High-density Lipoprotein Composition Research Articles

Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.

Cardiovascular disease is a leading cause of death around the world. Overall diet quality and dietary behaviors are core contributors to metabolic health. While therapeutic targets have traditionally focused on levels of lipoprotein cholesterol when evaluating cardiovascular risk, current perspectives on high-density lipoprotein (HDL) have shifted to evaluating the functionality of this lipoprotein particle. Effects of diet on cardiovascular health are mediated through multiple pathways, but the impact on HDL composition and function deserves greater attention. Potential areas of investigation involve changes in particle characteristics, distribution, microRNA cargo, and other functional changes such as improvements to cholesterol efflux capacity. Various dietary patterns like the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diet have beneficial effects on cardiovascular health and may prevent cardiovascular events. These healthful dietary patterns tend to be rich in plant-based foods, with cardiovascular benefits likely resulting from synergistic effects of the individual dietary components. The purpose of this review is to summarize current perspectives on selected functions of HDL particles and how various dietary patterns affect cardiovascular health biomarkers, with a focus on HDL functionality.

Correlation between serum amyloid A and high density lipoprotein composition in dialysis patients

Correlation between serum amyloid A and high density lipoprotein composition in dialysis patients

Cardiometabolic Profile after Pediatric Cancer Treatment: Insight into HDL Composition and Nutritional Intake

Few studies have investigated the impact of pediatric cancer treatment on cardiometabolic health, although chemotherapy in children can cause rapid weight gain, transient hypertension, elevated blood glucose and hyperlipidemia. Besides, we have previously shown that young survivors of childhood leukemia are at increased risk of having the metabolic syndrome, dyslipidemia, hypertension and altered high‐density lipoprotein (HDL) composition. This study aims to examine the cardiometabolic profile of children after cancer treatment in relation to their diet, as well as HDL2 and HDL3 composition.MethodsPatients were recruited at Sainte‐Justine University Health Center in Montreal as part of the VIE Program (Valorization, Implication, Education). Fasting blood samples were collected and we assessed participants' anthropometric, metabolic, and biochemical profiles. Three day food records were used to evaluate dietary intake. HDL2 and HDL3 fractions were isolated from plasma by ultracentrifugation, and total protein and lipids were measured by colorimetric reactions.ResultsTo date, 63 patients (44.4% boys) were recruited. Mean age was 11.7 ± 5.6 years and 46.0% were treated for acute lymphoblastic leukemia. The time elapsed since the last treatment was 17.0 ± 9.7 months. We found that 25.4% of participants (n=16/63) had hypertension, 22.2% (n=14/63) were obese and 8.9% (n=5/56) were insulin resistant. One third of patients had dyslipidemia (n=21/63), a risk that was increased by age (OR: 1.31, 95%CI: 1.16–1.50, P<0.01). Patients over 10 years old had insufficient intakes of several nutrients (vitamins A and E, folate, magnesium, zinc). Compared to healthy children, the proportion of esterified cholesterol in HDL2 was lower (18.6 ± 1.2% vs. 11.9 ± 1.4%, P<0.01), but protein content was higher (41.1 ± 1.6% vs. 48.8 ± 1.0, P<0.01). The proportion of esterified cholesterol was also lower in HDL3 fractions of patients treated for cancer (12.6 ± 1.3% vs. 10.1 ± 0.7%, P<0.01).ConclusionThese results indicate cardiometabolic disturbances and anomalies in HDL composition in children shortly after cancer treatment. They emphasize the need for nutritional interventions in this high‐risk population.Support or Funding InformationThis work is funded by The Foundation Centre de cancérologie Charles‐Bruneau and The Joy of Eating Better Foundation and the CHU Sainte‐Justine Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Serum amyloid A levels are associated with polymorphic variants in the serum amyloid A 1 and 2 genes

BackgroundSerum amyloid A (SAA) is secreted by liver hepatocytes in response to increased inflammation whereupon it associates with high-density lipoprotein (HDL) and alters the protein and lipid composition of HDL negating some of its anti-atherogenic properties.AimsTo identify variants within the SAA gene that may be associated with SAA levels and/or cardiovascular disease (CVD).MethodsWe identified exonic variants within the SAA genes by deoxyribonucleic acid (DNA) Sanger sequencing. We tested the association between SAA variants and serum SAA levels in 246 individuals with and without CVD.ResultsIncreased SAA was associated with rs2468844 (beta [β] = 1.73; confidence intervals [CI], 1.14–1.75; p = 0.01), rs1136747 (β = 1.53 (CI, 1.11–1.73); p = 0.01) and rs149926073 (β = 3.37 (CI, 1.70–4.00); p = 0.02), while rs1136745 was significantly associated with decreased SAA levels (β = 0.70 (CI, 0.53–0.94); p = 0.02). Homozygous individuals with the SAA1.3 haplotype had significantly lower levels of SAA compared with those with SAA1.1 or SAA1.5 (β = 0.43 (CI, 0.22–0.85); p = 0.02) while SAA1.3/1.5 heterozygotes had significantly higher SAA levels compared with those homozygous for SAA1.1 (β = 2.58 (CI, 1.19–5.57); p = 0.02).ConclusionsWe have identified novel genetic variants in the SAA genes associated with SAA levels, a biomarker of inflammation and chronic disease. The utility of SAA as a biomarker for inflammation and chronic disease may be influenced by underlying genetic variation in baseline levels.

UPTAKE OF CHOLESTEROL ESTERS BEING A PART OF THE DIFFERENT FRACTIONS OF BLOOD PLASMA LIPOPROTEINS BY RATS ORGANS AND TISSUES

The paper deals with the functions of the main classes of blood plasma lipoproteins (LP) that are associated with the transport of cholesterol esters included in their composition. The aim of the study was to investigate the features of the uptake of cholesterol esters associated with plasma LP fractions (very low (VLDL), low (LDL), and high density LPs (HDL)) by rat organs and tissues, and to show the participation of various subfractions of HDL (HDL 2 and HDL 3 ) as specific cholesterol carriers in the main steroid-producing organs of rats. Material and methods. The in vivo studies with intravenous LP injection of 14 C labeled cholesterol oleate ( 14 C-OCh) associated with plasma LP fractions have been carried out. Results. Intravenous injection of a 14 C-OCh) in the composition with VLDL led to the maximal mark uptake by the liver. Three times less uptake of labeled cholesterol was observed in the adrenal glands, testes and heart muscle. In other tissues radioactivity gradually decreased in the raw: spleen > lungs > kidneys > thyroid gland and adipose tissue. After the injection of 14 C-OCh in the composition of LDL marked predominant uptake of the label by the adrenal glands, testes, and liver. A feature of the use of HDL as a carrier platform for 14 C-OCh is the high accumulation of label in steroid-producing organs: the adrenal glands and testis. The dynamics of uptake of 14 C-OCh in the composition of HDL by the adrenal glands and testes of rats in different time intervals after injection (30 min, 3, 6 and 12 h) was studied. Adrenal cells actively uptake 14 C-OCh from HDL, as a result of which the radioactivity of the tissue increased rapidly and after 30 minutes almost reached its maximum. In contrast to the adrenal glands uptake of the testis was characterized by a gradual increase in radioactivity with a maximum of 6 hours and a rather sharp decrease to 12 hours from the beginning of the experiment. In vitro experiments showed the differences in the effect of HDL 2 and HDL 3 on the corticosterone production by the adrenal glands of rats. Conclusions. The paper presents the features of uptake of cholesterol esters by organs and tissues of rats depending on the used LP-transporter (VLDL, LDL, HDL). In addition, the results suggest that HDL 3 subfraction may be the more preferred source of cholesterol for steroid synthesis in the adrenal cortex of rats compared to HDL 2 subfraction.

Associations between epicardial adipose tissue, subclinical atherosclerosis and high-density lipoprotein composition in type 1 diabetes

BackgroundThe pathophysiology of cardiovascular complications in people with type 1 diabetes (T1DM) remains unclear. An increase in epicardial adipose tissue (EAT) and alterations in the composition of high-density lipoprotein (HDL) are associated with coronary artery disease, but information on its relationship in T1DM is very limited. Our aim was to determine the association between EAT volume, subclinical atherosclerosis, and HDL composition in type 1 diabetes.MethodsSeventy-two long-term patients with T1DM without clinical atherosclerosis were analyzed. EAT volume and subclinical atherosclerosis were measured using cardiac computed tomography angiography. EAT was adjusted according to body surface to obtain an EAT index (iEAT). HDL composition was determined.ResultsThe mean iEAT was 40.47 ± 22.18 cc/m2. The bivariate analysis showed positive associations of the iEAT with gender, age, hypertension, dyslipidemia, smoking, body mass index, waist circumference, insulin dose, and triglyceride (P < 0.05). The iEAT correlated positively with small HDL, increased content of apolipoprotein (apo)A-II and apoC-III, and decreased content of apoE and free cholesterol. Multiple linear regression showed that age, apoA-II content in HDL, and waist circumference were independently associated with the iEAT. Fifty percent of the patients presented subclinical atherosclerotic lesions. These patients had a higher iEAT, and their HDL contained less cholesterol and more apoA-II and lipoprotein-associated phospholipase A2 than patients without subclinical atherosclerosis.ConclusionAlterations in the composition of HDL in TIDM are associated with increased iEAT and the presence of subclinical atherosclerosis. We propose that these abnormalities of HDL composition could be useful to identify T1DM patients at highest cardiovascular risk.

Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile.

According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10-22) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 × 10-6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.

Reconstituted Discoidal High-Density Lipoproteins: Bioinspired Nanodiscs with Many Unexpected Applications.

Summarize the initial discovery of discoidal high-density lipoprotein (HDL) in human plasma and review more recent innovations that span the use of reconstituted nanodisc HDL for membrane protein characterization to its use as a drug carrier and a novel therapeutic agent for cardiovascular disease. Using a wide variety of biophysical techniques, the structure and composition of endogenous discoidal HDL have now largely been solved. This has led to the development of new methods for the in vitro reconstitution of nanodisc HDL, which have proven to have a wide variety of biomedical applications. Nanodisc HDL has been used as a platform for mimicking the plasma membrane for the reconstitution and investigation of the structures of several plasma membrane proteins, such as cytochrome P450s and ABC transporters. Nanodisc HDL has also been designed as drug carriers to transport amphipathic, as well as hydrophobic small molecules, and has potential therapeutic applications for several diseases. Finally, nanodisc HDL itself like native discoidal HDL can mediate cholesterol efflux from cells and are currently being tested in late-stage clinical trials for cardiovascular disease. The discovery of the characterization of native discoidal HDL has inspired a new field of synthetic nanodisc HDL, which has offered a growing number of unanticipated biomedical applications.

High-density lipoproteins (HDL) composition and function in preeclampsia.

To evaluate (a) the properties of high-density lipoproteins (HDL)/cholesterol, which include apolipoprotein A-1 (ApoA1) and paraoxonase1 (PON1), both are negative predictors of cardiovascular risk and (b) HDL function, among women with preeclampsia (PE). PE is a multi-system disorder, characterized by onset of hypertension and proteinuria or other end-organ dysfunction in the second half of pregnancy. Preeclampsia is associated with increased risk for later cardiovascular disease. The inverse association between HDL, cholesterol levels and the risk of developing atherosclerotic cardiovascular disease is well-established. Twenty-five pregnant women [19 with PE and 6 with normal pregnancy (NP)] were recruited during admission for delivery. HDL was isolated from blood samples. PON1 activity and HDL were analyzed. An in vitro model of endothelial cells was used to evaluate the effect of HDL on the transcription response of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) mRNA expression. PON1 activity (units/ml serum) was lower in the PE group compared to normal pregnancy (NP) (6.51 ± 0.73 vs. 9.98 ± 0.54; P = 0.015). Increased ApoA1 was released from PE-HDL as compared to NP-HDL (3.54 ± 0.72 vs. 0.89 ± 0.35; P = 0.01). PE-HDL exhibited increased VCAM-1 mRNA expression and decreased eNOS mRNA expression on TNF-α stimulated endothelial cells as compared to NP-HDL. HDL from women with PE reduced PON1 activity and increased ApoA1 release from HDL particles. This process was associated with increased HDL diameter, suggesting impaired HDL anti-oxidant activity. These changes might contribute to higher long-term cardiovascular risks among women with PE.

Abstract 389: The Impact of Phospholipid Composition of Synthetic High-Density Lipoprotein on Its Pharmacological Activity

Objective: Synthetic high-density lipoprotein (sHDL) is a nanoparticle that can mimic biological activities of endogenous HDL such as reverse cholesterol transport (RCT) and anti-inflammatory properties. We hypothesize that differences in the fluidity of sHDL phospholipids at body temperature effect plasma stability of sHDL, particle ability to efflux cholesterol and inhibit inflammation. Methods: sHDL particles with different membrane fluidities were prepared complexing phospholipids with different fatty acid chain length and saturation (POPC, DMPC, DPPC, and DSPC) with the apoA-I mimetic peptide, PVLDLFRELLNELLEALKQKLK (22A). The ability of various sHDL compositions to efflux cholesterol, inhibit NF-kB activation and cytokine release, and cause lipid raft disruption was examined in RAW264.7 macrophages. Various sHDL were administered to mice challenged by injection of 0.05 mg/kg LPS at 10 mg/kg dose and the levels of cytokine release were measured at 2 hours post-dose. Various sHDL were dosed to normal rats at 50 mg/kg and cholesterol mobilization and pharmacokinetics were examined. Results: 22A-POPC and 22A-DMPC sHDL have relatively fluid phospholipid layer at body temperature compared to 22A-DPPC and 22A-DSPC sHDL due to lower phospholipid transition temperature. 22A-POPC and 22A-DMPC sHDL inhibited NF-κB activation and cytokine release in a concentration-dependent manner. From murine endotoxin infusion studies, 22A-DMPC displayed the significant inhibition of cytokine release. Cholesterol efflux studies demonstrated that 22A-POPC and 22A-DMPC displayed highest cholesterol efflux. Interestingly, in vivo RCT study showed that 22A-DSPC had longest plasma residence time and resulted in greatest cholesterol mobilization. Conclusions: Phospholipid composition of sHDL particles has a significant effect on its cholesterol efflux and anti-inflammatory properties, yet the effect appears to be different in vitro and in vivo . in vitro effect is driven by the ability of fluid phospholipid bilayer to bind LPS, cholesterol, and LCAT, while in vivo effect is defined by particle stability in plasma and residence time in the body.

A short-term increase in dietary cholesterol and fat intake affects high-density lipoprotein composition in healthy subjects

Background and AimsHigh-cholesterol and high-fat diets alter biochemical composition and anti-oxidant properties of high-density lipoproteins (HDL) in animals. Whether this occurs in humans is unknown. Therefore, we examined the effect of a short-term elevation in dietary cholesterol and fat intake on HDL composition in healthy subjects. Methods and ResultsIn a randomized, crossover clinical trial, 14 healthy young volunteers followed a 14-day low-cholesterol/low-fat diet (LChF) and a 14-day isocaloric high-cholesterol/high-fat diet (HChF) in a random order. After each diet, we measured HDL concentrations of hydroxyeicosatetraenoic acids (HETE), hydroxyoctadecadienoic acids (HODE), and haptoglobin, as well as serum amyloid A (SAA) and paroxonase-1 activity (PON-1). HDL concentrations of 15-HETE (+254%, p = 0.002), 5-HETE (+116%, p = 0.004), 13-HODE (+102%, p = 0.049), and SAA levels (+75%, p = 0.007) were significantly higher after the HChF than after the LChF. Furthermore, haptoglobin was marginally increased (+32%, p = 0.091) while PON-1 activity was unaffected (−16%, p = 0.366) by the HChF. ConclusionIn healthy subjects, a short-term elevation in dietary cholesterol and fat intake increases HDL lipid hydroperoxide content (15-HETE, 5-HETE, 13-HODE) and SAA levels, which are key features of dysfunctional HDL. This is the first study showing that a physiologic manipulation of dietary cholesterol and fat intake affects HDL lipidome and proteome in healthy subjects independently of weight changes. Clinical Trial RegistrationNCT02549144.

Transcoronary gradients of HDL-associated MicroRNAs in unstable coronary artery disease

AimsMicroRNAs (miRNAs) are transported on high-density lipoproteins (HDLs) and HDL-associated miRNAs are involved in intercellular communication. We explored HDL-associated miRNAs concentration gradients across the coronary circulation in stable and unstable coronary artery disease patients and whether changes in the transcoronary gradient were associated with changes in HDL composition and size. MethodsAcute coronary syndrome (ACS, n=17) patients, those with stable coronary artery disease (stable CAD, n=19) and control subjects without CAD (n=6) were studied. HDLs were isolated from plasma obtained from the coronary sinus (CS), aortic root (arterial blood) and right atrium (venous blood). HDL-associated miRNAs (miR-16, miR-20a, miR-92a, miR-126, miR-222 and miR-223) were quantified by TaqMan miRNA assays. HDL particle sizes were determined by non-denaturing polyacrylamide gradient gel electrophoresis. HDL composition was measured immunoturbidometrically or enzymatically. ResultsA concentration gradient across the coronary circulation was observed for all the HDL-associated miRNAs. In ACS patients, there was a significant inverse transcoronary gradient for HDL-associated miR-16, miR-92a and miR-223 (p<0.05) compared to patients with stable CAD. Changes in HDL-miRNA transcoronary gradients were not associated with changes in HDL composition or size. ConclusionHDLs are depleted of miR-16, miR-92a and miR-223 during the transcoronary passage in patients with ACS compared to patients with stable CAD.

Progression of Chronic Kidney Disease Affects HDL Impact on Lipoprotein Lipase (LPL)-Mediated VLDL Lipolysis Efficiency

Background/Aims: Hypertriglyceridaemia (HTG) and reduction and dysfunction of high density lipoprotein (HDL) are common lipid disturbances in chronic kidney disease (CKD). HTG in CKD is caused mainly by the decreased efficiency of lipoprotein lipase (LPL)-mediated very low density lipoprotein triglyceride (VLDL-TG) lipolysis. It has not been clarified whether HDL dysfunction in CKD contributes directly to HTG development; thus, the aim of this study was to assess the impact of CKD progression on the ability of HDL to enhance LPL-mediated VLDL-TG lipolysis efficiency. Methods: VLDL was isolated from non-dialysis patients in CKD stages 3 and 4 and from non-CKD patients. The VLDL was incubated with LPL at the constant LPL:VLDL-TG ratio, in the absence or presence of HDL. After incubation, the VLDL was separated and the percentage (%) of hydrolyzed TG was calculated. Results: HDL presence increased the lipolysis efficiency of VLDL isolated from CKD and non-CKD patients, for the VLDL-TG> 50 mg/dl. Its effect was dependent on the VLDL-TG and HDL-cholesterol concentrations in the reaction mixtures: the higher the concentrations of VLDL-TG and HDL-cholesterol, the greater the effect. The positive impact of HDL on VLDL lipolysis was modified by CKD progression: the percentage of lipolyzed VLDL-TG in the presence of HDL decreased with a reduction in eGFR (r=0.43, p=0.009), and for patients with stage 4 CKD, no positive impact of HDL on lipolysis was observed. The percentage of lipolyzed TG correlated negatively with apoE and apoCs content in VLDL, and positively with HDL-apoCII, as well as with VLDL and HDL apoCII/ apoCIII ratios. The progression of CKD was associated with unfavourable changes in VLDL and HDL composition; apoE and apoCs levels increased in VLDL with a decrease in eGFR whereas the HDL-cholesterol level decreased. Conclusion: The progression of CKD affects lipoprotein composition and properties, and modulates the positive impact of HDL on VLDL lipolysis efficiency. In CKD patients, HDL deficiency and dysfunction can directly affect hypertriglyceridaemia development.

Weight Loss and Exercise Alter the High-Density Lipoprotein Lipidome and Improve High-Density Lipoprotein Functionality in Metabolic Syndrome.

High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943.

HDL acceptor capacities for cholesterol efflux from macrophages and lipid transfer are both acutely reduced after myocardial infarction

BackgroundThe transport of lipids from the artery wall is one of the most essential anti-atherogenic functions of high-density lipoprotein (HDL). Recent reports of changes in the HDL composition, during myocardial infarction (MI), suggest that this function may be altered. MethodsForty-one consecutive patients with ST-segment elevation MI enrolled at the Brasilia Heart Study were selected. The following HDL-related measures were determined upon admission (D1) and on the fifth day (D5) after MI: C-reactive protein, CETP and PLTP activity, HDL composition, efflux of cholesterol from J774 macrophages to HDL, and transfer of unesterified and esterified cholesterol, triglycerides and phospholipids from a donor nanoemulsion to HDL. ResultsFrom D1 to D5, the activity of CETP decreased by 25%, but PLTP activity remained unchanged. Esterified cholesterol (−23%) and phospholipid (−9.5%) contents of HDL decreased. Transfer of triglycerides (−36.5%) and esterified cholesterol (−14.7%) to HDL from nanoemulsions was reduced, but other lipids transfers were unchanged. Cholesterol efflux to HDL was also diminished by 8.5% (p=0.04) on D5 compared to D1. It was more pronounced in patients above the 75th percentile of C-reactive protein. ConclusionsAfter an MI, a simultaneous decrease in lipid transfer to HDL and in the capacity of HDL to efflux cholesterol from cells occurs. Thus, HDL with inferior atheroprotective properties may be generated in the acute post-MI period.

Kidney function is associated with an altered protein composition of high-density lipoprotein

Patients with chronic kidney disease (CKD) exhibit a myriad of metabolic derangements, including dyslipidemia characterized by low plasma concentrations of high-density lipoprotein (HDL)-associated cholesterol. However, the effects of kidney disease on HDL composition have not been comprehensively determined. Here we used a targeted mass spectrometric approach to quantify 38 proteins contained in the HDL particles within a CKD cohort of 509 participants with a broad range of estimated glomerular filtration rates (eGFRs) (CKD stages I-V, and amean eGFR of 45.5 mL/min/1.73m2). After adjusting formultiple testing, demographics, comorbidities, medications, and other characteristics, eGFR was significantly associated with differences in four HDL proteins. Compared to participants with an eGFR of 60mL/min/1.73m2 or more, those with an eGFR under 15mL/min/1.73m2 exhibited 1.89-fold higher retinol-binding protein 4 (95% confidence interval 1.34-2.67), 1.52-fold higher apolipoprotein C-III (1.25-1.84), 0.70-fold lower apolipoprotein L1 (0.55-0.92), and 0.64-fold lower vitronectin (0.48-0.85). Although the HDL apolipoprotein L1was slightly lower among African Americans than among Caucasian individuals, the relationship to eGFR didnot differ by race. After adjustment, no HDL-associated proteins associated with albuminuria. Thus, modest changes in the HDL proteome provide preliminary evidence for an association between HDL proteins and declining kidney function, but this needs to be replicated. Future analyses will determine if HDL proteomics is indeed a clinical predictor of declining kidney function or cardiovascular outcomes.

Metabolism of high density lipoprotein and the research progress of its effects on sepsis

Sepsis is a high-risk factor for the death of critical patients. High density lipoprotein (HDL) are the major protective serum proteins, and the serum levels of HDL are closely related to the severity of sepsis. The anti-inflammatory and anti-oxidation properties of HDL, may be able to play an important role in the innate immune response. Thereby it may reduce the damage of septic shock and multiple organ dysfunction syndrome (MODS) in animals or human beings, and improve the prognosis. In order to unveil the metabolism of HDL in septic patients and its effects on both progression and prognosis of sepsis, this review not only focuses on the composition and structure of HDL, but also analyzes its pivotal role in inflammatory immune response and anti-oxidation.

Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease.

The vascular effects of high-density lipoproteins (HDL) differ under certain clinical conditions. The composition of HDL is modified in patients with chronic kidney disease (CKD). As a consequence, uremic HDL induces endothelial dysfunction. We have previously shown that accumulation of symmetric dimethylarginine (SDMA) in HDL causes these adverse effects of HDL in CKD. The aim of the study is to determine the impact of the accumulation of SDMA on the association between HDL and mortality. Mortality, renal function, serum SDMA and HDL-cholesterol (HDL-C) were assessed in the LURIC study including 3310 subjects undergoing coronary angiography. All-cause mortality was 30.0% during median follow-up of 9.9 years. Serum SDMA levels significantly predicted all-cause and cardiovascular mortality, and were significantly correlated with SDMA accumulation in HDL. Notably, higher serum SDMA was independently associated with lower cholesterol efflux (P = 0.004) as a measure of HDL functionality. In subjects with low SDMA levels, higher HDL-C was associated with significantly lower mortality. In contrast, in subjects with high SDMA, HDL-C was associated with higher mortality. These findings were confirmed in 1424 participants of the MONICA/KORA S3 cohort. Of note, we derived an algorithm allowing for calculation of biologically effective HDL-C' based on measured HDL-C and SDMA. We corroborated these clinical findings with invitro evidence showing that SDMA accumulation abolishes the anti-inflammatory and regenerative properties of HDL. The data identify SDMA as a marker of HDL dysfunction. These findings highlight on the pivotal role of SDMA accumulation in HDL as a mediator of pre-mature cardiovascular disease in patients with CKD.

Abstract P118: Cardioprotective Association Between High Density Lipoprotein Cholesterol and Endothelial Function Attenuated at Lower Levels of Estradiol in Women at Midlife. The SWAN Heart Study

Objective: Growing evidence suggests that the cardioprotective effects of high density lipoproteins (HDL) may be diminished over the menopause transition. Estradiol (E2), the leading ovarian estrogen that declines substantially during the menopause transition, is considered a potent antioxidant with potential impact on lipid peroxidation and formation of reactive oxygen species that could affect HDL cardioprotective capacities. Whether the cardioprotective effects of HDL on atherosclerotic subclinical measures are apparent only in the presence of high levels of E2 in women at midlife is not clear. We hypothesized that the expected positive association between levels of high density lipoprotein cholesterol (HDL-C) and endothelial function as indexed by flow-mediated dilation (FMD) is weaker at lower levels of E2. Methods: Participants were fromthe baseline visit of the Study of Women’s Health Across the Nation (SWAN) Heart study. Women with hysterectomy and/or bilateral oophorectomy and those on hormone therapy were excluded. B-mode ultrasound images of the right brachial artery before and after deflation were obtained to estimate % change in FMD. Linear regression analyses were utilized to model the difference between log-baseline arterial diameter and log-post-deflation arterial diameter as a function of the interaction between log-E2 and HDL-C levels. To illustrate, the interaction between E2 tertiles and HDL-C was presented as well. The final model adjusted for log-baseline arterial diameter, race, study site, cycle day of blood draw, menopause status, body mass index, and diastolic blood pressure. Results were presented as % change in FMD (95% CI). Results: The study included 322 women (60% White and 40% Black) aged 50.7±2.8 years who were either in pre-/early perimenopause (63%) or late peri-/postmenopause (37%). In the final model, a significant interaction between HDL-C and log-E2 levels on %FMD was found, P value for interaction=0.01; such that a positive association between HDL-C and %FMD was only evident among women in the high E2 tertile (E2 ≥51.1 pg/ml) [%FMD (95%CI) per 1 SD increase in HDL-C: 0.93%(0.21%, 1.64%)] and that %FMD per 1 SD increase in HDL-C was significantly lower in women in the low E2 tertile (E2 &lt;21.5 pg/ml) compared to women in the high E2 tertile [%FMD difference (95%CI): low E2 tertile vs. high E2 tertile: -0.98 (-1.88, -0.07), P-value=0.03]. Conclusions: The cardioprotective association of HDL-C on endothelial function depends on levels of E2 in women at midlife, such that HDL-C may not be protective to the vascular endothelium in the setting of low endogenous E2. Our analyses should be replicated in longitudinal settings. Future studies should investigate potential mechanistic pathways by which dynamic changes in E2 levels may impact HDL composition and functionality over the menopausal transition.

Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial.

The biological functions of high-density lipoproteins (HDLs) contribute to explaining the cardioprotective role of the lipoprotein beyond quantitative HDL cholesterol levels. A few small-scale interventions with a single antioxidant have improved some HDL functions. However, to date, no long-term, large-scale, randomized controlled trial has been conducted to assess the effects of an antioxidant-rich dietary pattern (such as a traditional Mediterranean diet [TMD]) on HDL function in humans. This study was performed in a random subsample of volunteers from the PREDIMED Study (Prevención con Dieta Mediterránea; n=296) after a 1-year intervention. We compared the effects of 2 TMDs, one enriched with virgin olive oil (TMD-VOO; n=100) and the other enriched with nuts (TMD-Nuts; n=100), with respect to a low-fat control diet (n=96). We assessed the effects of both TMDs on the role of HDL particles on reverse cholesterol transport (cholesterol efflux capacity, HDL ability to esterify cholesterol, and cholesteryl ester transfer protein activity), HDL antioxidant properties (paraoxonase-1 arylesterase activity and total HDL antioxidant capacity on low-density lipoproteins), and HDL vasodilatory capacity (HDL ability to induce the release of nitric oxide in endothelial cells). We also studied the effects of a TMD on several HDL quality-related characteristics (HDL particle oxidation, resistance against oxidative modification, main lipid and protein composition, and size distribution). Both TMDs increased cholesterol efflux capacity relative to baseline (P=0.018 and P=0.013 for TMD-VOO and TMD-Nuts, respectively). The TMD-VOO intervention decreased cholesteryl ester transfer protein activity (relative to baseline, P=0.028) and increased HDL ability to esterify cholesterol, paraoxonase-1 arylesterase activity, and HDL vasodilatory capacity (relative to control, P=0.039, P=0.012, and P=0.026, respectively). Adherence to a TMD induced these beneficial changes by improving HDL oxidative status and composition. The 3 diets increased the percentage of large HDL particles (relative to baseline, P<0.001). The TMD, especially when enriched with virgin olive oil, improved HDL atheroprotective functions in humans. URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639.