High-density Lipoprotein Quantity Research Articles

S1P content as a characteristic of the cardioprotective properties of HDL in coronary heart disease and diabetes mellitus

Abstract Background Many basic science studies have demonstrated the cardioprotective effect of high-density lipoprotein (HDL). At the same time, several clinical studies in which plasma levels of HDL were pharmacologically increased showed no benefit in cardiovascular risk patients. Accordingly, HDL quantity seems to be less important than HDL quality. Many beneficial effects of HDL are attributed to the bioactive sphingolipid S1P in HDL (HDL-S1P). Purpose In this study, we are now investigating a) the cardioprotective properties of HDL of different patient groups and b) the possibility of loading S1P to restore cardioprotection that may be lacking. Methods HDL was extracted from plasma of diabetic (dmHDL), as well as CHD patients (CHD-HDL) and healthy subjects (healthy HDL) of the same age by ultracentrifugation and injected i.v. into the mouse five minutes before 30 minutes of ischemia (43 mg/KG). This was followed by 24 hours of reperfusion. Systolic cardiac function was determined by ultrasound, infarct size by TTC (2,3,5-triphenyltetrazolium chloride) staining, and S1P levels by mass spectrometry. The level of apolipoprotein M in HDL was determined by ELISA. Results Mice treated with healthy HDL showed smaller infarct size and improved ejection fraction (EF) after I/R than control mice (IS: control 42.95±7.40% [n=26] vs. healthy HDL 33.15±4.68% [n=16], p=0.0001; EF: control 33.68±4.49% vs. healthy HDL 40.00±5.74%, p=0.0016). Treatment with CHD-HDL or dmHDL showed no cardioprotective effects compared to control mice (IS: CHD-HDL 42.22±6.53% [n=16], p=0.9863; dmHDL 43.67±7.81% [n=12], p=0.9899). In both cases, the lack of cardioprotection is associated with lowered HDL-S1P levels (total HDL 210.6±32.6 pmol/mg; CHD-HDL 157.6±49.0 pmol/mg, p=0.0073; dmHDL 171.1±64.7 pmol/mg, p=0.0176). Loading the "sick" HDL with S1P restores cardioprotection only in CHD-HDL (IS: CHD-HDL 42.22±6.53% [n=16] vs. CHD-HDL loaded 32.03±6.45% [n=10], p=0.0023), but not in dmHDL (IS: dmHDL 43.67±7.81% [n=12] vs. dmHDL loaded 38.44±5.98% [n=7], p=0.5110). The very low level of apolipoprotein M (ApoM), responsible for S1P binding, could be a reason for this (total HDL 23.45±6.23 µg/mg [n=15] vs. dmHDL 13.79±4.72 µg/mg [n=14], p=0.0007). Conclusion We highlighted worsened cardioprotection as another characteristic of HDL dysfunction in CHD and in diabetes. This characteristic was based on a lower HDL-S1P content and could be therapeutically corrected by loading S1P in the case of CHD-HDL. A low content of ApoM in dmHDL may prevent successful restoration of cardioprotection by S1P loading.

Enhancement of High-Density Lipoprotein (HDL) Quantity and Quality by Regular and Habitual Exercise in Middle-Aged Women with Improvements in Lipid and Apolipoprotein Profiles: Larger Particle Size and Higher Antioxidant Ability of HDL.

Regular exercise, especially aerobic exercise, is beneficial for increasing serum high-density lipoprotein-cholesterol (HDL-C) levels in the general population. In addition to the HDL-C quantity, exercise enhances HDL functionality, antioxidants, and cholesterol efflux. On the other hand, the optimal intensity and frequency of exercise to increase HDL quantity and enhance HDL quality in middle-aged women need to be determined. The current study was designed to compare the changes in HDL quantity and quality among middle-aged women depending on exercise intensity, frequency, and duration; participants were divided into a sedentary group (group 1), a middle-intensity group (group 2), and a high-intensity group (group 3). There were no differences in anthropometric parameters among the groups, including blood pressure, muscle mass, and handgrip strength. Although there was no difference in serum total cholesterol (TC) among the groups, the serum HDL-C and apolipoprotein (apo)A-I levels remarkably increased to 17% and 12%, respectively, in group 3. Serum low-density lipoprotein-cholesterol (LDL-C), glucose, triglyceride, and the apo-B/apoA-I ratio were remarkably decreased in the exercise groups depending on the exercise intensity; group 3 showed 13%, 10%, and 45% lower LDL-C, glucose, and triglyceride (TG), respectively, than group 1. The hepatic and muscle damage parameter, aspartate aminotransferase (AST), was significantly decreased in the exercise groups, but high-sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GTP) were similar in the three groups. In LDL, the particle size was increased 1.5-fold (p < 0.001), and the oxidation extent was decreased by 40% with a 23% lower TG content in group 3 than in group 1. In the exercise groups (groups 2 and 3), LDL showed the slowest electromobility with a distinct band intensity compared to the sedentary group (group 1). In HDL2, the particle size was 2.1-fold increased (p < 0.001) in the exercise group (group 3) with a 1.5-fold increase in TC content compared to that in group 1, as well as significantly enhanced antioxidant abilities, paraoxonase (PON) activity, and ferric ion reduction ability (FRA). In HDL3, the particle size was increased 1.2-fold with a 45% reduction in TG in group 3 compared to group 1. With increasing exercise intensity, apoA-I expression was increased in HDL2 and HDL3, and PON activity and FRA were enhanced (p < 0.001). In conclusion, regular exercise in middle-aged women is associated with the elevation of serum HDL-C and apoA-I with the enhancement of HDL quality and functionality and an increase in the TC content, particle size, and antioxidant abilities. With the reduction in TG and oxidized products in LDL and HDL, lipoproteins could have more anti-atherogenic properties through regular exercise in an intensity-dependent manner.

Changing Perspectives on HDL: From Simple Quantity Measurements to Functional Quality Assessment.

High-density lipoprotein (HDL) comprises a heterogeneous group of particles differing in size, density, and composition. HDL cholesterol (HDL-C) levels have long been suggested to indicate cardiovascular risk, inferred from multiple epidemiological studies. The failure of HDL-C targeted interventions and genetic studies has raised doubts on the atheroprotective role of HDL-C. The current consensus is that HDL-C is neither a biomarker nor a causative agent of cardiovascular disorders. With better understanding of the complex nature of HDL which comprises a large number of proteins and lipids with unique functions, recent focus has shifted from HDL quantity to HDL quality in terms of atheroprotective functions. The current research is focused on developing laboratory assays to assess HDL functions for cardiovascular risk prediction. Also, HDL mimetics designed based on the key determinants of HDL functions are being investigated to modify cardiovascular risk. Improving HDL functions by altering its composition is the key area of future research in HDL biology to reduce cardiovascular risk.

Understanding the Role of HDL during COVID-19 Infection

Background: Recently emerged COVID-19 pandemic has caused a large number of deaths with lacs of confirmed cases worldwide posturing a grim situation and severe threat to public health. There is an imperative necessity of analyzing emerging clinical and laboratory data of COVID-19 patients, which may contribute to elucidate the pathogenic mechanism and development of effective prevention and treatment countermeasures. Methods: Under this article, the emerging role of High-Density Lipoprotein (HDL) was analyzed by collecting recently published articles related to this field having clinical data of COVID-19 patients. Results: Based on the recently published reports of laboratory-confirmed COVID-19 infected hospitalized patients it was consistently observed that levels of HDL were low at the time of admission to hospital and remained relatively low during the disease course i.e., treatment, recovery, and discharge stage. It was also reported critically that levels of HDL in the patients, those did not survive, decreased continuously until death. Conclusion: These clinical reports of patients have risen the concern about probable infection and worsen the clinical outcome of a healthy person having a compromised level of HDL for COVID-19 infection. Eventually, these findings stated that there is a strong association of low HDL levels with a higher risk of COVID-19 infection and further severity of the illness. Proper attention is needed to understand the significance of altered quantity and quality of HDL in COVID-19 patients compared to healthy controls, so that appropriate therapies could be given at the right time to combat severity and mortality due to this infection.

HDL Cholesterol Efflux Capacity is Impaired in Severe Short-Term Hypothyroidism Despite Increased HDL Cholesterol.

Severe hypothyroidism has profound effects on lipoprotein metabolism including high-density lipoprotein (HDL) cholesterol elevations but effects on HDL function metrics are unknown. To determine the impact of severe short-term hypothyroidism on HDL particle characteristics, HDL cholesterol efflux capacity (CEC), and HDL antioxidative capacity. Observational study with variables measured during severe short-term hypothyroidism (median TSH 81 mU/L) and after 20 weeks of thyroid hormone supplementation (median TSH 0.03 mU/L) (Netherlands Trial Registry ID 7228). University hospital setting in The Netherlands. Seventeen patients who had undergone a total thyroidectomy for differentiated thyroid carcinoma. HDL particle characteristics (nuclear magnetic resonance spectrometry), CEC (human THP-1-derived macrophage foam cells and apolipoprotein B-depleted plasma), and HDL anti-oxidative capacity (inhibition of low-density lipoprotein oxidation). During hypothyroidism plasma total cholesterol, HDL cholesterol and apolipoprotein A-I were increased (P ≤ 0.001). HDL particle concentration was unchanged, but there was a shift in HDL subclasses toward larger HDL particles (P < 0.001). CEC was decreased (P = 0.035), also when corrected for HDL cholesterol (P < 0.001) or HDL particle concentration (P = 0.011). HDL antioxidative capacity did not change. During severe short-term hypothyroidism CEC, an important antiatherogenic metric of HDL function, is impaired. HDL cholesterol and larger HDL particles are increased but HDL particle concentration is unchanged. Combined, these findings suggest that HDL quality and quantity are not improved, reflecting dysfunctional HDL in hypothyroidism.

Cholesterol Efflux Gene Expression In Peripheral Blood Mononuclear Cells Following High Intensity Interval Exercise

Reverse cholesterol transport (RCT) is critical to the regulation of blood cholesterol levels and prevention of macrophage foam cell formation. A critical step in RCT is the efflux of cholesterol from macrophages to high-density lipoprotein (HDL). Numerous studies have shown exercise to regulate HDL quantity and function, but little is known about how exercise affects the expression of cholesterol efflux genes in circulating monocytes. PURPOSE: To determine changes in mRNA expression of cholesterol efflux genes (ATP-Binding Cassette A1, ABCA1; ATP Binding Cassette G1, ABCG1; mitochondrial sterol 27-hydroxylase, CYP27A1) in peripheral blood mononuclear cells (PBMCs) following a single bout of high intensity interval exercise. METHODS: Six (Female = 4, Male = 2) healthy participants (Age = 25 ± 6 yr, BMI = 26.1 ± 4.1 kg/m2, VO2peak = 36.4 ± 7.4 ml x kg x min-1) completed a single bout (work load = 300 kcal) of high intensity interval exercise (repeated intervals of 3 min @ 55% VO2peak + 1 min @ 110% VO2peak). RNA was isolated from PBMCs from whole blood prior to (PRE), immediately following (POST), two hours following (POST-2) and 24 hours following (POST-24) exercise. Expression levels of ABCA1, ABCG1, and CYP27A1 were analyzed via RT-qPCR. Gene expression fold changes, in comparison to PRE, were determined via the delta-delta Ct method and analyzed via Student T-Tests. Significance was set a priori as alpha = 0.01 to correct for multiple testing. RESULTS: Exercise did not significantly modify ABCA1 (Fold Change = 0.8 ± 0.5 (POST), 0.9 ± 0.7 (POST-2), and 1.3 ± 1.1 (POST-24)) at any time point following exercise. ABCG1 expression was elevated POST (1.6 ± 0.9; p < 0.001), POST-2 (1.4 ± 0.8; p = 0.01), and POST-24 (1.5 ± 0.5, p = 0.001) following exercise. CYP27A1 expression was unaltered by exercise at all time points (0.8 ± 0.2, 1.4 ± 1.2, 1.5 ± 2.3; all p > 0.01). CONCLUSION: ABCG1 plays a significant role in maintaining cellular cholesterol levels through the efflux of cholesterol from the intracellular compartment to HDL. Our results show elevations in PBMC ABCG1 expression following a single bout of high intensity interval exercise. Along with improved lipid profiles (e.g. increased HDL concentrations), exercise may promote increased cholesterol efflux from monocytes and macrophages by upregulation of cholesterol efflux genes.

High-Density Lipoprotein (HDL) Triglyceride and Oxidized HDL: New Lipid Biomarkers of Lipoprotein-Related Atherosclerotic Cardiovascular Disease.

Lipid markers are well-established predictors of vascular disease. The most frequently measured lipid markers are total cholesterol, high-density lipoprotein (HDL)-cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglyceride. HDL reduces atherosclerosis by multiple mechanisms, leading to a reduced risk of cardiovascular disease, and HDL-C, as a metric of HDL quantity, is inversely associated with cardiovascular disease, independent of LDL-C. However, the quality of the HDL appears to be more important than its quantity, because HDL loses its antiatherogenic functions due to changes in its composition and becomes “dysfunctional HDL”. Although there is evidence of the existence of “dysfunctional HDL”, biomarkers for monitoring dysfunctional HDL in clinical practice have not yet been established. In this review, we propose a new lipid panel for the assessment of dysfunctional HDL and lipoprotein-related atherosclerotic cardiovascular disease. The lipid panel includes the measurement of lipid peroxide and triglyceride contents within HDL particles.

Unravelling HDL-Looking beyond the Cholesterol Surface to the Quality Within.

High-density lipoprotein (HDL) particles have experienced a turbulent decade of falling from grace with widespread demotion from the most-sought-after therapeutic target to reverse cardiovascular disease (CVD), to mere biomarker status. HDL is slowly emerging from these dark times due to the HDL flux hypothesis wherein measures of HDL cholesterol efflux capacity (CEC) are better predictors of reduced CVD risk than static HDL-cholesterol (HDL-C) levels. HDL particles are emulsions of metabolites, lipids, protein, and microRNA (miR) built on the backbone of Apolipoprotein A1 (ApoA1) that are growing in their complexity due to the higher sensitivity of the respective “omic” technologies. Our understanding of particle composition has increased dramatically within this era and has exposed how our understanding of these particles to date has been oversimplified. Elucidation of the HDL proteome coupled with the identification of specific miRs on HDL have highlighted the “hormonal” characteristics of HDL in that it carries and delivers messages systemically. HDL can dock to most peripheral cells via its receptors, including SR-B1, ABCA1, and ABCG1, which may be a critical step for facilitating HDL-to-cell communication. The composition of HDL particles is, in turn, altered in numerous disease states including diabetes, auto-immune disease, and CVD. The consequence of changes in composition, however, on subsequent biological activities of HDL is currently poorly understood and this is an important avenue for the field to explore in the future. Improving HDL particle quality as opposed to HDL quantity may, in turn, prove a more beneficial investment to reduce CVD risk.

Impact of a one-year lifestyle modification program on cholesterol efflux capacities in men with abdominal obesity and dyslipidemia.

Cholesterol efflux capacities (CECs) are negatively associated with cardiovascular disease risk, irrespective of plasma high-density lipoprotein (HDL) cholesterol levels. Whether interventions targeting lifestyle improve HDL-CECs is unknown. Our objective was to determine whether improving dietary quality and increasing physical activity levels improves HDL-CECs in men with abdominal obesity and dyslipidemia. Our study sample included men (48 ± 8.5 yr) with an elevated waist circumference (≥90 cm) associated with dyslipidemia (triglycerides ≥1.69 and/or HDL cholesterol <1.03 mmol/l); 113 men completed a 1-yr intervention, consisting of a healthy eating and physical activity/exercise program, and 32 were included in a control group. An oral lipid tolerance test (OLTT) was performed in a subsample of 28 men who completed the intervention, and blood was collected every 2 h for 8 h. HDL-CECs were measured using [3H]cholesterol-labeled J774 macrophages and HepG2 hepatocytes. The lifestyle modification program led to an overall improvement in the cardiometabolic risk profile, increases in J774-HDL-CEC by 14.1% (+0.88 ± 1.09%, P < 0.0001), HepG2-HDL-CEC by 3.4% (+0.17 ± 0.75%, P = 0.01), and HDL cholesterol and apolipoprotein A-1 levels (13.5%, P < 0.0001 and 14.9%, P < 0.0001, respectively). J774-HDL-CECs and HepG2-HDL-CECs did not change in the control group. The best predictor for changes in HDL-CEC was apolipoprotein A-1 level. The lifestyle modification program also improved HDL-CEC response in postprandial lipemia during an OLTT. HDL-CEC did not change during the OLTT. Our results suggest that increasing physical activity levels and improving diet quality can have a positive impact on both HDL quantity and quality in men with abdominal obesity and dyslipidemia.

Temporary sequestration of cholesterol and phosphatidylcholine within extracellular domains of ABCA1 during nascent HDL generation

The quality and quantity of high-density lipoprotein (HDL) in blood plasma are important for preventing coronary artery disease. ATP-binding cassette protein A1 (ABCA1) and apolipoprotein A-I (apoA-I) play essential roles in nascent HDL formation, but controversy persists regarding the mechanism by which nascent HDL is generated. In the “direct loading model”, apoA-I acquires lipids directly from ABCA1 while it is bound to the transporter. By contrast, in the “indirect model”, apoA-I acquires lipids from the specific membrane domains created by ABCA1. In this study, we found that trypsin treatment causes rapid release of phosphatidylcholine (PC) and cholesterol from BHK/ABCA1 cells, and that the time course of lipid release coincides with those of trypsin digestion of extracellular domains (ECDs) of surface ABCA1 and of release of ECD fragments into the medium. This trypsin-dependent lipid release was dependent on ABCA1 ATPase activity, and did not occur in cells that express ABCG1, which exports lipids like ABCA1 but does not have large ECDs. These results suggest that the trypsin-sensitive sites on the cell surface are the large ECDs of ABCA1, and that lipids transported by ABCA1 are temporarily sequestered within the ECDs during nascent HDL formation.

Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).

Recent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol. HDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD. Cholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r= 0.39, 0.48, and 0.39 respectively; P<0.001). Baseline HDL particle number was inversely associated with incident CVD (adjusted odds ratio per SD increment [OR/SD], 0.69; 95% confidence interval [CI], 0.56-0.86; P<0.001), whereas no significant association was found for baseline cholesterol efflux capacity (OR/SD, 0.89; 95% CI, 0.72-1.10; P=0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66-1.02; P=0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67-1.03; P=0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average percentage change -1.5%, 95% CI, -13.3 to +10.2; P=0.80), but increased HDL cholesterol (+7.7%), apolipoprotein A-I (+4.3%), and HDL particle number (+5.2%). On-statin cholesterol efflux capacity was inversely associated with incident CVD (OR/SD, 0.62; 95% CI, 0.42-0.92; P=0.02), although HDL particle number again emerged as the strongest predictor (OR/SD, 0.51; 95% CI, 0.33-0.77; P<0.001). In JUPITER, cholesterol efflux capacity was associated with incident CVD in individuals on potent statin therapy but not at baseline. For both baseline and on-statin analyses, HDL particle number was the strongest of 4 HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Increased Antioxidant Quality Versus Lower Quantity of High Density Lipoprotein in Benign Prostatic Hyperplasia.

SummaryBackgroundOxidative stress may be involved in the pathogenesis of every human disease. To understand its possible role in benign prostatic hyperplasia (BPH), we measured the overall oxidative status of patients with BPH and the serum activity of the high density lipoprotein (HDL)-related antioxidant enzymes paraoxonase 1 (PON1) and arylesterase (ARE).MethodsFifty-six urology outpatient clinic patients with BPH (mean age 64±8.6 years) were prospectively included in the study. Forty volunteer healthy controls from the laboratory staff (mean age 62±10 years) were enrolled for comparison. Serum total antioxidant status (TAS), total oxidant status (TOS), PON1, ARE, and HDL levels were measured by commercially available, ready-to-use kits.ResultsSerum TAS and HDL levels were significantly lower in the BPH group than in the control group (P=0.004 and P=0.02, respectively). No significant between-group differences were observed for TOS levels or PON1 and ARE enzyme activities (P=0.30, P=0.89, and P=0.74, respectively). In the BPH group, the calculated parameters PON1/HDL and ARE/HDL were significantly higher (P=0.02 and P=0.04, respectively).ConclusionsOur findings agree with the previous reports of impaired oxidant/antioxidant balance in BPH patients. The activities of HDL-related enzymes between groups with significantly different HDL levels may be deceptive; adjusted values may help to reach more accurate conclusions.

Current Treatment of Dyslipidemia: Evolving Roles of Non-Statin and Newer Drugs.

Since their introduction, statin (HMG-CoA reductase inhibitor) drugs have advanced the practice of cardiology to unparalleled levels. Even so, coronary heart disease (CHD) still remains the leading cause of death in developed countries, and is predicted to soon dominate the causes of global mortality and disability as well. The currently available non-statin drugs have had limited success in reversing the burden of heart disease, but new information suggests they have roles in sizeable subpopulations of those affected. In this review, the status of approved non-statin drugs and the significant potential of newer drugs are discussed. Several different ways to raise plasma high-density lipoprotein (HDL) cholesterol (HDL-C) levels have been proposed, but disappointments are now in large part attributed to a preoccupation with HDL quantity, rather than quality, which is more important in cardiovascular (CV) protection. Niacin, an old drug with many antiatherogenic properties, was re-evaluated in two imperfect randomized controlled trials (RCTs), and failed to demonstrate clear effectiveness or safety. Fibrates, also with an attractive antiatherosclerotic profile and classically used for hypertriglyceridemia, lacks evidence-based proof of efficacy, save for a subgroup of diabetic patients with atherogenic dyslipidemia. Omega-3 fatty acids fall into this category as well, even with an impressive epidemiological evidence base. Omega-3 research has been plagued with methodological difficulties yielding tepid, uncertain, and conflicting results; well-designed studies over longer periods of time are needed. Addition of ezetimibe to statin therapy has now been shown to decrease levels of low-density lipoprotein (LDL) cholesterol (LDL-C), accompanied by a modest decrease in the number of CV events, though without any improvement in CV mortality. Importantly, the latest data provide crucial evidence that LDL lowering is central to the management of CV disease. Of drugs that inhibit cholesteryl ester transfer protein (CETP) tested thus far, two have failed and two remain under investigation and may yet prove to be valuable therapeutic agents. Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, now in phase III trials, lower LDL-C by over 50% and are most promising. These drugs offer new ability to lower LDL-C in patients in whom statin drug use is, for one reason or another, limited or insufficient. Mipomersen and lomitapide have been approved for use in patients with familial hypercholesterolemia, a more common disease than appreciated. Anti-inflammatory drugs are finally receiving due attention in trials to elucidate potential clinical usefulness. All told, even though statins remain the standard of care, non-statin drugs are poised to assume a new, vital role in managing dyslipidemia.

High-density lipoprotein: structural and functional changes under uremic conditions and the therapeutic consequences.

High-density lipoprotein (HDL) has attracted interest as a therapeutic target in cardiovascular diseases in recent years. Although many functional mechanisms of the vascular protective effects of HDL have been identified, increasing the HDL plasma level has not been successful in all patient cohorts with increased cardiovascular risk. The composition of the HDL particle is very complex and includes diverse lipids and proteins that can be modified in disease conditions. In patients with chronic kidney disease (CKD), the accumulation of uremic toxins, high oxidative stress, and chronic micro-inflammatory conditions contribute to changes in the HDL composition and may also account for protein/lipid modifications. These conditions are associated with a decreased protective function of HDL. Therefore, the HDL quantity and the functional quality of the particle must be considered. This review summarizes the current knowledge of dyslipidemia in CKD patients, the effects of lipid-modulating therapy, and the structural modifications of HDL that are associated with dysfunction.

Decreased basal activity of HDL associated enzyme: Paraoxonase (PON) during uncompensated oxidative stress among type 2 diabetes mellitus patients

The inverse relationship between serum levels of High Density Lipoprotein (HDL) and the development of Cardio Vascular Disease (CVD) risk among diabetic patients was known for several decades. Besides the decreasing quantity of HDL, the qualitative functions of HDL are adversely affected during uncompensated oxidative stress among diabetics and leads to implication of several complications such as dyslipidemia, lipid peroxidation, endothelial dysfunction and atherosclerosis. Therefore we have undertaken this study to determine anti-atherogenic property of HDL by measuring it's one of the associated enzymes; paraoxonase (PON) among type 2 diabetes patients, along with the serum activity of superoxide dismutase (SOD) as an index of antioxidant status and lipid peroxidation end product, i.e malondialdehyde (MDA) as a marker for oxidative stress. This study included a total of 56 untreated type 2 diabetic patients and 29 healthy volunteers as controls. FBS, PPBS, HbA1C and fasting lipid profile were measured in both the study groups. Activity of basal PON, SOD and plasma MDA levels was determined in both the study groups according to standard clinical laboratory procedures. All the diabetic patients were under poor glycemic control. Serum levels of HDL between the two study groups are not significantly differed. But, serum basal PON and SOD activity were significantly decreased, whereas MDA levels were highly elevated (284 ± 59 nM/mL/min, 111 ± 35 μmol/L, 10.38 ± 4.17 IU/mL respectively) when compared with healthy controls (371 ± 46 nM/mL/min, 63 ± 12 μmol/L, 16.91 ± 2.89 IU/mL respectively). Although there is no significant reduction in concentrations of HDL in diabetics when compared with controls, but there was a significant decrease in anti-atherogenic property i.e. activity of paraoxonase enzyme. Moreover the serum activity of paraoxonase was significant and negatively correlated with MDA levels (r = - 0.53, P < 0.001) as well as with FBS (r = - 0.30, P < 0.05). Therefore the qualitative functions of HDL are significantly affected by hyperglycemia induced oxidative stress. Hence, we concluded that the quality of HDL is most important in order to determine oxidative stress related complications in diabetes mellitus than its concentration.

Macrophage-independent regulation of reverse cholesterol transport by liver X receptors.

The ability of high-density lipoprotein (HDL) particles to accept cholesterol from peripheral cells, such as lipid-laden macrophages, and to transport cholesterol to the liver for catabolism and excretion in a process termed reverse cholesterol transport (RCT) is thought to underlie the beneficial cardiovascular effects of elevated HDL. The liver X receptors (LXRs; LXRα and LXRβ) regulate RCT by controlling the efflux of cholesterol from macrophages to HDL and the excretion, catabolism, and absorption of cholesterol in the liver and intestine. Importantly, treatment with LXR agonists increases RCT and decreases atherosclerosis in animal models. Nevertheless, LXRs are expressed in multiple tissues involved in RCT, and their tissue-specific contributions to RCT are still not well defined. Using tissue-specific LXR deletions together with in vitro and in vivo assays of cholesterol efflux and fecal cholesterol excretion, we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonist-stimulated RCT. In contrast, the ability of LXR agonists primarily acting in the intestine to increase HDL mass and HDL function seems to underlie the ability of LXR agonists to stimulate RCT in vivo. We demonstrate that activation of LXR in macrophages makes little or no contribution to LXR agonist-stimulated RCT. Unexpectedly, our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated by macrophage activity but is primarily determined by the quantity and functional activity of HDL.

Effects of cigarette smoking on HDL quantity and function: Implications for atherosclerosis

Cigarette smoking has been identified as an independent and preventable risk factor for atherosclerosis and cardiovascular disease. Population studies have shown that plasma high density lipoprotein (HDL) cholesterol levels are inversely related to the risk of developing cardiovascular disease. Cigarette smoking is associated with reduced HDL cholesterol levels. Cigarette smoking can alter the critical enzymes of lipid transport, lowering lecithin: cholesterol acyltransferase (LCAT) activity and altering cholesterol ester transfer protein (CETP) and hepatic lipase activity, which attributes to its impact on HDL metabolism and HDL subfractions distribution. In addition, HDL is susceptible to oxidative modifications by cigarette smoking, which makes HDL become dysfunctional and lose its atheroprotective properties in smokers. Therefore, cigarette smoking has a negative impact on both HDL quantity and function, which can explain, in part, the increased risk of cardiovascular disease in smokers.

Importance of high-density lipoprotein quality: evidence from chronic kidney disease.

This review will examine advances in our understanding of the association between high-density lipoprotein (HDL) function and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Large randomized statin trials and related meta-analyses confirm that lipid-lowering therapy benefits patients with mild to moderate CKD, leaving a degree of residual cardiovascular risk similar to that documented in the general population. However, patients with advanced CKD on dialysis show little to no cardiovascular benefits from lipid-lowering therapy and have an exaggerated residual cardiovascular risk. HDL quantity and functionality may explain some of the residual risk. CKD modulates the level, composition and functionality of HDL, including impaired cholesterol acceptor function and pro-inflammatory effects. Although these abnormalities prevail in CKD, they do not track together and thus support the idea of separate and distinct mechanistic pathways for each of these critical functions of HDL. CKD-induced perturbations in HDL composition, metabolism and functionality may contribute to the excess CVD in patients with CKD and present new therapeutic targets for intervention in this population.

Next stop for HDL: the lung

Next stop for <scp>HDL</scp>: the lung

The versatility of HDL: a crucial anti‐inflammatory regulator

Low levels of plasma high-density lipoprotein (HDL) represent a major cardiovascular risk factor and therefore raising HDL has been proposed to positively affect patients with atherosclerotic heart disease. However, the current evidence that raising HDL per se will reduce atherosclerosis and thereby cardiovascular events still remains controversial. In this review, we discuss the diverse anti-atherogenic and anti-inflammatory properties of HDL in the light of recent findings indicating that the quality rather than the mere quantity of HDL determines its beneficial effects against atherosclerosis. More specifically, we will focus on the conspicuous anti-inflammatory properties of HDL as this might contribute to the overall beneficial effects of HDL in diseased patients such as modulation of costimulatory/adhesion molecule expression, cytokine production and inhibition of the prototypical proinflammatory transcription factor NF-κB. A range of clinical disorders share permanent inflammation as a characteristic hallmark including coronary artery disease, chronic kidney disease, diabetes mellitus or rheumatoid arthritis and also display distinct qualitative changes in the HDL compartment. Loss of anti-inflammatory functions of HDL is emerging as an important risk factor for disease progression and survival in these clinical entities. It will be important to define the anti-inflammatory effects of HDL at the molecular level and to dissect the manifold functional implications to develop both novel functional assays that enable meaningful outcome studies and foster new therapeutic concepts in patients with altered HDL function.