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Policosanols from various sources, such as sugar cane, rice bran, and insects, have been marketed to prevent dyslipidemia, diabetes, and hypertension by increasing the blood high-density lipoproteins cholesterol (HDL-C) levels. On the other hand, there has been no study on how each policosanol influences the quality of HDL particles and their functionality. Reconstituted high-density lipoproteins (rHDLs) with apolipoprotein (apo) A-I and each policosanol were synthesized using the sodium cholate dialysis method to compare the policosanols in lipoprotein metabolism. Each rHDL was compared regarding the particle size and shape, antioxidant activity, and anti-inflammatory activity in vitro and in zebrafish embryos. This study compared four policosanols including one policosanol from Cuba (Raydel® policosanol) and three policosanols from China (Xi’an Natural sugar cane, Xi’an Realin sugar cane, and Shaanxi rice bran). The synthesis of rHDLs with various policosanols (PCO) from Cuba or China using a molar ratio of 95:5:1:1 with palmitoyloleoyl phosphatidylcholine (POPC): free cholesterol (FC): apoA-I:PCO (wt:wt) showed that rHDL containing Cuban policosanol (rHDL-1) showed the largest particle size and the most distinct particle shape. The rHDL-1 showed a 23% larger particle diameter and increased apoA-I molecular weight with a 1.9 nm blue shift of the maximum wavelength fluorescence than rHDL alone (rHDL-0). Other rHDLs containing Chinese policosanols (rHDL-2, rHDL-3, and rHDL-4) showed similar particle sizes with an rHDL-0 and 1.1–1.3 nm blue shift of wavelength maximum fluorescence (WMF). Among all rHDLs, the rHDL-1 showed the strongest antioxidant ability to inhibit cupric ion-mediated LDL oxidation. The rHDL-1-treated LDL showed the most distinct band intensity and particle morphology compared with the other rHDLs. The rHDL-1 also exerted the highest anti-glycation activity to inhibit the fructose-mediated glycation of human HDL2 with the protection of apoA-I from proteolytic degradation. At the same time, other rHDLs showed a loss of anti-glycation activity with severe degradation. A microinjection of each rHDL alone showed that rHDL-1 had the highest survivability of approximately 85 ± 3%, with the fastest developmental speed and morphology. In contrast, rHDL-3 showed the lowest survivability, around 71 ± 5%, with the slowest developmental speed. A microinjection of carboxymethyllysine (CML), a pro-inflammatory advanced glycated end product, into zebrafish embryos resulted in severe embryo death of approximately 30 ± 3% and developmental defects with the slowest developmental speed. On the other hand, the phosphate buffered saline (PBS)-injected embryo showed 83 ± 3% survivability. A co-injection of CML and each rHDL into adult zebrafish showed that rHDL-1 (Cuban policosanol) induced the highest survivability, around 85 ± 3%, while rHDL-0 showed 67 ± 7% survivability. In addition, rHDL-2, rHDL-3, and rHDL-4 showed 67 ± 5%, 62 ± 37, and 71 ± 6% survivability, respectively, with a slower developmental speed and morphology. In conclusion, Cuban policosanol showed the strongest ability to form rHDLs with the most distinct morphology and the largest size. The rHDL-containing Cuban policosanol (rHDL-1) showed the strongest antioxidant ability against LDL oxidation, anti-glycation activity to protect apoA-I from degradation, and the highest anti-inflammatory activity to protect embryo death under the presence of CML.

Reconstituted high-density lipoproteins (rHDLs) can transport and specifically release drugs and imaging agents, mediated by the Scavenger Receptor Type B1 (SR-B1) present in a wide variety of tumor cells, providing convenient platforms for developing theranostic systems. Usually, phospholipids or Apo-A1 lipoproteins on the particle surfaces are the motifs used to conjugate molecules for the multifunctional purposes of the rHDL nanoparticles. Cholesterol has been less addressed as a region to bind molecules or functional groups to the rHDL surface. To maximize the efficacy and improve the radiolabeling of rHDL theranostic systems, we synthesized compounds with bifunctional agents covalently linked to cholesterol. This strategy means that the radionuclide was bound to the surface, while the therapeutic agent was encapsulated in the lipophilic core. In this research, HYNIC-S-(CH2)3-S-Cholesterol and DOTA-benzene-p-SC-NH-(CH2)2-NH-Cholesterol derivatives were synthesized to prepare nanoparticles (NPs) of HYNIC-rHDL and DOTA-rHDL, which can subsequently be linked to radionuclides for SPECT/PET imaging or targeted radiotherapy. HYNIC is used to complexing 99mTc and DOTA for labeling molecules with 111, 113mIn, 67, 68Ga, 177Lu, 161Tb, 225Ac, and 64Cu, among others. In vitro studies showed that the NPs of HYNIC-rHDL and DOTA-rHDL maintain specific recognition by SR-B1 and the ability to internalize and release, in the cytosol of cancer cells, the molecules carried in their core. The biodistribution in mice showed a similar behavior between rHDL (without surface modification) and HYNIC-rHDL, while DOTA-rHDL exhibited a different biodistribution pattern due to the significant reduction in the lipophilicity of the modified cholesterol molecule. Both systems demonstrated characteristics for the development of suitable theranostic platforms for personalized cancer treatment.

Air particulate matter (PM) exposure has been associated with increased cardiovascular risk, especially in obesity. By triggering inflammation and oxidative stress, PM could impact atheroprotection by high-density lipoproteins (HDL). The aim of the study was to assess the relationship between short-term exposure to PM and HDL function, and the modifying effect of body mass index (BMI). Daily exposures to PM10 and PM2.5 of 50 subjects with overweight/obesity and 41 healthy volunteers with BMI < 30 kg/m2 were obtained from fixed monitoring stations. HDL function was assessed as promotion of nitric oxide (NO) release by endothelial cells and reduction in cholesterol in macrophages. HDL-induced NO release progressively declined with the increase in BMI. No association was found between HDL function and PM exposure, but a modifying effect of BMI was observed. The positive association between PM10 exposure at day −1 and NO production found at normal BMI values was lost in participants with higher BMI. Similar results were obtained for the reduction in macrophage cholesterol. The loss of the compensatory response of HDL function to PM exposure at increasing BMI levels could contribute to the endothelial dysfunction induced by PM and help to explain the susceptibility of subjects with obesity to air pollution.

Atherosclerosis progression is driven by an imbalance of cholesterol and unresolved local inflammation in the arteries. The administration of recombinant apolipoprotein A-I (ApoA-I)-based high-density lipoprotein (HDL) nanoparticles has been used to reduce the size of atheroma and rescue inflammatory response in clinical studies. Because of the difficulty in producing large quantities of recombinant ApoA-I, here, we describe the preparation of phospholipid-based, ApoA-I-free micelles that structurally and functionally resemble HDL nanoparticles. Micelles were prepared using various phosphatidylcholine (PC) lipids combined with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[azido(polyethylene glycol)-2000] (DSPE-PEG2k) to form nanoparticles of 15–30 nm in diameter. The impacts of PC composition and PEGylation on the anti-inflammatory activity, cholesterol efflux capacity, and cholesterol crystal dissolution potential of micelles were investigated in vitro. The effects of micelle composition on pharmacokinetics and cholesterol mobilization ability were evaluated in vivo in Sprague Dawley rats. The study shows that the composition of HDL-mimicking micelles impacts their overall atheroprotective properties and supports further investigation of micelles as a therapeutic for the treatment of atherosclerosis.

Background: Measuring lipoprotein particle concentrations may help to improve cardiovascular risk stratification. Both the lipofit (Numares) and lipoprofile (LabCorp) NMR methods are widely used for the quantification of lipoprotein particle concentrations. Objective: The aim of the present work was to perform a method comparison between the lipofit and lipoprofile NMR methods. In addition, there was the objective to compare lipofit and lipoprofile measurements of standard lipids with clinical chemistry-based results. Methods: Total, LDL, and HDL cholesterol and triglycerides were measured with ß-quantification in serum samples from 150 individuals. NMR measurements of standard lipids and lipoprotein particle concentrations were performed by Numares and LabCorp. Results: For both NMR methods, differences of mean concentrations compared to ß-quantification-derived measurements were ≤5.5% for all standard lipids. There was a strong correlation between ß-quantification- and NMR-derived measurements of total and LDL cholesterol and triglycerides (all r > 0.93). For both, the lipofit (r = 0.81) and lipoprofile (r = 0.84) methods, correlation coefficients were lower for HDL cholesterol. There was a reasonable correlation between LDL and HDL lipoprotein particle concentrations measured with both NMR methods (both r > 0.9). However, mean concentrations of major and subclass lipoprotein particle concentrations were not as strong. Conclusions: The present analysis suggests that reliable measurement of standard lipids is possible with these two NMR methods. Harmonization efforts would be needed for better comparability of particle concentration data.

High-density lipoproteins (HDL) are the densest plasma lipoproteinsand theircomplex protein and lipid constitution interfereswith several physiological mechanisms. The most well characterized HDL functionis reverse cholesterol transport,but other functions have also been attributed to HDL, namelyanti-oxidative, vasodilatoryand anti-inflammatory properties. However, the HDL immunomodulatoryfunction is poorly understood. HDL mediation of cholesterol efflux and consequent lipid raft disruption is one of the main mechanisms by which HDL modulatestheimmune response, but other mechanisms are also involved.Most ofthe existent knowledge comes from animal studies, withlimitations related to the animal model lipid metabolism. Thefew human studiesare heterogeneous and demonstrate both anti-inflammatory and pro-inflammatory effects.Paradoxically, HDL can also suffer transformation to dysfunctional particles, by many different mechanisms. One of these mechanisms is related with the production of antibodies to HDL particles, with themain target beingapolipoprotein A-I (ApoA-I).In this thesis, I questioned the role ofHDL in immune functionwitha specialfocus on the HDL effects on T celllipid metabolism and T cell response, using cells from patients with systemic lupus erythematosus and healthy controls.This work studied: 1)the conditions in which HDL induces cholesterol depletion from CD4+T cells in vitro; 2)the HDL influence on ABCA1 and lipid raft organization inthe plasma membrane (PM)of cultured CD4+T cells; 3) the HDL effect on immune conjugate formation; 4) CD4+T cell lipid metabolismin relation toanti-HDL antibodies; 5)the presence of anti-ABCA1 antibodies; 6) the HDL modulation of T cell response in vitro.The main methodologies used in this thesiswere peripheral blood mononuclear cells (PBMCs)isolation by density gradient separation, immune-based assays such as ELISA, cell culture experimentsandflow cytometry.The results give importantclues to the importance of HDL to T cell metabolism and response: 1)HDL depletes cholesterol from the PM of CD4+T cellsin 24hourcultures, suggesting that this is the ideal time-lapse for in vitrostudies; 2)cholesterol content in the PM of healthy CD4+T cells varies between different T cell subsets, with effector memory (EM)T cells showing the highestlevels of PM cholesteroland less abundant glycosphingolipids (lipid raft constituents); 3) anti-HDL antibodies associate with an increase in the prevalence of EM T cells and a decrease in naïve and regulatory T cells (Treg). The presence of anti-HDL antibodies is also associated withanincreased expression of lipid rafts in CD4+T cells from SLE patients and withaderegulated membrane cholesterol and lipid transporter ABCA1; 4)anti-ABCA1 antibodies are presentin some patients with SLE; 5)24 hour culture with HDL induces the expression of TGF-β1 in CD4+T cellswithout affecting inflammatory cytokines; 6)HDL inhibited the proliferation of CD4+T cells from patients with SLE but did not affect the proliferation in healthy T cells; 7)in the presence of HDL,TCRzeta phosphorylation is reduced. In conclusion, this worksupports the conceptthat HDL has essentially regulatory functions in the immune system, with a notorious effect in the production of TGF-β1 in CD4+T cells. HDL seems toreduceexaggerated inflammation and maintain normal immune function, withimmune modulatory effects that are context dependent. Modifications in lipid metabolism occur in lymphocytes from patients with SLE, reinforcing the importance ofthelipid metabolism for the immune response. These discoveries add new information to the current knowledge on HDL immune functionin humansthat will hopefully be further studied in the research of atherosclerosis, autoimmune diseases and other pathologiesin which lipid metabolism anomalies concurwith immune dysfunction.

Background and aims Liver X receptors (LXRs) exert anti-inflammatory effects even though their hepatic activation is associated with hypertriglyceridemia and hepatic steatosis. Selective induction of LXRs in the gut might provide protective signal(s) in the aberrant wound healing response that induces fibrosis during chronic liver injury, without hypertriglyceridemic and steatogenic effects. Methods Mice with intestinal constitutive LXRα activation (iVP16-LXRα) were exposed to intraperitoneal injection of carbon tetrachloride (CCl4 ) for 8 weeks, and in vitro cell models were used to evaluate the beneficial effect of high-density lipoproteins (HDL). Results After CCl4 treatment, the iVP16-LXRα phenotype showed reduced M1 macrophage infiltration, increased expression M2 macrophage markers, and lower expression of hepatic pro-inflammatory genes. This anti-inflammatory effect in the liver was also associated with decreased expression of hepatic oxidative stress genes and reduced expression of fibrosis markers. iVP16-LXRα exhibited increased reverse cholesterol transport in the gut by ABCA1 expression and consequent enhancement of the levels of circulating HDL and their receptor SRB1 in the liver. No hepatic steatosis development was observed in iVP16-LXRα. In vitro, HDL induced a shift from M1 to M2 phenotype of LPS-stimulated Kupffer cells, decreased TNFα-induced oxidative stress in hepatocytes and reduced NF-kB activity in both cells. SRB1 silencing reduced TNFα gene expression in LPS-stimulated KCs, and NOX-1 and IL-6 in HepG2. Conclusions Intestinal activation of LXRα modulates hepatic response to injury by increasing circulating HDL levels and SRB1 expression in the liver, thus suggesting this circuit as potential actionable pathway for therapy.

The results of a number of studies have proved the relationship between the functional state of the pineal gland and renal function. However, violations of the melatonin-forming function of the epiphysis (MFE) in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) and its relationship with dyslipidemia in this patient population is a poorly understood issue. The objective: to analyze disorders of MFE and blood lipid spectrum in patients with CKD of 5 stage treated with HD and to determine the relationship of epiphysis dysfunction with dyslipidemia. Materials and methods. 130 people (50% of men) aged 58.5 were surveyed [43; 66] which are on permanent hemodialysis treatment. Control passed 20 healthy individuals. The determination of day and night level of melatonin (MT) in saliva was conducted, based on the level of which patients (treated with HD) were divided into two groups: group I – 110 patients with impaired MFE, group II – 20 patients with normal MFE. Clinical and laboratory researches were carried out for all patients: general and biochemical analyzes of blood with determination of cholesterol level and its fractions, measurements of office blood pressure (BP) were made. Results. Significant prevalence of MFE disorders in patients with CKD of 5 stage treated with hemodialysis and its relationship with blood lipid spectrum were found. The level of total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) in patients with impaired MFE was higher by 26.4 % (p

The results of a number of studies have proved the relationship between the functional state of the pineal gland and renal function. However, violations of the melatonin-forming function of the epiphysis (MFE) in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) and its relationship with dyslipidemia in this patient population is a poorly understood issue. The objective: to analyze disorders of MFE and blood lipid spectrum in patients with CKD of 5 stage treated with HD and to determine the relationship of epiphysis dysfunction with dyslipidemia. Materials and methods. 130 people (50% of men) aged 58.5 were surveyed [43; 66] which are on permanent hemodialysis treatment. Control passed 20 healthy individuals. The determination of day and night level of melatonin (MT) in saliva was conducted, based on the level of which patients (treated with HD) were divided into two groups: group I – 110 patients with impaired MFE, group II – 20 patients with normal MFE. Clinical and laboratory researches were carried out for all patients: general and biochemical analyzes of blood with determination of cholesterol level and its fractions, measurements of office blood pressure (BP) were made. Results. Significant prevalence of MFE disorders in patients with CKD of 5 stage treated with hemodialysis and its relationship with blood lipid spectrum were found. The level of total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) in patients with impaired MFE was higher by 26.4 % (p

مقدمه: نارسایی ‌مزمن‌کلیوی به نقص غیر قابل‌ برگشت عملکرد کلیه اطلاق می‌شود که سیر پیش‌رونده‌ دارد و در نهایت، بیشتر این موارد، به دیالیز منجر می‌شوند. مطالعات نشان داده‌اند که این بیماران، به مرور ممکن ‌است با اختلالات پروفایل چربی مواجه شوند. به همین منظور، مطالعه‌ی ‌حاضر با هدف ارزیابی علل‌ مؤثر بر تغییرات پروفایل‌ چربی این بیماران طی یک سال انجام شد. روش‌ها: در مطالعه‌ی ‌مقطعی‌ حاضر، 251 نفر از بیماران دیالیز ‌صفاقی که پرونده‌های آن‌ها در طی سال‌های 98-1397 در بایگانی بیمارستان ‌الزهرای (س) اصفهان موجود بود، به صورت تصادفی ساده انتخاب شدند. اطلاعات دموگرافیک و پروفایل‌چربی این بیماران شامل کلسترول ‌تام (Total cholesterol یا TCH)، لیپوپروتئین با تراکم پایین (Low density lipoprotein یا LDL)، لیپوپروتیئن با تراکم ‌بالا (High density lipoprotein یا HDL)، تری‌گلیسیرید (Triglyceride یا TG) و قند خون در سه‌ مقطع زمانی در ابتدای‌ شروع‌ دیالیز، 6 ماه و یک سال پس از شروع‌ دیالیز ثبت شدند و مورد تجزیه ‌و ‌تحلیل قرار ‌گرفتند. یافته‌ها: تغییرات پروفایل‌ چربی و تری‌گلیسیرید این بیماران در طی یک سال دیالیز، قابل‌ ملاحظه و معنی‌دار بود (050/0 > P). در بررسی عوامل مؤثر بر آن‌ها، مشخص ‌شد که جنسیت، ارتباط‌ مستقیم و معنی‌داری بر تمامی متغیرهای لیپیدمی ارزیابی ‌شده، داشته ‌است (001/0 > P). علاوه بر آن، افزایش سطح هموگلوبین، همراهی و ارتباط‌مستقیم و معنی‌داری بر افزایش LDL، TCH و TG داشت (001/0 > P). قند خون نیز ارتباط معنی‌داری با افزایش TCH (040/0 = P) و TG (014/0 = P) داشت. در نهایت، محلول ‌دیالیز دکستروز 5/2 درصد بر افزایش TCH (035/0 = P) و دکستروز 25/4 درصد بر افزایش LDL (040/0 = P) تأثیر مستقیم و معنی‌داری داشت. نتیجه‌گیری: بر طبق نتایج مطالعه‌ی ‌حاضر، پروفایل‌ چربی بیماران تحت‌ دیالیز‌ صفاقی، نوسانات ‌معنی‌داری داشت که از جمله مهم‌ترین عوامل مرتبط با آن نوع محلول ‌دیالیز، قند خون و سطح هموگلوبین بود.

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. Methods: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B–depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. Results: Low values of cholesterol efflux capacity (OR 1SD , 0.58; 95% CI, 0.40–0.83) and low levels of sphingosine-1-phosphate (OR 1SD , 0.70; 95% CI, 0.52–0.92) and apolipoprotein A-I (OR 1SD , 0.58; 95% CI, 0.42–0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR 1SD , 1.27; 95% CI, 0.99–1.63). Low values of cholesterol efflux capacity (OR 1SD , 0.33; 95% CI, 0.18–0.61), sphingosine-1-phosphate (OR 1SD : 0.60; 95% CI: 0.40–0.89), and apolipoprotein A-I (OR 1SD , 0.59; 95% CI, 0.37–0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR 1SD , 1.53; 95% CI, 1.01–2.33) and low apolipoprotein A-I levels (OR 1SD , 0.52; 95% CI, 0.31–0.88) were associated with unstable angina. Conclusions: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk. Clinical Trial Registration: URL: https://www.controlled-trials.com/ISRCTN35739639 . Unique identifier: ISRCTN35739639.

Chronic, non-healing wounds are a significant cause of global morbidity and mortality, and strategies to improve delayed wound closure represent an unmet clinical need. High-density lipoproteins (HDL) can enhance wound healing, but exploitation of this finding is challenging due to the complexity and instability of these heterogeneous lipoproteins. The responsiveness of primary human neonatal keratinocytes, and neonatal and human dermal fibroblasts (HDF) to HDL was confirmed by cholesterol efflux, but promotion of ‘scrape’ wound healing occurred only in primary human neonatal (HDFn) and adult fibroblasts (HDFa). Treatment of human fibroblasts with HDL induced multiple changes in the expression of small non-coding microRNA sequences, determined by microchip array, including hsa-miR-6727-5p. Intriguingly, levels of hsa-miR-6727-5p increased in HDFn, but decreased in HDFa, after exposure to HDL. Delivery of a hsa-miR-6727-5p mimic elicited repression of different target genes in HDFn (ZNF584) and HDFa (EDEM3, KRAS), and promoted wound closure in HDFn. By contrast, a hsa-miR-6727-5p inhibitor promoted wound closure in HDFa. We conclude that HDL treatment exerts distinct effects on the expression of hsa-miR-6727-5p in neonatal and adult fibroblasts, and that this is a sequence which plays differential roles in wound healing in these cell types, but cannot replicate the myriad effects of HDL.

Alcohol abuse, a global health problem, is closely associated with many pathological processes, such as dyslipidemia and cardiovascular disease. In particular, excessive alcohol consumption promotes dyslipidemia and liver damage, such as hepatic steatosis, fibrosis, and cirrhosis. Beeswax alcohol (BWA) is a natural product used for its antioxidant properties that has not been evaluated for its efficacy in alcohol-induced liver injury. In the present study, zebrafish were exposed to 1% ethanol with supplementation of 10% fermented black rice bran (BRB-F), 10% BWA, or 10% mixtures of BWA+BRB-F (MIX). The BRB-F, BWA, and MIX supplementation increased the survival rate dramatically without affecting the body weight changes. In histology of hepatic tissue, alcoholic foamy degeneration was ameliorated by the BWA or MIX supplements. Moreover, dihydroethidium (DHE) and immunohistochemistry staining suggested that the MIX supplement decreased the hepatic ROS production and interleukin-6 expression significantly owing to the enhanced antioxidant properties, such as paraoxonase. Furthermore, the MIX supplement improved alcohol-induced dyslipidemia and oxidative stress. The BWA and MIX groups showed lower blood total cholesterol (TC) and triglyceride (TG) levels with higher high-density lipoprotein-cholesterol (HDL-C) than the alcohol-alone group. The MIX group showed the highest HDL-C/TC ratio and HDL-C/TG ratio with the lowest low-density lipoprotein (LDL)-C/HDL-C ratio. In conclusion, BWA and BRB-F showed efficacy to treat alcohol-related metabolic disorders, but the MIX supplement was more effective in ameliorating the liver damage and dyslipidemia, which agrees with an enhanced antioxidant and anti-inflammatory activity exhibited by BWA/BRB-F in a synergistic manner.

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.

Metabolizam, struktura i funkcionalnost lipoproteina visoke gustine (high-density lipoproteins-HDL) su blisko povezani. Procenom kvalitatitvnih karakteristika HDL čestica se može dobiti detaljniji uvid u njihovu ateroprotektivnu aktivnost. U ovom istraživanju su ispitane karakteristike HDL čestica kod metaboličkog sindroma (MS) i pridruženih stanja koja predstavljaju faktore rizika za razvoj kardiovaskularnih bolesti (KVB). Uvid u remodelovanje HDL čestica je omogućen određivanjem relativne zastupljenosti pojedinačnih HDL subfrakcija, aktivnosti markera remodelovanja: lecitin-holesterol-acil transferaze (lecithin–cholesterol acyltransferase-LCAT) i holesterol-estar transfernog proteina (cholesteryl ester transfer protein-CETP), kao i koncentracije CETP. Antioksidativna funkcija HDL čestica je procenjena određivanjem paraoksonazne aktivnosti paraoksonaze 1 (PON1) i koncentracije PON1 i paraoksonaze 3 (PON3). Stepen oksidativne modifikacije antiaterogenih lipoproteinskih čestica je ispitan određivanjem koncentracije oksidovanog HDL (OxHDL). Dodatno su određene koncentracije serumskog amiloida A (SAA), leptina i adiponektina. Radi potvrde prisustva nealkoholne masne bolesti jetre (non-alcoholic fatty liver disease-NAFLD) je izračunat indeks masne jetre (fatty liver index-FLI). Dodatno. karakteristike HDL čestica su ispitane kod različitih metaboličkih fenotipova gojaznih i ispitanika sa prekomernom telesnom masom. Kod ispitanika sa MS su utvrđeni: dominacija manjih HDL subfrakcija, povišena aktivnost LCAT i koncentracija CETP. U grupi ispitanika sa MS su takođe uočeni povišena koncentracija OxHDL i vrednosti odnosa OxHDL/HDL-holesterol. Analizom karakteristika HDL čestica u odnosu na prisustvo pojedinačnih komponenti MS je utvrđeno remodelovanje u korist povećane zastupljenosti malih HDL subfrakcija u kategorijama ispitanika sa sniženom koncentracijom HDLholesterola, hipertrigliceridemijom i povećanim obimom struka. Snižena koncentracija PON3 je uočena kod ispitanika sa sniženom koncentracijom HDL-holesterola i povećanim obimom struka. Povišene vrednosti odnosa OxHDL/HDL-holesterol su utvrđene u kategorijama ispitanika sa sniženom koncentracijom HDL-holesterola, hipertrigliceridemijom i povišenom glukozom našte. Aktivnost LCAT je bila značajan prediktor povišenih vrednosti FLI. Odnos OxHDL/HDL-holesterol je bio značajan prediktor metabolički nezdravog fenotipa u kategorijama gojaznih i ispitanika sa prekomernom telesnom masom. Korelacionom analizom u celoj grupi ispitanika je utvrđeno da je odnos leptin/adiponektin je bio u pozitivnoj korelaciji sa relativnom zastupljenošću malih HDL čestica i negativno sa koncentracijom PON3. Aktivnost LCAT je pozitivno korelirala sa koncentracijom triglicerida, relativnom zastupljenošću malih HDL čestica i odnosom leptin/adiponektin. U ovom istraživanju su utvrđene izmenjene kvalitativne karakteristike HDL čestica kod MS i pridruženih stanja. Dominacija manjih HDL subfrakcija i povišen stepen oksidativne modifikacije HDL čestica su pokazatelji izmenjenih kvalitativnih odlika HDL čestica u uslovima višestrukih metaboličkih fakora rizika za KVB koji su prisutni kod MS. Dokazana je pozitivna veza između aktivnosti LCAT, kao markera remodelovanja HDL čestica, sa faktorima rizika za KVB: prisustvom MS i visokim vrednostima FLI, kao surogat markerom NAFLD. Izmenjene strukturne karakteristike HDL čestica, izražene kroz povišen stepen oksidativne modifikacije, mogu biti dodatni pokazatelj narušenog metaboličkog zdravlja gojaznih i ispitanika sa prekomernom telesnom masom. Sve ovo pokazuje da promenjene kvalitativne osobine antiaterogenih lipoproteina kod MS i srodnih stanja mogu biti dodatni element dislipidemije i faktor rizika za razvoj kardiometaboličkih komplikacija. High-density lipoproteins (HDL) metabolism, structure, and functionality are interrelated. Evaluation of HDL qualitative characteristics could give a more detailed insight into its atheroprotective activity. In this study, we evaluated HDL characteristics in subjects with metabolic syndrome (MS) and related conditions associated with higher risk for cardiovascular diseases (CVD). HDL particles remodeling was evaluated by estimating the relative proportion of each HDL subfraction, the activity of remodeling markers: lecithin–cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), and CETP concentration. HDL antioxidative function was assessed through the determination of paraoxonase activity of paraoxonase 1 (PON1), as well as PON1 and paraoxonase 3 (PON3) concentrations. Oxidative modification of HDL particles was estimated as oxidatively modified HDL (OxHDL) concentration. Additionally, the concentrations of serum amyloid A (SAA), leptin and adiponectin were measured. Fatty liver index (FLI) was used as a surrogate marker for the presence of non-alcoholic fatty liver disease (NAFLD). In addition, HDL characteristics were evaluated in different metabolic phenotypes in the categories of overweight and obese subjects. Domination of smaller HDL subfractions, elevated LCAT activity, and CETP concentration, as well as increased OxHDL concentration and OxHDL/HDL-cholesterol ratio, were observed in subjects with MS. The analysis of HDL characteristics in the presence of individual MS components revealed remodeling in favor of smaller HDL subfractions in subjects with low HDL-cholesterol, hypertriglyceridemia, and elevated waist circumference. We found lower PON3 concentration in subjects with low HDL-cholesterol and elevated waist circumference. Increased OxHDL/HDLcholesterol ratio was found in subjects with low HDL-cholesterol, hypertriglyceridemia, and elevated fasting glucose. LCAT activity was positively associated with FLI. OxHDL/HDL-cholesterol ratio was a significant predictor of the metabolically unhealthy phenotype in overweight and obese subjects. In the entire group of subjects, leptin/adiponectin ratio correlated positively with the relative proportion of small HDL particles, and negatively with PON3 concentration. LCAT activity correlated positively with triglyceride concentration, relative proportion of small HDL particles, and leptin/adiponectin ratio. In this study, altered qualitative HDL characteristics in subjects with MS and related conditions were observed. Domination of smaller HDL subfractions and increased degree of HDL oxidative modification in subjects with MS indicate impaired HDL qualitative characteristics in the presence of multiple metabolic CVD risk factors associated with the presence of MS. LCAT activity was positively associated with the CVD risk factors: the presence of MS and elevated FLI values i.e. the presence of NAFLD. Altered HDL structural features, observed as an increased degree of HDL oxidative modification, can be an additional indicator of the metabolically unhealthy phenotype of overweight and obese subjects. Altered qualitative characteristics of antiatherogenic lipoproteins may represent additional components of dyslipidemia and cardiometabolic diseases risk factor in MS and related conditions.

High-density lipoprotein (HDL) plays an important role in lipid metabolism and especially contributes to the reverse cholesterol transport pathway. Over recent years it has become clear that the effect of HDL on immune modulation is not only dependent on HDL concentration but also and perhaps even more so on HDL function. This review will provide a concise general introduction to HDL followed by an overview of post-translational modifications of HDL and a detailed overview of the role of HDL in inflammatory diseases. The clinical potential of HDL and its main apolipoprotein constituent, apoA-I, is also addressed in this context. Finally, some conclusions and remarks that are important for future HDL-based research and further development of HDL-focused therapies are discussed. (C) 2020 The Author(s). Published by Elsevier B.V.

High-density lipoprotein (HDL) plays an important role in lipid metabolism and especially contributes to the reverse cholesterol transport pathway. Over recent years it has become clear that the effect of HDL on immune modulation is not only dependent on HDL concentration but also and perhaps even more so on HDL function. This review will provide a concise general introduction to HDL followed by an overview of post-translational modifications of HDL and a detailed overview of the role of HDL in inflammatory diseases. The clinical potential of HDL and its main apolipoprotein constituent, apoA-I, is also addressed in this context. Finally, some conclusions and remarks that are important for future HDL-based research and further development of HDL-focused therapies are discussed. (C) 2020 The Author(s). Published by Elsevier B.V.

Background: Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice. Methods: APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results: In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions: ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Here, we review the impact of high-density lipoproteins (HDL) on sepsis from the perspective of biochemistry and pathophysiology, epidemiological research, and intervention studies in animals. Pathogen lipid moieties are major ligands for innate immunity receptors, such as toll-like receptors. The binding of pathogen-associated lipids to lipoproteins leads to sequestration, neutralization, and inactivation of their pro-inflammatory effects. Lipoproteins constitute an arm of the innate immune system. Pathogen-associated lipids can be removed from the body via the reverse lipopolysaccharide transport pathway in which HDL play a key role. Independent of the capacity for sequestration, the direct anti-inflammatory effects of HDL may counteract the development of sepsis. Mendelian randomization research using genetic variants associated with HDL cholesterol as an instrumental variable was consistent with a probable causal relationship between increased HDL cholesterol levels and decreased risk of infectious hospitalizations. Low HDL cholesterol independently predicts an adverse prognosis in sepsis both in observational epidemiology and in Mendelian randomization studies. Several HDL-associated enzymes, including phospholipid transfer protein (PLTP) and cholesterol ester transfer protein (CETP), undergo profound changes during sepsis. Potential HDL-directed interventions for treatment of sepsis include apolipoprotein A-I-based therapies, recombinant PLTP, and CETP inhibition. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:21 ispartof: location:Switzerland status: published

Light-to-moderate alcohol drinking is associated with a low incidence of cardiovascular disease (CVD) via an elevation of high-density lipoproteins-cholesterol (HDL-C), particularly with the short-term supplementation of alcohol. However, there is no information on the change in the HDL qualities and functionalities between non-drinkers and mild drinkers in the long-term consumption of alcohol. This study analyzed the lipid and lipoprotein profiles of middle-aged Korean female non-drinkers, mild-drinkers, and binge-drinkers, who consumed alcohol for at least 10 years. Unexpectedly, the serum levels of HDL-C and apolipoprotein A-I (apoA-I) were decreased significantly depending on the alcohol amount; the binge-drinker group showed 18% and 13% lower HDL-C (p = 0.011) and apoA-I levels (p = 0.024), respectively, than the non-drinker group. Triglyceride (TG) and oxidized species, malondialdehyde (MDA), and low-density lipoproteins (LDL) levels were significantly elevated in the drinker groups. Interestingly, the binge-drinker group showed 1.4-fold higher (p = 0.020) cholesterol contents in HDL2 and 1.7-fold higher (p < 0.001) TG contents in HDL3 than those of the non-drinker group. The mild-drinker group also showed higher TG contents in HDL3 (p = 0.032) than the non-drinker group, while cholesterol contents were similar in the HDL3 of all groups. Transmission electron microscopy (TEM) showed that the non-drinker group showed a more distinct and clear particle shape of the LDL and HDL image with a larger particle size than the drinker group. Electrophoresis of LDL showed that the drinker group had faster electromobility with a higher smear band intensity and aggregation in the loading position than the non-drinker group. The HDL level of binge drinkers showed the lowest paraoxonase activity, the highest glycated extent, and the most smear band intensity of HDL and apoA-I, indicating that HDL quality and functionality were impaired by alcohol consumption. In conclusion, long-term alcohol consumption in middle-aged women, even in small amounts, caused a significant decrease in the serum HDL-C and apoA-I with atherogenic changes in LDL and HDL, such as an increase in TG and MDA content with a loss of paraoxonase activity.

The composition and properties of apolipoprotein (apo) A-I and apoA-II in high-density lipoproteins (HDL) might be critical to SARS-CoV-2 infection via SR-BI and antiviral activity against COVID-19. HDL containing native apoA-I showed potent antiviral activity, while HDL containing glycated apoA-I or other apolipoproteins did not. However, there has been no report to elucidate the putative role of apoA-II in the antiviral activity of HDL.

Beta (β)-amyloid (Aβ) is a causative protein of Alzheimer’s disease (AD). In the pathogenesis of AD, the apolipoprotein (apo) A-I and high-density lipoprotein (HDL) metabolism is essential for the clearance of Aβ. In this study, recombinant Aβ42 was expressed and purified via the pET-30a expression vector and E.coli production system to elucidate the physiological effects of Aβ on HDL metabolism. The recombinant human Aβ protein (51 aa) was purified to at least 95% purity and characterized in either the lipid-free and lipid-bound states with apoA-I. Aβ was incorporated into the reconstituted HDL (rHDL) (molar ratio 95:5:1, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I) with various apoA-I:Aβ ratios from 1:0 to 1:0.5, 1:1 and 1:2. With an increasing molar ratio of Aβ, the α-helicity of apoA-I was decreased from 62% to 36% with a red shift of the Trp wavelength maximum fluorescence from 337 to 340 nm in apoA-I. The glycation reaction of apoA-I was accelerated further by the addition of Aβ. The treatment of fructose and Aβ caused more multimerization of apoA-I in the lipid-free state and in HDL. The phospholipid-binding ability of apoA-I was impaired severely by the addition of Aβ in a dose-dependent manner. The phagocytosis of LDL into macrophages was accelerated more by the presence of Aβ with the production of more oxidized species. Aβ severely impaired tissue regeneration, and a microinjection of Aβ enhanced embryotoxicity. In conclusion, the beneficial functions of apoA-I and HDL were severely impaired by the addition of Aβ via its detrimental effect on secondary structure. The impairment of HDL functionality occurred more synergistically by means of the co-addition of fructose and Aβ.

Reverse cholesterol transport or cholesterol efflux is part of an extensive plasma membrane remodeling process in spermatozoa that is imperative for fertilization. For ram spermatozoa, sheep serum is well known to support in vitro fertilization (IVF), but knowledge of its explicit role is limited. Though, it is postulated to elicit cholesterol efflux owing to the presence of high-density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as adenosinetriphosphate (ATP)-binding cassette transporter A1 (ABCA1) and scavenger receptor class B, type I (SR-BI). In this study, we report that both sheep serum and HDLs were able to elicit cholesterol efflux alone by up to 20-40% (as measured by the boron dipyrromethene (BODIPY)-cholesterol assay). Furthermore, when the antagonists glibenclamide and valspodar were used to inhibit the function of ABCA1 and SR-BI or ABCA1 alone, respectively, cholesterol efflux was only marginally reduced (8-15%). Nevertheless, it is likely that in ram spermatozoa, a specific facilitated pathway of cholesterol efflux is involved in the interaction between cholesterol acceptors and transporters. Interestingly, exposure to HDLs also induced hyperactivated motility, another critical event required for successful fertilization. Taken together, this study details the first report of the dual action of HDLs on ram spermatozoa, providing both an insight into the intricacy of events leading up to fertilization in vivo as well as demonstrating the possible application of HDL supplementation in media for IVF.

Reverse cholesterol transport or cholesterol efflux is part of an extensive plasma membrane remodeling process in spermatozoa that is imperative for fertilization. For ram spermatozoa, sheep serum is well known to support in vitro fertilization (IVF), but knowledge of its explicit role is limited. Though, it is postulated to elicit cholesterol efflux owing to the presence of high-density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as adenosinetriphosphate (ATP)-binding cassette transporter A1 (ABCA1) and scavenger receptor class B, type I (SR-BI). In this study, we report that both sheep serum and HDLs were able to elicit cholesterol efflux alone by up to 20–40% (as measured by the boron dipyrromethene (BODIPY)-cholesterol assay). Furthermore, when the antagonists glibenclamide and valspodar were used to inhibit the function of ABCA1 and SR-BI or ABCA1 alone, respectively, cholesterol efflux was only marginally reduced (8–15%). Nevertheless, it is likely that in ram spermatozoa, a specific facilitated pathway of cholesterol efflux is involved in the interaction between cholesterol acceptors and transporters. Interestingly, exposure to HDLs also induced hyperactivated motility, another critical event required for successful fertilization. Taken together, this study details the first report of the dual action of HDLs on ram spermatozoa, providing both an insight into the intricacy of events leading up to fertilization in vivo as well as demonstrating the possible application of HDL supplementation in media for IVF., First report of the dual action of high-density lipoproteins on ram spermatozoa in mediating critical fertilization-dependent processes.

High-density lipoproteins (HDLs) represent a class of lipoproteins very heterogeneous in structure, composition, and biological functions, which carry out reverse cholesterol transport, antioxidant, anti-inflammatory, antithrombotic, and vasodilator actions. Despite the evidence suggesting a clear inverse relationship between HDL cholesterol (HDL-c) concentration and the risk for cardiovascular disease, plasma HDL cholesterol levels do not predict the functionality and composition of HDLs. The importance of defining both the amount of cholesterol transported and lipoprotein functionality has recently been highlighted. Indeed, different clinical conditions such as obesity, diabetes mellitus type 2 (T2DM), and cardiovascular disease (CVD) can alter the HDL functionality, converting normal HDLs into dysfunctional ones, undergoing structural changes, and exhibiting proinflammatory, pro-oxidant, prothrombotic, and proapoptotic properties. The aim of the current review is to summarize the actual knowledge concerning the physical–chemical alteration of HDLs related to their functions, which have been found to be relevant in several pathological conditions associated with systemic inflammation and oxidative stress.

Debido a que la terapia antirretroviral no logra controlar la activación inmune asociada a la infección por VIH-1, el estudio de moléculas inmunomoduladoras puede proporcionar alternativas para su control. En este sentido, el propósito de este estudio fue evaluar la expresión transcripcional de moléculas asociadas con el metabolismo del colesterol-HDL (C-HDL) y con la respuesta inflamatoria mediada por el inflamasoma NLRP3 en pacientes infectados con VIH-1. En este estudio transversal, se incluyeron 23 pacientes VIH-1 sin tratamiento antirretroviral, con diferentes estadios de progresión, 7 de los cuales son controladores (Carga viral 2000 copias/mL), además de 7 controles sanos. En células mononucleares de sangre periférica, se cuantificaron los niveles de la expresión transcripcional de ABCA-1, ABCA-3, Caspasa-5 y TXNIP mediante RT-PCR. Se evaluó la asociación de estos parámetros con variables demográficas y de laboratorio, y se encontró que los individuos VIH-1 progresores mostraron niveles significativamente menores de TXNIP y ABCA-3, sugiriendo que durante la infección por VIH-1 se produce una alteración en la expresión de estas moléculas. Dada la complejidad de las interacciones inmuno-metabólicas durante la infección por VIH-1, se necesitan estudios adicionales para establecer los mecanismos precisos involucrados en estas alteraciones, {"references": ["ONUSIDA [Internet]. [citado 15 de febrero de 2021]. Disponible en: https://www.unaids.org/es", "Perdomo-Celis F, Taborda NA, Rugeles MT. Circulating CXCR5-Expressing CD8+ T-Cells Are Major Producers of IL-21 and Associate With Limited HIV Replication. J Acquir Immune Defic Syndr [Internet]. 2018;78(4):476-82. 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Beta cell failure is one of the most important features of type 2 diabetes mellitus (T2DM). High‐density lipoprotein (HDL) has been proposed to improve β‐cell function. However, the mechanisms involved in this process are still poorly understood. The aim of this study was to investigate the contribution of sphingosine‐1‐phosphate (S1P) in the impact of HDL treatment on insulin secretion by pancreatic β‐cells and to determine its mechanisms. Primary cultures of β‐cells isolated from rat were treated with or without HDL in the presence or absence of S1P pathway inhibitors and insulin secretion response was analyzed. The S1P content of HDL (HDL‐S1P) isolated from T2DM patients was analyzed and correlated to the HDL‐induced insulin secretion. The expression of genes involved in the biosynthesis of the insulin was also evaluated. HDL as well as S1P treatment enhanced glucose‐stimulated insulin secretion (GSIS). In HDL isolated from T2DM patients, while HDL‐S1P was strongly correlated to its pro‐secretory capacity (r = 0.633, p = 0.005), HDL‐cholesterol and apolipoprotein AI levels were not. HDL‐induced GSIS was blocked by the S1P1/3 antagonist but not by the S1P2 antagonist, and was also accompanied by increased intracellular S1P in β‐cells. We also observed that HDL improved GSIS without significant changes in expression levels of insulin biosynthesis genes. Our present study highlights the importance HDL‐S1P in GSIS in T2DM patients and demonstrates that HDL induces insulin secretion by a process involving both intra‐ and extra‐cellular sources of S1P independently of an effect on insulin biosynthesis genes., HDL improves insulin secretion by beta cells S1P plays a role in HDL‐induced insulin secretion HDL increases intracellular S1P content.

Цереброваскулярные заболевания (ЦВЗ) являются важной медико-социальной проблемой. Их преимущественный атеросклеротический генез, высокая коморбидность обусловливают актуальность разработки биомаркеров метаболических нарушений, помогающих определить риск сосудистых событий. Одним из наиболее распространенных патологических сочетаний в современной ангионеврологии является ЦВЗ и сахарный диабет 2-го типа, при котором прогрессирование атеростеноза, в том числе сонных артерий, происходит на фоне сочетания хронической гипергликемии и дислипидемии, что нередко приводит к развитию нарушений мозгового кровообращения. В статье отражены новые данные о проатерогенных изменениях липидного спектра крови у пациентов с ЦВЗ, протекающими на фоне гемодинамически значимых стенозов сонных артерий. Наличие сахарного диабета 2-го типа сопровождается более выраженными проатерогенными изменениями крови, что связано с нарушениями углеводного обмена у этой категории больных ЦВЗ, Cerebrovascular diseases (CVDs) represent a major medical and social challenge. Their predominant atherosclerotic nature and high comorbidity demand identification of metabolic disorders biomarkers that will facilitate the evaluation of vascular event risk. CVDs and type 2 diabetes mellitus are two of the most common pathological combinations in current vascular neurology. In type 2 diabetes mellitus, atherosclerotic stenosis progression, including the involvement of carotid arteries, occurs in the circumstances of a combination of chronic hyperglycemia and dyslipidemia, which oftentimes result in a cerebrovascular accident. The paper provides new data on the pro-atherogenic shifts in the blood lipid profile in patients with CVD that occur in patients with hemodynamically significant carotid artery stenoses. Type 2 diabetes mellitus is associated with more pronounced pro-atherogenic blood changes, which are linked to carbohydrate metabolism disorders in this group of patients with CVDs

The main and common constituents of high-density lipoproteins (HDLs) are apolipoprotein A-I, cholesterol, and phospholipids. Biochemical heterogeneity of HDL particles is based on the variable presence of one or more representatives of at least 180 proteins, 200 lipid species, and 20 micro RNAs. HDLs are circulating multimolecular platforms that perform divergent functions whereby the potential of HDL-targeted interventions for treatment of heart failure can be postulated based on its pleiotropic effects. Several murine studies have shown that HDLs exert effects on the myocardium, which are completely independent of any impact on coronary arteries. Overall, HDL-targeted therapies exert a direct positive lusitropic effect on the myocardium, inhibit the development of cardiac hypertrophy, suppress interstitial and perivascular myocardial fibrosis, increase capillary density in the myocardium, and prevent the occurrence of heart failure. In four distinct murine models, HDL-targeted interventions were shown to be a successful treatment for both pre-existing heart failure with reduced ejection fraction (HFrEF) and pre-existing heart failure with preserved ejection fraction (HFrEF). Until now, the effect of HDL-targeted interventions has not been evaluated in randomized clinical trials in heart failure patients. As HFpEF represents an important unmet therapeutic need, this is likely the preferred therapeutic domain for clinical translation. ispartof: BIOMEDICINES vol:8 issue:12 ispartof: location:Switzerland status: published

High-density lipoprotein (HDL) is well-known for its cardioprotective effects, as it possesses anti-inflammatory, anti-oxidative, anti-thrombotic, and cytoprotective properties. Traditionally, studies and therapeutic approaches have focused on raising HDL cholesterol levels. Recently, it became evident that, not HDL cholesterol, but HDL composition and functionality, is probably a more fruitful target. In disorders, such as chronic kidney disease or cardiovascular diseases, it has been observed that HDL is modified and becomes dysfunctional. There are different modification that can occur, such as serum amyloid, an enrichment and oxidation, carbamylation, and glycation of key proteins. Additionally, the composition of HDL can be affected by changes to enzymes such as cholesterol ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and phospholipid transfer protein (PLTP) or by modification to other important components. This review will highlight some main modifications to HDL and discuss whether these modifications are purely a consequential result of pathology or are actually involved in the pathology itself and have a causal role. Therefore, HDL composition may present a molecular target for the amelioration of certain diseases, but more information is needed to determine to what extent HDL modifications play a causal role in disease development.

High-density lipoprotein (HDL) is well-known for its cardioprotective effects, as it possesses anti-inflammatory, anti-oxidative, anti-thrombotic, and cytoprotective properties. Traditionally, studies and therapeutic approaches have focused on raising HDL cholesterol levels. Recently, it became evident that, not HDL cholesterol, but HDL composition and functionality, is probably a more fruitful target. In disorders, such as chronic kidney disease or cardiovascular diseases, it has been observed that HDL is modified and becomes dysfunctional. There are different modification that can occur, such as serum amyloid, an enrichment and oxidation, carbamylation, and glycation of key proteins. Additionally, the composition of HDL can be affected by changes to enzymes such as cholesterol ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and phospholipid transfer protein (PLTP) or by modification to other important components. This review will highlight some main modifications to HDL and discuss whether these modifications are purely a consequential result of pathology or are actually involved in the pathology itself and have a causal role. Therefore, HDL composition may present a molecular target for the amelioration of certain diseases, but more information is needed to determine to what extent HDL modifications play a causal role in disease development.

In the search to develop new cardioprotective therapies, considerable interest has focussed on approaches for targeting the biological functions of high-density lipoproteins (HDL). This is based on data from population and animal studies demonstrating a potentially protective impact of HDL on cardiovascular risk. The findings of recent clinical trials of a range of therapeutic interventions aimed at promoting HDL have been disappointing and raise considerable uncertainty regarding the potential utility of this target. More recent evidence has highlighted the importance of HDL functionality, which may ultimately be important in terms of its association with cardiovascular risk. This has led to ongoing efforts to develop new risk markers and therapeutics focussing on HDL quality as opposed to quantity. The evidence supporting a protective role for HDL and findings of clinical trials of HDL-targeted therapies are reviewed here.

Background Mounting evidence suggested a complex correlation between host lipid metabolism and Toxoplasma gondii (T. gondii) infection. However, the inherent association between T. gondii infection and host lipid state remains elusive either in mice or in human hosts. Methods Through a study in a sample of 1045 healthy participants from eastern China, we determined the association of T. gondii infection and host lipid levels using serological methods. We then examined the host lipid levels in C57BL/6 J mice at both acute and chronic T. gondii infection stages (for a period up to 36 weeks post infection). Results In our case-control study, T. gondii seropositive individuals had higher low-density lipoproteins (LDL) (P = 0.0043) and total cholesterol (TC) (P = 0.0134) levels compared to seronegative individuals. Furthermore, individuals with LDL (OR = 3.25; 95% CI:1.60–6.61) and TC (OR = 2.10; 95% CI:1.22–3.63) levels above the upper limit of normal range had higher odds ratio to be T. gondii IgG positive. Consistently, in vivo data revealed that a significantly increased LDL level was first observed at early acute stage but plateaued to later time (chronic infection with T. gondii). Conclusions In both healthy population and T. gondii-infected mice, seropositive individuals had higher LDL level. Individuals with positive T. gondii IgG had more odds of being with LDL and TC abnormality. Latent T. gondii infection is common worldwide, potential medical interventions to host lipid metabolism may be a breakthrough point to the prevention and control of this parasite infection.

The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)

The results of a number of studies have proved the relationship between the functional state of the pineal gland and renal function. However, violations of the melatonin-forming function of the epiphysis (MFE) in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) and its relationship with dyslipidemia in this patient population is a poorly understood issue.The objective: to analyze disorders of MFE and blood lipid spectrum in patients with CKD of 5 stage treated with HD and to determine the relationship of epiphysis dysfunction with dyslipidemia.Materials and methods. 130 people (50% of men) aged 58.5 were surveyed [43; 66] which are on permanent hemodialysis treatment. Control passed 20 healthy individuals. The determination of day and night level of melatonin (MT) in saliva was conducted, based on the level of which patients (treated with HD) were divided into two groups: group I – 110 patients with impaired MFE, group II – 20 patients with normal MFE. Clinical and laboratory researches were carried out for all patients: general and biochemical analyzes of blood with determination of cholesterol level and its fractions, measurements of office blood pressure (BP) were made.Results. Significant prevalence of MFE disorders in patients with CKD of 5 stage treated with hemodialysis and its relationship with blood lipid spectrum were found. The level of total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) in patients with impaired MFE was higher by 26.4 % (p, Результаты ряда исследований доказали наличие взаимосвязи между функциональным состоянием эпифиза и функцией почек. Однако нарушения мелатонинобразовательной функции эпифиза (МФЭ) у больных хронической болезнью почек (ХБП), находящихся на гемодиализе (ГД), и ее связь с дислипидемией в данной популяции пациентов является малоизученным вопросом.Цель исследования: анализ нарушения МФЭ и липидный спектр крови у больных ХБП V стадии, которые лечатся ГД, и определение взаимосвязи дисфункции эпифиза с дислипидемией.Материалы и методы. Обследованы 130 человек (50% из них – мужчины) в возрасте 58,5 [43; 66] года, которые находятся на постоянном лечении ГД. В группу контроля вошли 20 здоровых лиц. Проведено определение дневного и ночного уровня мелатонина (МТ) в слюне, на основании чего, больных на ГД разделили на две группы: группа I – 110 больных с нарушенной МФЭ, группа II – 20 пациентов с нормальной МФЭ. Всем больным проведены клинико-лабораторные исследования: общий и биохимический анализы крови с определением уровня холестерина и его фракций, проведено измерение офисного артериального давления (АД).Результаты. Обнаружена значительная распространенность нарушения МФЭ у больных ХБП V стадии, которые лечатся ГД, и ее взаимосвязь с липидным спектром крови. Уровень общего холестерина (ОХ), триглицеридов (ТГ) и липопротеидов низкой плотности (ЛПНП) у пациентов с нарушенной МФЭ выше на 26,4 % (р, Результати низки наукових досліджень довели наявність взаємозв’язку між функціональним станом епіфізу та функцією нирок. Проте порушення мелатонінутворювальної функції епіфізу (МФЕ) у хворих на хронічну хворобу нирок (ХХН), що лікуються гемодіалізом (ГД), та її зв’язок з дисліпідемією у даної когорти пацієнтів є маловивченим питанням.Мета дослідження: аналіз порушень МФЕ та ліпідного спектра крові у хворих на ХХН V стадії, що лікуються ГД, та визначення взаємозв’язку дисфункції епіфізу з дисліпідемією.Матеріали та методи. Обстежено 130 осіб (50% з них – чоловіки) віком 58,5 [43; 66] року, що перебувають на постійному лікуванні ГД. До контрольної групи увійшли 20 здорових осіб. Проведено визначення денного та нічного рівня мелатоніну (МТ) у слині, на підставі рівня якого хворих, що лікуються ГД, розподілили на дві групи: група І – 110 хворих з порушеною МФЕ, група ІІ – 20 пацієнтів з нормальною МФЕ. Усім хворим проведені клініко-лабораторні дослідження: загальний та біохімічний аналізи крові з визначенням рівня холестерину та його фракцій, проведено вимірювання офісного артеріального тиску (АТ).Результати. Виявлено значну поширеність порушення МФЕ у хворих на ХХН V стадії, що лікуються ГД, та її взаємозв’язок з ліпідним спектром крові. Рівень загального холестерину (ЗХ), тригліцеридів (ТГ) та ліпопротеїдів низької щільності (ЛПНЩ) у пацієнтів з порушеною МФЕ вищий на 26,4 % (р

Результаты ряда исследований доказали наличие взаимосвязи между функциональным состоянием эпифиза и функцией почек. Однако нарушения мелатонинобразовательной функции эпифиза (МФЭ) у больных хронической болезнью почек (ХБП), находящихся на гемодиализе (ГД), и ее связь с дислипидемией в данной популяции пациентов является малоизученным вопросом.Цель исследования: анализ нарушения МФЭ и липидный спектр крови у больных ХБП V стадии, которые лечатся ГД, и определение взаимосвязи дисфункции эпифиза с дислипидемией.Материалы и методы. Обследованы 130 человек (50 % из них – мужчины) в возрасте 58,5 [43; 66] года, которые находятся на постоянном лечении ГД. В группу контроля вошли 20 здоровых лиц. Проведено определение дневного и ночного уровня мелатонина (МТ) в слюне, на основании чего, больных на ГД разделили на две группы: группа I – 110 больных с нарушенной МФЭ, группа II – 20 пациентов с нормальной МФЭ. Всем больным проведены клинико-лабораторные исследования: общий и биохимический анализы крови с определением уровня холестерина и его фракций, проведено измерение офисного артериального давления (АД).Результаты. Обнаружена значительная распространенность нарушения МФЭ у больных ХБП V стадии, которые лечатся ГД, и ее взаимосвязь с липидным спектром крови. Уровень общего холестерина (ОХ), триглицеридов (ТГ) и липопротеидов низкой плотности (ЛПНП) у пациентов с нарушенной МФЭ выше на 26,4 % (р, Результати низки наукових досліджень довели наявність взаємозв’язку між функціональним станом епіфізу та функцією нирок. Протее порушення мелатонінутворювальної функції епіфізу (МФЕ) у хворих на хронічну хворобу нирок (ХХН), що лікуються гемодіалізом (ГД), та її зв’язок з дисліпідемією у даної когорти пацієнтів є маловивченим питанням.Мета дослідження: аналіз порушень МФЕ та ліпідного спектра крові у хворих на ХХН V стадії, що лікуються ГД, та визначення взаємозв’язку дисфункції епіфізу з дисліпідемією.Матеріали та методи. Обстежено 130 осіб (50% чоловіки) віком 58,5 [43; 66] року, що перебувають на постійному лікуванні ГД. До контрольної групи увійшли 20 здорових осіб. Проведено визначення денного та нічного рівня мелатоніну (МТ) у слині, на підставі чого хворих, що лікуються ГД, розподілили на дві групи: група І – 110 хворих з порушеною МФЕ, група ІІ – 20 пацієнтів з нормальною МФЕ. Усім хворим проведені клініко-лабораторні дослідження: загальний та біохімічний аналізи крові з визначенням рівня холестерину та його фракцій, проведено вимірювання офісного артеріального тиску (АТ).Результати. Виявлено значну поширеність порушення МФЕ у хворих на ХХН V стадії, що лікуються ГД, та її взаємозв’язок з ліпідним спектром крові. Рівень загального холестерину (ЗХ), тригліцеридів (ТГ) та ліпопротеїдів низької щільності (ЛПНЩ) у пацієнтів з порушеною МФЕ вищий на 26,4 % (р, The results of a number of studies have proved the relationship between the functional state of the pineal gland and renal function. However, violations of the melatonin-forming function of the epiphysis (MFE) in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD) and its relationship with dyslipidemia in this patient population is a poorly understood issue.The objective: to analyze disorders of MFE and blood lipid spectrum in patients with CKD of 5 stage treated with HD and to determine the relationship of epiphysis dysfunction with dyslipidemia.Materials and methods. 130 people (50% of men) aged 58.5 were surveyed [43; 66] which are on permanent hemodialysis treatment. Control passed 20 healthy individuals. The determination of day and night level of melatonin (MT) in saliva was conducted, based on the level of which patients (treated with HD) were divided into two groups: group I – 110 patients with impaired MFE, group II – 20 patients with normal MFE. Clinical and laboratory researches were carried out for all patients: general and biochemical analyzes of blood with determination of cholesterol level and its fractions, measurements of office blood pressure (BP) were made.Results. Significant prevalence of MFE disorders in patients with CKD of 5 stage treated with hemodialysis and its relationship with blood lipid spectrum were found. The level of total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) in patients with impaired MFE was higher by 26.4 % (p

Background: Primary aldosteronism (PA) may confer increased cardiovascular risk beyond effects on systemic blood pressure, but contributing mechanisms remain incompletely understood. We compared plasma (apo)lipoproteins and lipoprotein particle characteristics, GlycA, a pro-inflammatory glycoprotein biomarker of enhanced chronic inflammation, and plasma total branched-chain amino acids (BCAA), measured using nuclear magnetic resonance (NMR) spectroscopy, between patients with PA, control subjects without hypertension, subjects with untreated hypertension and subjects with treated hypertension. Methods: Twenty PA patients were individually matched with 2819 control subjects without hypertension, 501 subjects with untreated hypertension and 878 subjects with treated hypertension participating in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort study with respect to age, sex, body mass index, smoking and statin use. The Vantera (R) Clinical Analyzer was used to determine NMR-based laboratory parameters. Results: Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) B, apolipoprotein A-I (apoA-I), LDL particle and HDL particle concentrations were all decreased in PA subjects vs control subjects and subjects with untreated hypertension (P Conclusions: Primary aldosteronism is associated with lower concentrations of LDL and HDL particles and to some extent also with lower TG and TRL particle concentrations. PA is also characterized by increased GlycA levels, indicating enhanced low-grade chronic inflammation. Low HDL particle concentrations and increased GlycA could contribute to accelerated cardiovascular disease development in PA.

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.

Decreased serum apolipoprotein A1 (Apo-A1) concentration is associated with mortality in human sepsis. The diagnostic and prognostic role of serum Apo-A1 concentrations in canine sepsis was evaluated. Serum samples from septic dogs (n = 91) and healthy controls (n = 15) were retrospectively analyzed. According to the sepsis origin, four categories were identified: parvoviral enteritis (n = 26), pyometra (n = 20), septic peritonitis (n = 19), and miscellanea (n = 26). The canine acute patient physiologic and laboratory evaluation fast score (APPLEfast), serum C-reactive protein (CRP) and albumin concentrations were reviewed in all enrolled dogs. Increased CRP (252.6 ± 119.2 mg/L; Reference Interval: 0–8.5 mg/L) and significant lower serum albumin and Apo-A1 concentrations were documented in dogs with sepsis (22.8 ± 5.3 g/L and 1.17 ± 0.27 g/L, respectively) compared to healthy ones (33.1 ± 2.5 g/L and 1.32 ± 0.05 g/L, respectively) (P < 0.0001). According to the origin of sepsis, only the subgroup of dogs with septic peritonitis had significantly lower Apo-A1 (1.03 ± 0.26 g/L) concentrations compared to healthy dogs (P < 0.001). No significant differences were found in serum albumin and CRP concentrations, and in APPLEfast score values among the different subgroups of sepsis. Diagnosis of septic peritonitis was associated with a higher frequency of death (P = 0.006). In septic dogs, significant lower Apo-A1 concentrations were detected in non-survivors (1.02 ± 0.28 g/L; n = 27) compared to survivors (1.23 ± 0.24 g/L; n = 64; P = 0.0007). Moreover, significant higher values of the APPLEfast score were calculated in non-survivors (26 ± 4; n = 19) compared to survivors (23 ± 4; n = 51) (P = 0.0114). According to the area under the ROC curve analysis, Apo-A1

This research analyzed archival health and wellness program data (2018: 169 males, 39 females; 2019: 194 males, 43 females) to document police officer lipid profiles, and correlate lipids with fitness. Bloodwork included total cholesterol (TC), low-density lipoproteins (LDL-C), high-density lipoproteins (HDL-C), and triglycerides (TG). Fitness data included maximal aerobic capacity (V·O2max); sit-and-reach; push-ups; vertical jump; grip strength; sit-ups; and relative bench press (RBP). Lipid profiles were compared to national standards. Spearman’s correlations derived relationships between lipids and fitness (p < 0.05). Over 2018–2019, 68–76% of officers had desirable TC (

Lecithin-cholesterol acyltransferase (LCAT), an enzyme that participates in lipoprotein metabolism, plays an important role in cholesterol homeostasis. Mutations in the LCAT gene can cause two rare genetic disorders: familial LCAT deficiency (FLD), which is characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure, and fish-eye disease (FED), which causes dyslipidemia and progressive corneal opacities. Herein, we report six suspected cases of FLD in the backlands of Piauí, located in northeast Brazil. A genetic diagnosis was performed in index cases. Among these, a further investigation was performed to identify new cases in the families. In addition, molecular analyses were performed to verify the levels of consanguinity within families and the existence of a genetic relationship between them. All six index cases were confirmed as FLD with an identical mutation (c.803G > A, p.R268H). The genetic investigation confirmed another 7 new cases of FLD, 52 heterozygous and 6 individuals without mutations. The rate of consanguinity revealed that marriages within the family did not contribute to the high number of FLD cases within the restricted region. The elders of each family (patriarchs and matriarchs) were subjected to a kinship analysis and were more genetically related to each other than the control group. Bayesian analysis was implemented to confirm the hypothesis of connectivity among patriarchs and matriarchs and indicated that they were genetically more related to each other than would be randomly expected, thus suggesting the occurrence of a possible founder effect in these families.

Background: Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL)-associated enzyme with antioxidative properties, which may protect against the development of cardiovascular disease. Alcohol consumption increases HDL cholesterol, but the extent to which alcohol consumption gives rise to higher serum PON-1 activity is uncertain.Objective: In a population-based study, we determined the relation of serum PON-1 activity with alcohol consumption when taking account of HDL cholesterol and apolipoprotein A-I (apoA-I), its major apolipoprotein.Design: A cross-sectional study was performed in 8224 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Alcohol consumption was categorized as 1) no/rarely (25.3%); 2) 0.1-10 g/d (49.3%); 3) 10-30 g/d (20.1%); and 4) >30 g/d (5.2%) with 1 drink equivalent to 10 g alcohol. Serum PON-1 activity was measured as its arylesterase activity (phenyl acetate as substrate).Results: Median serum PON-1 activity was 50.8, 53.1, 54.4, and 55.7 U/L in the 4 categories of alcohol consumption, respectively (P 30 g/d. Multivariable linear regression analysis demonstrated that PON-1 activity was related to alcohol consumption independently from clinical covariates, high sensitivity C-reactive protein, and lipid concentrations, including HDL cholesterol (P 30 g alcohol/d.Conclusions: Alcohol consumption is associated with an increase in serum PON-1 activity, but its effect seems to reach a plateau with alcohol consumption of 10-30 g/d.

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

Supplemental Digital Content is available in the text., Objective— Reverse cholesterol transport (RCT) is a major mechanism by which HDL (high-density lipoprotein) protects against atherosclerosis. Endothelial lipase (EL) reportedly reduces HDL levels, which, in theory, would increase atherosclerosis. However, it remains unclear whether EL affects RCT in vivo. Approach and Results— Adenoviral vectors expressing EL or luciferase were intravenously injected into mice, and a macrophage RCT assay was performed. As expected, hepatic EL overexpression markedly reduced HDL levels. In parallel, plasma 3H-cholesterol counts from the EL-expressing mice decreased by 85% compared with control. Surprisingly, there was no difference in fecal 3H-cholesterol excretion between the groups. Kinetic studies revealed increased catabolism/hepatic uptake of 3HDL-cholesteryl ether, resulting in no change in fecal HDL-cholesteryl ester excretion in the mice. To explore underlying mechanisms for the preservation of RCT despite low HDL levels in the EL-expressing mice, we investigated the effects of hepatic SR-BI (scavenger receptor class B type I) knockdown. RCT assay revealed that knockdown of SR-BI alone reduced fecal excretion of macrophage-derived 3H-cholesterol. Interestingly, hepatic EL overexpression under SR-BI inhibition further attenuated fecal tracer counts as compared with control. Finally, we observed that EL overexpression enhanced in vivo RCT under pharmacological inhibition of hepatic ABCA1 (ATP-binding cassette transporter A1) by probucol. Conclusions— Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo. In contrast, EL-modified HDL might negatively regulate RCT via hepatic ABCA1. Despite extreme hypoalphalipoproteinemia, RCT is maintained in EL-expressing mice via SR-BI/ABCA1-dependent pathways.

Visual Abstract, Highlights • The atheroprotective effects of apoA-I are dependent on the plaque stage from which apoA-I is infused. • The atheroprotective effects of apoA-I infusions are also impaired in older mice with a greater disease milieu. • Ex vivo studies with mouse HDL found an impairment in HDL functionality with increasing disease/age of the mice as well as a reduced ability of apoA-I infusions to improve the atheroprotective functions of HDL. • Our study provides understanding regarding the disparity between the very positive results of HDL/apoA-I raising in preclinical studies, largely performed in younger animals with early-stage disease, and the large-scale HDL-raising clinical trials in more elderly patients with established plaque that have failed to show benefit., Summary Preclinical studies have shown benefit of apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL) raising in atherosclerosis; however, this has not yet translated into a successful clinical therapy. Our studies demonstrate that apoA-I raising is more effective at reducing early-stage atherosclerosis than late-stage disease, indicating that the timing of HDL raising is a critical factor in its atheroprotective effects. To date, HDL-raising clinical trials have only been performed in aged patients with advanced atherosclerotic disease. Our findings therefore provide insight, related to important temporal aspects of HDL raising, as to why the clinical trials have thus far been largely neutral.

Background Recent evidence suggests that the association between dietary saturated fatty acids (SFAs) and coronary artery disease risk varies according to food sources. How SFAs from butter and cheese influence HDL-mediated cholesterol efflux capacity (CEC), a key process in reverse cholesterol transport, is currently unknown. Objective In a predefined secondary analysis of a previously published trial, we have examined how diets rich in SFAs from either cheese or butter influence HDL-mediated CEC, compared with diets rich in either monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids (PUFAs). Methods In a randomized crossover controlled consumption trial, 46 men and women with abdominal obesity consumed 5 isocaloric diets, each for 4 wk. Two diets were rich in SFAs either from cheese (CHEESE) or butter (BUTTER) [12.4-12.6% of energy (%E) as SFAs, 32%E as fat, 52%E as carbohydrates]. In 2 other diets, SFAs (5.8%E) were replaced with either MUFAs from refined olive oil (MUFA) or PUFAs from corn oil (PUFA). Finally, a lower fat and carbohydrate diet was used as a control (5.8%E as SFAs, 25.0%E as fat, 59%E as carbohydrates; CHO). Post-diet HDL-mediated CEC was determined ex vivo using radiolabelled J774 macrophages incubated with apolipoprotein B-depleted serum from the participants. Results Mean (±SD) age was 41.4 ± 14.2 y, and waist circumference was 107.6 ± 11.5 cm in men and 94.3 ± 12.4 cm in women. BUTTER and MUFA increased HDL-mediated CEC compared with CHEESE (+4.3%, P = 0.026 and +4.7%, P = 0.031, respectively). Exploring the significant diet × sex interaction (P = 0.044) revealed that the increase in HDL-mediated CEC after BUTTER compared with CHEESE was significant among men (+6.0%, P = 0.047) but not women (+2.9%, P = 0.19), whereas the increase after MUFA compared with CHEESE was significant among women (+9.1%, P = 0.008) but not men (-0.6%, P = 0.99). Conclusion These results provide evidence of a food matrix effect modulating the impact of dairy SFAs on HDL-mediated CEC with potential sex-related differences that deserve further investigation. This trial was registered at clinicaltrials.gov as NCT02106208.

Background: Due to the high prevalence of diabetes and dyslipidemia, which are risk factors for diseases such as metabolic syndrome in today's modern society, especially in the working population, the aim of this study was to determine the effect of shift work on fasting blood glucose and lipid profiles in workers in Isfahan City, Iran, during the years 2014-2015. Methods: In this cross-sectional study, 6983 employees referred to labor centers for periodic examinations were entered according to the inclusion and exclusion criteria. The patients were divided into three groups based on the type of work shift as day, fixed night, and rotate shift workers, and two groups based of type of work as official and non-official workers. The level of blood glucose and lipid profiles [cholesterol, triglyceride, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)] were evaluated and compared between the groups. Findings: There were no significant differences between three groups according to the levels of fasting blood glucose (FBS), triglyceride, and high-density lipoprotein (P > 0.050); but there was a significant difference between the three groups based on the cholesterol and low-density lipoprotein (P < 0.001, for both); so that the cholesterol and low-density lipoprotein levels were higher in day shift worker than others. Conclusion: Based on the results of this study, cholesterol and low-density lipoprotein levels was higher in day shift worker than fixed night and rotate shift workers in high sample sizes of workers in Isfahan City.

α-synuclein (α-syn) is a major culprit of Parkinson’s disease (PD), although lipoprotein metabolism is very important in the pathogenesis of PD. α-syn was expressed and purified using the pET30a expression vector from an E. coli expression system to elucidate the physiological effects of α-syn on lipoprotein metabolism. The human α-syn protein (140 amino acids) with His-tag (8 amino acids) was expressed and purified to at least 95% purity. Isoelectric focusing gel electrophoresis showed that the isoelectric point (pI) of α-syn and apoA-I were pI = 4.5 and pI = 6.4, respectively. The lipid-free α-syn showed almost no phospholipid-binding ability, while apoA-I showed rapid binding ability with a half-time (T1/2) = 8 ± 0.7 min. The α-syn and apoA-I could be incorporated into the reconstituted HDL (rHDL, molar ratio 95:5:1:1, palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I:α-syn with the production of larger particles (92 Å) than apoA-I-rHDL (86 and 78 Å) and α-syn-rHDL (65 Å). An rHDL containing both apoA-I and α-syn showed lower α-helicity around 45% with a red shift of the Trp wavelength maximum fluorescence (WMF) from 339 nm, while apoA-I-HDL showed 76% α-helicity and 337 nm of WMF. The denaturation by urea addition showed that the incorporation of α-syn in rHDL caused a larger increase in the WMF than apoA-I-rHDL, suggesting that the destabilization of the secondary structure of apoA-I by the addition of α-syn. On the other hand, the addition of α-syn induced two-times higher resistance to rHDL glycation at apoA-I:α-syn molar ratios of 1:1 and 1:2. Interestingly, low α-syn in rHDL concentrations, molar ratio of 1:0.5 (apoA-I:α-syn), did not prevent glycation with more multimerization of apoA-I. In the lipid-free and lipid-bound state, α-syn showed more potent antioxidant activity than apoA-I against cupric ion-mediated LDL oxidation. On the other hand, microinjection of α-syn (final 2 μM) resulted in 10% less survival of zebrafish embryos than apoA-I. A subcutaneous injection of α-syn (final 34 μM) resulted in less tail fin regeneration than apoA-I. Interestingly, incorporation of α-syn at a low molar ratio (apoA-I:α-syn, 1:0.5) in rHDL resulted destabilization of the secondary structure and impairment of apoA-I functionality via more oxidation and glycation. However, at a higher molar ratio of α-syn in rHDL (apoA-I:α-syn = 1:1 or 1:2) exhibited potent antioxidant and anti-glycation activity without aggregation. In conclusion, there might be a critical concentration of α-syn and apoA-I in HDL-like complex to prevent the aggregation of apoA-I via structural and functional enhancement.

Introduction Genetic variants have been replicated for association with type 2 diabetes mellitus (T2D) and many of them with diabetes-related traits. Because T2D is highly prevalent in Mexico, this study aimed to test the association of CDKN2A/B, PPARGC1A, VEGFA, SIRT1 and UCP2 gene polymorphisms (rs10811661, rs8192678, rs2010963, rs7896005 and rs659366 respectively) with metabolic traits in 415 unrelated Mexican mestizos with T2D under three models of inheritance. Material and methods A total of 415 unrelated Mexican mestizos were genotyped by TaqMan assays. Triglycerides, cholesterol, glucose, high-density lipoprotein cholesterol (HDL-C), insulin and anthropometric measurements were determined and the HOMA-IR was calculated. Association studies were tested by the Kruskal-Wallis test, linear regression, statistical power analysis, Bonferroni correction, paired SNP analysis, and physical interaction by GeneMANIA. Results All polymorphisms were in Hardy-Weinberg equilibrium, and the association by genotype with T2D-related traits displayed nominal significance for rs8192678 with glucose (p = 0.023) and triglycerides (p = 0.013); rs2010963 with diastolic blood pressure (DBP) (p = 0.012) and cholesterol (p = 0.013); rs7896005 with DBP (p = 0.012) and insulin (p = 0.011); and rs659366 with cholesterol (p = 0.034), glucose (p = 0.031) and triglycerides (p = 0.028); and the association of rs2010963 with HDL-C (p = 0.0007) was significant. Linear regression performed with three models of inheritance, adjusted by age + sex + BMI and corrected with Bonferroni, showed a significant association of rs2010963 with HDL-C in an additive model (p = 0.007); and rs7896005 was significantly associated with DBP in the recessive model (p = 0.006). Conclusions Rigorous analysis evidenced the association of VEGFA rs2010963 and SIRT1 rs7896005 with HDL-C and DBP respectively; these traits are known predictors of cardiovascular complications, which increase the risk of cardiovascular diseases in this population.