis aimed at finding the underlying cause for the disparate HDL-C phenotypes amongst H1068 carriers initiated. A further investigation into HDL-C levels aimed to find other genetic factors that contribute to HDL-C in New Zealanders. Subjects were selected from those taking part in the Otago Vascular Disease study, and placed into three groups based on their HDL-C lipid measurement: low (n=154), mid (n=105), and high (n=102) HDL-C. Mutations in ABCAI and the apolipoprotein AI gene (APOAI) were identified in subjects with low HDL-C. Polymorphisms in ABCA1 and APOAI were also investigated as contributors to HDL-C concentrations. Seventeen SNPs in functionally relevant regions were genotyped in the three HDL-C groups. Five single polymorphisms and one polymorphism haplotype showed a statistically significant association with HDL-C concentrations. The final analysis investigated plasma lipoprotein compositions in individuals with low HDL-C to identify if other lipoprotein abnormalities concurred. Individuals with HDL-C below 0.65 mmol/L were almost invariably associated with triglyceride-rich VLDL and/or triglyceride-rich LDL. This finding may have relevance for an increased atherosclerotic risk for those with low HDL-C.

[Truncated abstract] The metabolic syndrome is characterized by cardiovascular risk factors including dyslipidemia, insulin resistance, visceral obesity, hypertension and diabetes. The dyslipidemia of the metabolic syndrome includes elevated plasma triglyceride and apolipoprotein (apo) B levels, accumulation of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol concentration. However, the precise mechanisms for this dyslipoproteinemia, specifically low plasma HDL cholesterol, are not well understood. This thesis therefore, focuses on HDL, its structure, function and metabolism. However, lipoprotein metabolism is a complex interconnected system, which includes forward and reverse cholesterol transport pathways. Hence, this thesis also examines and discusses the metabolism of apoB-containing lipoproteins. This thesis tests the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that lipid regulating therapies can improve these kinetic abnormalities. The aims were first, to compare and establish the clinical, metabolic and kinetic differences between metabolic syndrome and lean subjects; and second, to determine the regulatory effects of statin therapy, specifically, rosuvastatin on lipoprotein transport in the metabolic syndrome. Five observation statements were derived from the general hypothesis and examined in the studies described below. The findings are presented separately as a series of original publications. Study 1 Twelve men with the metabolic syndrome and ten lean men were studied in a case-control setting. ... These findings explain the HDL raising effects of rosuvastatin in the metabolic syndrome. Collectively, these studies suggest that the dyslipidemia of the metabolic syndrome results from increased production rates of VLDL and LDL particles, reduced fractional catabolic rates of these lipoproteins, together with accelerated catabolism of HDL particles. Treatment with rosuvastatin increases the catabolic rates of all apoB-containing lipoproteins and at a higher dose, decreases LDL apoB production. These effects are consistent with inhibition of cholesterol synthesis leading to an upregulation of LDL receptors. Rosuvastatin decreases the fractional catabolism of HDL particles. The effects of rosuvastatin on HDL kinetics may be related to a reduction in triglyceride concentration and cholesterol ester transfer protein activity. These findings are consistent with the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that statin therapy improves these kinetic abnormalities.

RESUMO:Aterosclerose é uma das principais causas de morbilidade e mortalidade no mundo ocidental. É responsável, direta ou indiretamente, pela maior percentagem de gastos com a saúde na maioria dos países europeus. A “teoria lipídica” da aterosclerose, que se baseia na dislipidemia como causa primária para a doença vascular tem algumas implicações práticas importantes: permite a definição de linhas de orientação e protocolos simples e ainda estabelece alvos terapêuticos que podem ser atingidos na maior parte dos casos com a atual intervenção farmacológica. A associação da aterosclerose com o sistema imunológico (a “teoria imunológica”), forneceu por sua vez novas formas de explorar os mecanismos envolvidos e abriu novas perspetivas para um conhecimento mais completo da doença. No entanto, levanta dificuldades evidentes no que diz respeito às possibilidades terapêuticas. De todos os intervenientes no processo aterosclerótico (bioquímicos, imunológicos e anatómicos), as lipoproteínas de elevada densidade (HDL) são atualmente reconhecidas como um dos fatores mais importantes na aterogénese. Isto é baseado no reconhecimento das múltiplas propriedades anti-aterogénicas das HDL como por exemplo: a anti-oxidante, a anti-inflamatória e a antitrombótica, bem como o seu importante papel na melhoraria da função endotelial. Atualmente, é consensual que as funções anti-aterogénicas das HDL vão além do seu papel no transporte reverso do colesterol (RCT) e a importância das HDL no processo aterosclerótico baseia-se não apenas no seu papel protetor impedindo a formação da placa de ateroma, mas também na estabilização destas, prevenindo a sua ruptura e, consequentemente o evento trombótico. Como fundamentais no processo aterosclerótico estão reconhecidos dois principais conjuntos de eventos: um caracterizado por alterações no metabolismo das lipoproteínas que resultam em lipoproteínas pró-inflamatórias e pró-oxidantes que interagem com os componentes celulares da parede arterial e que conduzem à formação da placa de ateroma; o outro evento é a resposta imunológica desencadeada contra um novo conjunto de antigénios que por sua vez leva à produção de citoquinas pró-inflamatórias. Dada a complexidade da HDL e das suas múltiplas funções estas lipoproteínas tornaram-se um potencial alvo para a resposta auto-imune, e cujas consequências podem explicar algumas das associações identificados em estudos clínicos e epidemiológicos. Contudo esta interação entre o sistema imunológico e HDL nunca foi exaustivamente estudada. Portanto, pomos a hipótese de que em condições oxidativas e pró-inflamatórias, um aumento do antigénio (HDL) conduz a um consequente acréscimo na produção de anticorpos anti-HDL (aHDL) responsáveis pela alteração quantitativa e / ou qualitativa das HDL. O conceito de que estes anticorpos podem contribuir tanto para a evolução a longo prazo do processo aterosclerótico, como para o desencadeamento de eventos clínicos pode também explicar a heterogeneidade encontrada em cada doente e nos grandes estudos clínicos, no que diz respeito aos fatores de risco e outcomes clínicos. Para além disso, a confirmação desta hipótese pode permitir explicar porque é que as intervenções terapêuticas atualmente em desenvolvimento para aumentar os níveis de HDL, não conseguem mostrar a tão esperada redução do risco vascular. O objetivo geral desta tese foi identificar e caracterizar a resposta humoral contra os componentes da HDL, e avaliar possíveis mecanismos que possam contribuir para a modificação das propriedades anti-aterogénicas das HDL. Para alcançar este objetivo investigou-se: 1) A presença de anticorpos aHDL em doentes com lúpus eritematoso sistémico (SLE) e em doentes com manifestações clínicas de aterosclerose, como os doentes com doença arterial coronária (CAD), acidente vascular cerebral isquémico (IS) e diabetes tipo 2; 2) Os principais alvos antigénicos dentro do complexo das HDL e a associação entre os títulos de anticorpos aHDL e diferentes características clínicas destas doenças; 3) As modificações das funções normais associadas às HDL, em particular da função anti-oxidante e anti-inflamatória; 4) A atividade biológica dos anticorpos aHDL isolados do soro de doentes através de um conjunto de experiências in vitro de inibição da atividade da paraoxonase 1 (PON1) e da expressão de moléculas de adesão em culturas de células endoteliais. Para tal foi necessário estabelecer um método de isolamento dos anticorpos. Os anticorpos aHDL isolados do soro de doentes foram utilizados de forma a identificar as potenciais alterações dos sistemas celulares utilizados; 5) O efeito de fármacos usados no tratamento das dislipidemias, em particular o ácido nicotínico e as estatinas, na variação dos títulos de anticorpos aHDL através de ensaios clínicos randomizados, controlados com placebo e em dupla ocultação. Os métodos utilizados neste trabalho incluíram: técnicas imunológicas (como por exemplo, enzyme-linked immunoabsorbent assay - ELISA, ensaio imunoturbidimetrico e cromatografia de imuno-afinidade) técnicas bioquímicas (tais como a quantificação de atividade enzimática por espectrofotometria e por luminescência), experiências com cultura de células e citometria de fluxo. Os nossos resultados mostram que: 1) A presença de anticorpos aHDL, e mais especificamente anticorpos contra alguns do seus principais componentes como a apolipoproteína A-I (ApoA-I, principal apolipoproteína presente nas HDL) e a PON1 (o enzima que mais contribui para a propriedade anti-oxidante das HDL), quer em doentes com doenças auto-imunes, como o SLE, quer em doentes com manifestações clínicas de aterosclerose, como CAD, IS e diabetes tipo 2. Os doentes apresentaram títulos de anticorpos IgG aHDL, aApoA-I e aPON1 significativamente mais elevados do que controlos saudáveis com a mesma idade e sexo. 2) A correlação positiva estatisticamente significativa entre os títulos de aHDL e aApoA-I e aPON1 sugere que estes sejam dois dos principais alvos antigénicos dentro do complexo das HDL. Os anticorpos encontrados nestes doentes estão associados com a diminuição da atividade da PON1 e a uma redução da capacidade anti-oxidante total (TAC) do soro, um aumento dos biomarcadores de disfunção endotelial (como por exemplo dos metabolitos do óxido nítrico - NO2- e NO3-, as moléculas de adesão vascular e intracelular - VCAM-1 e ICAM-1 e os níveis de 3-nitrotirosina). Nos doentes com SLE os títulos destes estão associados a um aumento do dano cardiovascular e à atividade global da doença avaliados pelas escalas SLICC/ACR DI e BILAG score, respetivamente. Enquanto que nos doentes com diabetes tipo 2 estes anticorpos estão associados com um aumento dos níveis de glicemia em jejum (FGP) e hemoglobina glicada (HbA1c). 3) Após se ter estabelecido um método de isolamento dos anticorpos que permite isolar quantidades significativas de anticorpos do soro de doentes sem perder a sua especificidade, foi identificada a capacidade dos anticorpos isolados do soro de doentes inibirem de uma forma dependente da concentração a atividade da PON1 até um máximo de 70% no caso dos doentes com SLE e ente 7-52% no caso dos anticorpos isolados de doentes com CAD e IS. 4) O efeito anti-inflamatório das HDL na inibição da produção de VCAM-1 induzida por citoquinas (como o TNF-) foi revertido em mais de 80% pelos anticorpos aHDL isolados do soro de doentes. 5) A angiogenesis induzida por HDL através do aumento do fator de crescimento do endotélio vascular (VEGF) foi anulada em 65% pelos anticorpos aHDL isolados do soro de doentes. 6) Os atuais agentes farmacológicos disponíveis para aumentar as concentrações de HDL-C estão associados a um aumento dos títulos de anticorpos.-------- ABSTRACTAtherosclerosis is the major cause of morbidity and mortality in the western world. It is also responsible, directly or indirectly, for the highest percentage of health costs in most European countries. Despite the use of new technologies for the diagnosis of vascular disease and regardless of the major advances in treatment, the atherosclerosis-related clinical burden is still raising. The “lipid theory” of atherogenesis, which identifies dyslipidemia as the primary cause of this vascular disease has some important practical implications: it allows the definition of simple guidelines and establishes therapeutic targets which can be generally met with current pharmacologic intervention. The association between atherosclerosis an the immune system (the immune concept) has in turn provided new ways of exploring the mechanisms involved in this condition and has opened new perspectives in the understanding of the disease. However, it raises obvious difficulties when it comes to treatment options. Of all the players (biochemical, immunological and anatomical) involved in this matter, high-density lipoproteins (HDL) are currently recognised as one of the most important factors in atherogenesis. This is based on the recognition of HDL's multiple anti-atherogenic properties: anti-oxidant, anti-inflammatory and antithrombotic, as well as its capacity to improve endothelial function. Nowadays, it is widely recognized that the anti-atherogenic functions of HDL go beyond reverse cholesterol transport (RCT), and the importance of HDL is based not just on its ability to reduce atheroma formation but also on its ability to stabilise plaques, therefore preventing their rupture and ultimately thrombosis. Two main set of events have been recognised as fundamental in atherogenesis: one, characterized by lipoprotein metabolism alterations, resulting in pro-inflammatory and pro-oxidative lipoproteins, which interact with the normal cellular elements of the arterial wall leading to atheroma formation; the other, the immune cellular response towards new sets of antigens which lead to the production of pro-inflammatory cytokines. Given to HDL complexity and multiple functions this lipoprotein has became a potential target for an auto-immune response, the consequences of which may explain some of the association identified in epidemiological and clinical studies, though the interaction between the immune system and HDL has never been thoroughly addressed. Therefore, we hypothesized that under oxidative and pro-inflammatory conditions, the increase in the antigen (HDL) would lead to a consequent increase in the production of anti-HDL (aHDL) antibodies be responsible for quantitative and/or qualitative changes of HDL. The concept that these antibodies may contribute either to the long-term evolution of atherosclerosis or to the triggering of clinical events may also explain the heterogeneity found in individual patients and in large cohorts regarding risk factors and clinical outcomes. Moreover this may be a major breakthrough in understanding why therapeutic interventions that increase HDL levels, failed to show the anticipated reduction in vascular risk. The overall aims of this thesis were to identified and characterize the humoral response towards HDL components and to evaluate the possible mechanisms that may contribute to the modifications of the anti-atherogenic properties of HDL. To achieve this objective we investigated: 1) the presence of aHDL antibodies in patients with systemic lupus erythematosus (SLE) and in patients with atherosclerosis-related clinical events, such as coronary artery disease (CAD), ischemic stroke (IS) and type 2 diabetes; 2) the association between the titres of aHDL antibodies and different clinical features of these diseases; 3) the modifications of the anti-atherogenic properties of HDL; 4) the biologic effect of aHDL antibodies isolated from serum of patients on the anti-oxidant and anti-inflammatory properties of HDL; 5) the effect of different pharmacologic treatments for dyslipidemia on the prevalence and activity of aHDL antibodies. The methodologies used in this work included immunologic-related techniques (e.g. enzyme-linked immunoabsorbent assay – ELISA, immunoturbidimetric immunoassay and immunoaffinity chromatography), biochemical techniques (enzymatic assays with quantification by spectrophotometry and luminescence methods), cell culture experiments and flow cytometry. Our results indicate that: 1) The titres of IgG aHDL, anti-apolipoprotein A-I (aApoA-I) and anti-paraoxonase 1 (aPON1) antibodies were higher in patients with SLE, CAD, IS and type 2 diabetes when compared with age and sex matched healthy controls. 2) The antibodies found in these patients were associated with decreased PON1 activity, (the enzyme responsible for most of the anti-oxidant effect of HDL), reduced total anti-oxidant capacity (TAC) of serum and increased biomarkers of endothelial dysfunction (nitric oxide metabolites, adhesion molecules, nitrotyrosine). In patients with SLE the antibody titres were associated with an increase in disease-related cardiovascular damage and activity whereas in patients with type 2 diabetes they were directly related with the fasting glucose plasma (FGP) levels and the glycosylated haemoglobin (HbA1c). 3) The antibodies isolated from serum of our patients, directly inhibited HDL-associated PON1 activity in a dose dependent way ranging from 7 to 52%. 4) The anti-inflammatory effect of HDL, measured by the percentage of inhibition of the cytokine-induced production of vascular adhesion molecules (VCAM-1), was reduced in more than 80% by aHDL antibodies isolated from our patients. 5) The HDL-induced angiogenesis by increasing vascular endothelial growth factor (VEGF) levels was abrogated in 65% by the antibodies isolated from serum of patients. 6) The current available pharmacologic agents for increasing HDL-C concentrations were associated with an increase in the titres of IgG aApoA-I antibodies. This increase was higher in the extended release niacin when compared to statins probably due to their dampening effect on oxidative stress. In conclusion, aHDL antibodies are present in different pathologic conditions. aHDL antibodies represent a family of self-reacting immunoglobulins, of which ApoA-I and PON1 might be the most relevant targets. These antibodies are biologically active, interfering with the HDL anti-oxidant and anti-inflammatory properties and, consequently, with the atherosclerotic process. The pathogenic potential of these antibodies may lead to the identification of a new biomarker for vascular disease, whilst presenting itself as a novel target for a different treatment approach which may redefine the treatment strategies and clinical trials design for HDL interventions in the future.

Human Platelets possess specific binding sites for low density lipoproteins (LDL) and high density lipoproteins(HDL)(1). Binding of both classes of plasma lipoproteins, though competitive, has been shown by several groups to facilitate platelet activation.Isolated washed platelets occasionally aggregate upon addition of high concentrations of LDL even in the absence of known platelet activators. The proteins responsible for this binding have been visualized by ligand blotting (2). Both types of ligand specifically bind to two glycoproteins with molecular weights of 135 and 115 kD, respectively. The conditions of binding to these two proteins, however, markedly differ from those known for other lipoprotein receptors.Following extensive purification, these two species are still present at concentrations relative to each other that depend markedly on the conditions of purification. The purified, solubilized receptor was tested under various conditions, including in the absence and presence of calcium, after disulfide-reduction, and following chymotrypsin digestion. In parallel experiments, the same preparations were tested with respect to binding of fibrinogen, different lectins, and thealloantibody anti-PlAI . The results strongly support the assumption, that the two protein bands associated with lipoprotein binding are constituents of the GP-IIb/IIIa complex.These first results may have greatimplications for our understanding ofthe mechanism by which lipoproteins facilitate platelet stimulation.

Lipoproteins are biochemical compounds containing both proteins and lipids. These particles carry chemicals like cholesterol and triglycerides that are not soluble in aqueous solutions. This paper presents modeling of lipoprotein system using coarse grain molecular dynamics technique and stability analysis of this system in a water solution like blood. A high density lipoprotein (HDL) that consists of two annular monomers is modeled. Also there are lipid bilayers located in center of the rings, so the whole HDL and lipid bilayers are called lipoprotein system. First, all atom model is provided and then coarse-grain model is obtained using MARTINI technique. Modeling of the system in all atom and coarse-grain is performed by VMD and simulation is executed by NAMD. System is simulated for 400ns with time step of 20fs in NPT ensemble. System temperature assumed similar to normal human body temperature. Finally the structure shape and stability of system were considered and results were analyzed.

Platelet Activating Factor (l-0-alkyl-2-acetyl-sn-glycerol-3-phosphocholine; PAF) plays an important role in allergic and inflammatory reactions and activates platelets in the nanomolar range. One of the main factors that controls PAF activity in blood is an enzyme that hydrolyzes the acetyl-chain thereby converting PAF to biologically inactive lyso-PAF. The enzyme is acid labile and normally associated with apo B-containing low density lipoproteins (LDL, density 1,006-1,063 g/ml).We investigated whether a deficiency in LDL would affect the enzyme activity. PAF-inactivating activity was measured in plasma from a patient with abetalipoproteinemia, a rare autosomal recessive disorder, characterized by the absence of apo B and apo B-containing lipoproteins (chylomicrons, VLDL and LDL). Plasma triglyceride was 0,2 mmol/1 (normal 1,40-2,20 mmol/1) and cholesterol 1,3 mmol/1 (normal 5,60-7,70 mmol/1). Separation of lipoproteins by density gradient centrifugation revealed a slightly decreased HDL content whereas VLDL and LDL were below the detection limit (0,20 mmol/1; based on cholesterol content).Despite the absence of LDL, PAF-inactivating activity in plasma of the patient (measured by (1) the decrease in aggregation inducing activity of PAF after incubation, (ii) the conversion of 3H-acyl-PAF to lysa PAF, separated on TLC, (iii) the liberation of 3H-label from 3H-acetyl PAF) was present and even slightly higher than in normal plasma (hydrolysis of 3 3H-PAF after 20 minutes incubation was 78 ± 4% and 65 ± 6% in patient and normals, respectively, n = 4). Subfractionation revealed that the enzyme activity was present in fractions with densities of 1,065-1,214 g/ml, which are typical for HDL.These results indicate that PAF-acetylhydrolase, although normally present in LDL, binds to HDL in a patient with extreme LDL-deficiency.Supported by the Dutch Heart Foundation (grant 85082)

Epidemiologic studies have shown an inverse relationship between HDL and coronary artery disease. We have previously demonstrated that in vivo administration of HDL-VHDL inhibits thedevelopment of atherosclerosis in cholesterol (cho)-fed rabbits. In the present study we have analyzed whether high levels of the physiological cholesterol acceptor, homologous HDL-VHDL,could inhibit the progression of established atherosclerotic lesions. Atherosclerosis was induced by feeding rabbits a 0.5% cho-rich diet for 2 months (140g/day). At that moment, a subgroup of animal (N=4) was sacrificed and their aortas showed 30 ± 8% of aortic atherosclerotic involvement. The remaining animals, kept on the same atherogenic diet, were randomly divided in two identical groups (N=7): a control and a treated group administered with 50 mg of HDL-VHDL a week for 4 weeks. HDL-VHDL fraction wasisolated from normal rabbit plasma byultracentrifugation at a density range of 1.063-1.25g/ml. The amount of HDL-VHDL administered was determined byits protein content according to Lowry"s technique. The 50mg of HDL-VHDL, measured as protein, contained1.4mg of total cholesterol, 1.43mg oftriglycerides and 0.6mg of phospholipids. At sacrifice, the treated group showed a marked decrease on the extent of aortic by fatty streaks (20 ± 6%X ± 1SE) as compared to(36% + 6) inthe control group (p < 0.05). Similar results were obtained in aortic wall lipid accumulation (See table, results expressed as X±1SEM; rag/gr dry aorta.)In conclusion, administration of HDL-VHDL induced a marked inhibition on the progression of atherosclerosis in cholesterol-fed rabbits.

Tissue factor rapidly loses procoagulant activity when incubated with defibrmated normal plasma and calcium ions. Inhibition is apparently directed against the tissue factor-Factor VII complex (TF-EVII) and requires Factor Xa and a component(s) found in A1 (OH)3-adsorbed plasma (AP). We have developed a two stage assay for the inhibitor which involves first, the incubation of a TF-FVII complex with test material in the presence of Factor Xa, followed by the amidolytic assay of residual TF-EVII activity.Our studies have indicated that the component of AP responsible for this effect is lipoprotein. Incubation of AP with antiserum to apo-lipoprotein B (apo B) reduced the inhibitory activity by 73%, whereas antisera to antithrombin III and a2-macroglobulin had no effect. Inhibition by AP does not appear to be caused by an artefact of adsorption, since the inhibitory-capacity of AP was 59% of normal, defibrinated plasma. This correlated well with the apo B antigen in AP, which was 64% of normal. Moreover, the dose/response lines of AP and normal plasma were parallel, suggesting that the inhibitor assay is not affected by the presence of normal levels of coagulation factors.Purified lipoprotein-rich fractions prepared from AP using density gradient ultracentrifugation all contained inhibitory activity. Incubation of these fractions with anti-apo B greatly reduced the inhibition by the very low density and low density lipoprotein-rich fractions (VLDL and LDL) but had essentially no effect on the high density lipoprotein-rich fractions (HDL). Incubation of LDL with Factor Xa produced an inhibitory component which eluted together with the apo B antigen during gel filtration. Inhibition appears to require the interaction of Factor Xa with plasma lipoproteins, particularly LDL. The product of this interaction is then able to bind and inhibit the TF EVII complex. The requirement of Factor Xa in order for inhibition to be expressed is indicative of a feedback anticoagulant response which may have physiological significance.

Platelet function and serum lipoprotein levels were studied in ten patients (two males and eight females) with hypothyroidism. Platelet aggregation and ATP release were determined by Lumi-aggregometer using ADP , collagen and epinephrine as stimulants. Platelet factor 4 (PF4) and thromboxane B2 (TXB2) were determined by radioimmunoassay. High density lipoproteincholesterol (HDL-C) was determined by heparin-manga-nese method. HDL subfractions were separated by gradient gel electrophoresis (PAA 4/30). Apolipopro-teins were measured by single radial immunodiffusion. Platelet aggregation increased in those patients at stimulating by epinephrine. ATP release also increased at stimulating by epinephrine. PF4 increased at stimulating by epinephrine. TXB2 increased at stimu-lating--by ADP or epinephrine significantly (p<0.05), respectively. Platelet aggregation was not correlated with thyroid hormones or total cholesterol levels.But it had a positive correlation tendency with HDL-C or HDL2-C and a negative one with HDL3-C levels.These results suggested some relationships between platelet function and HDL metabolism in patients with hypothyroidism.

Review question / Objective: The objective of the study was to compare the mean difference and AUROC of Visceral Adiposity Index (VAI) in NAFLD/NASH/liver fibrosis patients and controls in observational studies. Condition being studied: Nonalcoholic fatty liver disease (NAFLD) is a multi-system disease, being mainly a liver pathology involving excessive hepatic fat accumulation unrelated to alcohol consumption or other secondary causes of hepatic steatosis. It is an emerging cause of concern and increasing clinical burden, imposing a public health challenge. NAFLD is the most common chronic liver disease and is predicted to be the most common indication for a liver transplant in Western countries by 2030, owing to a prevalence of 25% worldwide. The visceral adiposity index (VAI) is a scoring system based on body mass index, triglycerides, high-density lipoproteins (HDLs), and waist circumferences (WCs).

Review question / Objective: Population：Patients diagnosed as obesity with insulin resistance. Obesity reference: Consensus of experts on the Prevention and treatment of adult obesity in China in 2011 and Consensus of Chinese experts on medical nutrition therapy for overweight/obesity in 2016 were developed by the Obesity Group of Chinese Society of Endocrinology(CSE); BMI≥28. IR reference: According to the Expert opinions on insulin resistance evaluation published by Chinese Diabetes Society, HOMA-IR≥2.68 is regarded as the standard for the diagnosis of IR. Regardless of age, gender and course of disease. Patients diagnosed as obesity with insulin resistance. Intervention：Any kind of acupuncture, moxibustion, acupuncture+moxibustion, warm acupuncture, electropuncture, auricular point, acupoint application and acupoint catgut embedding. Comparison：Other acupuncture treatments, Drug therapy or blank control. Outcome：Primary outcomes: ①Fasting blood-glucose (FBG); ②Fasting serum insulin (FINS); ③Homeostasis model assessment-IR (HOMA-IR); ④Body Mass Index (BMI). Secondary outcomes: ①Waistline; ②Waist-hip ratio;③Triglyceride (TG); ④Total cholesterol (TC); ⑤High-density lipoprotein (HDL); ⑥Low-density lipoprotein (LDL). Study: Randomized controlled trials (RCTs) of different acupuncture methods in the treatment on obesity with insulin resistance, blind method and language are not limited. Randomized controlled trials (RCTs).