Capacity Of HDL Research Articles

CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet.

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL’s antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.

Paraoxonase-1 polymorphisms and cerebral ischemic stroke: a pilot study in mexican patients.

Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke.Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke.Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum.Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant.Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.

Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes

Background and aimsResearch on the biologic activities of HDL, such as cholesterol efflux capacity and HDL composition, has allowed the understanding of the effect of interventions directed to improve cardiovascular risk. Previously, statin therapy has shown conflicting results about its effects on cholesterol efflux capacity of HDL; the underlying mechanisms are unclear but studies with positive effects are associated with an increase of HDL-cholesterol levels. We investigated if 10 weeks of atorvastatin therapy changes HDL efflux capacity and the chemical composition of its subpopulations. MethodsIn a before-after design basis, HDL-cholesterol levels, chemical composition and cholesterol efflux capacity from HDL subpopulations isolated by isophynic ultracentrifugation were assessed in plasma samples from 60 patients with type 2 diabetes mellito (T2DM) at baseline and after 10 weeks of treatment with 20 mg atorvastatin. Cholesterol efflux was measured from human THP-1 cells using large, light HDL2b and small, dense 3c subpopulations as well as total HDL as acceptors. Changes of cholesterol efflux and chemical composition of HDL after treatment were analyzed. Correlations among variables potentially involved in cholesterol efflux were evaluated. ResultsA significant decrease of 4% in HDL-cholesterol levels was observed from 47 (42–54) to 45 (39–56) mg/dL, p = 0.02. Cholesterol efflux from total-HDL and HDL2b and 3c subfractions was maintained unchanged after treatment. The total mass of HDL remained unaffected, except for the HDL3a subpopulation accounted for by a significant increase in total protein content. No significant correlations for variables previously known to be associated with cholesterol efflux were found in our study. ConclusionsShort therapy of 10 weeks with 20 mg of atorvastatin does not modify the cholesterol efflux capacity neither the total mass of HDL2b, HDL3c and total HDL. The discrepancy with previous reports may be due to the selective effects among different classes of statins or differences in the approaches to measure cellular cholesterol efflux.

Cholesterol efflux capacity in young acute coronary syndrome in Malaysia

Aim: In recent years, patients with acute coronary syndrome (ACS) are significantly younger. We hypothesized that the capacity of HDL to accept cholesterol from macrophages, via cholesterol efflux capacity (CEC) would serve as a predictor of atherosclerotic disease. Hence, we aim to compare CEC of young ACS to a healthy control cohort.

High-density lipoprotein function is associated with atherosclerotic burden and cardiovascular outcomes in type 2 diabetes

Background and aimsMeasures of HDL function are emerging tools for assessing cardiovascular disease (CVD) event risk. HDL-apoA-I exchange (HAE) reflects HDL capacity for reverse cholesterol transport. MethodsHAE was measured in 93 participants with type 2 diabetes (T2D) and at least one additional CVD risk factor in the Asker and Bærum Cardiovascular Diabetes study. At baseline and after seven years, the atherosclerotic burden was assessed by invasive coronary angiography. Major CVD events were registered throughout the study. ResultsLinear regression analysis demonstrated a significant inverse association between HAE and atherosclerotic burden. Cox proportional hazard regression analysis showed a significant association between HAE and a composite of major CVD events when controlling for waist-hip ratio, HR = 0.89, 95% CI = 0.80–1.00 and p=0.040. ConclusionsDespite the relatively small size of the study population and the limited number of CVD events, these findings suggest that HAE provides valuable information in determining CVD risk.

High-Density Lipoprotein Function in Cardiovascular Disease and Diabetes Mellitus.

Cardiovascular disease (CVD) is the most common cause of death worldwide.1 Major CVD risk factors are hypertension, smoking, physical inactivity, abnormal glucose levels/diabetes mellitus, and dyslipidemia. Among these, dyslipidemia characterized by a low level of HDL-C (high-density lipoprotein cholesterol) is strongly and inversely correlated with CVD risk,2–4 and low HDL-C levels is part of the atherogenic dyslipidemia complex associated with diabetes mellitus.5 These observations triggered intense interest in increasing HDL-C levels for therapeutic intervention of CVD.6,7 However, several recent lines of evidence now suggest that the association between HDL-C levels and CVD status may be indirect or more complicated than previously recognized.7 Thus, human genetic studies demonstrate that genetically altered HDL-C levels do not necessarily translate to an altered risk of CVD.8–12 Phase III clinical trials of drugs that elevate HDL-C, such as niacin and CETP (cholesteryl ester transfer protein) inhibitors, also have largely failed to reduce CVD events in statin-treated subjects with established CVD.13–15 For several CETP inhibitors, improvement in CVD prevention was unsuccessful because of off-target effects (torcetrapib) or lack of efficacy (dalcetrapib and evacetrapib).14,16–18 The exception is the recent REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification), which included more subjects and was performed for longer than previous CETP inhibitor trials. The REVEAL demonstrated that the CETP inhibitor anacetrapib exhibited beneficial effects on cardiovascular outcomes on top of those of statin therapy, although the risk reduction was moderate19,20 and might have been due, at least in part, to a reduction in non-HDL-C rather than elevated HDL-C.21 Considering these cumulative observations, it remains uncertain whether increased HDL-C directly impacts atherosclerosis and the …

Improving of HDL capacity for macrophages cholesterol efflux after plasma incubation with phospholipid nanoparticles

In connection with recent data about antiatherogenic importance of not only plasma HDL concentration, but of their cell cholesterol efflux capacity as well, the possibility of its correction by phospholipid (PL) nanoparticles was studied. Blood plasma was incubated with earlier elaborated PL nanoparticles emulsion with the particle diameter up to 30 nm, and HDL cholesterol efflux capacity of apo B-depleted plasma was studied. Using macrophages THP-1 preloaded 3H-cholesterol were used. The addition of incubated plasma supernatants with the elevated PL/apo A-1 ratio to cell media resulted in almost increase in two fold 3H-cholesterol efflux as compared with native HDL. The maximal efflux was observed at the PL/apo A-1 ratio of 1.06 as compared with native apo B-depleted plasma (the PL/apo A-1 ratio of 0.85). Results suggest possible usage of ultrasmall PL nanoparticles for regeneration of impaired antiatherogenic HDL functionality. This approach seems to be predominant compared with the usage of PL emulsions with detergent or apoprotein A1.

Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer.

Cholesterol efflux capacity of HDL (CEC) is inversely associated with cardiovascular risk. HDL composition, fluidity, oxidation, and size are related with CEC. We aimed to assess which HDL parameters were CEC determinants after virgin olive oil (VOO) ingestion. Post-hoc analyses from the VOHF study, a crossover intervention with three types of VOO. We assessed the relationship of 3-week changes in HDL-related variables after intervention periods with independence of the type of VOO. After univariate analyses, mixed linear models were fitted with variables related with CEC and fluidity. Fluidity and Apolipoprotein (Apo)A-I content in HDL was directly associated, and HDL oxidative status inversely, with CEC. A reduction in free cholesterol, an increase in triglycerides in HDL, and a decrease in small HDL particle number or an increase in HDL mean size, were associated to HDL fluidity. HDL fluidity, ApoA-I concentration, and oxidative status are major determinants for CEC after VOO. The impact on CEC of changes in free cholesterol and triglycerides in HDL, and those of small HDL or HDL mean size, could be mechanistically linked through HDL fluidity. Our work points out novel therapeutic targets to improve HDL functionality in humans through nutritional or pharmacological interventions.

Cholesterol Uptake Capacity: A New Measure of HDL Functionality for Coronary Risk Assessment.

Recent studies have shown that the cholesterol efflux capacity of HDL is a better predictor of cardiovascular disease (CVD) than HDL cholesterol. However, the standard procedures used for measuring cholesterol efflux capacity involve radioisotope-labeled cholesterol and cultured macrophages. Thus, a simpler method to measure HDL functionality is needed for clinical application. We established a cell-free assay system to evaluate the capacity of HDL to accept additional cholesterol, which we named cholesterol "uptake capacity," using fluorescently labeled cholesterol and an anti-apolipoprotein A1 antibody. We quantified cholesterol uptake capacity of apolipoprotein B (apoB)-depleted serum samples from patients with coronary artery disease who had previously undergone revascularization. This assay system exhibited high reproducibility (CV <10%) and a short processing time (<6 h). The myeloperoxidase-mediated oxidation of apoB-depleted serum impaired cholesterol uptake capacity. Cholesterol uptake capacity correlated significantly with cholesterol efflux capacity (r2 = 0.47, n = 30). Furthermore, cholesterol uptake capacity correlated inversely with the requirement for revascularization because of recurrence of coronary lesions in patients with optimal control of LDL cholesterol (P < 0.01, n = 156). A multivariate analysis adjusted for traditional coronary risk factors showed that only cholesterol uptake capacity remained significant (odds ratio, 0.48; 95% CI, 0.29-0.80; P = 0.0048). Cholesterol uptake capacity assay evaluates the functionality of HDL in a sensitive and high-throughput manner without using radioisotope label and cells. This assay system could be used for the assessment of CVD risk in the clinical settings.

Lactonase activity of HDL is increased in morbidly obese subjects and is associated to atherogenic index of plasma

Aim: The relationship between HDL and cardiovascular risk is complex because the cardiovascular risk assessment does not depend only of HDL levels. One of the properties of HDL is the antioxidant capacity, due to paraoxonase, lactonase and arylesterase activities of the paraoxonase enzyme present in HDL. We aim to analyze the antioxidant capacity of HDL in subjects with morbid obesity, and its evolution after Roux-en-Y gastric bypass (RYGB).

Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency

The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend = 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 ± 0.24-fold vs. 1.34 ± 0.07-fold, P= 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 ± 8.6%; heterozygotes, 53.1 ± 7.2%; controls, 44.4 ± 4.1%; PTrend = 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality.

Glycovariations in Key HDL‐Associated Glycoproteins Differentiate Between Clinical Groups and Affect the Immunomodulatory Capacity of HDL

The goal of this pilot study was to determine whether HDL composition, particularly key HDL‐associated glycoproteins, affects HDL immunomodulatory function. HDL were purified from healthy controls (n=13), subjects with metabolic syndrome (MetS) (n=13), and diabetic hemodialysis (HD) patients, who experienced an infectious hospitalization event within 60 days (HD+) (n=12), and those with no event (HD−) (n=12). Concentrations of HDL‐bound serum amyloid A (SAA), lipopolysaccharide binding protein (LBP), apolipoprotein A‐I (ApoA‐I), apolipoprotein C‐III (ApoC‐III), α‐1‐antitrypsin (A1AT), and α‐2‐HS‐glycoprotein (A2HSG); and the site‐specific glycovariations of ApoC‐III, A1AT, and A2HSG were measured. Secretion of interleukin 6 (IL‐6) in stimulated monocytes was measured to assess HDL immunomodulatory capacity. HDL from HD patients were enriched in SAA, LBP, ApoC‐III, disialylated ApoC‐III (ApoC‐III2) and desialylated A2HSG. HDL that increased IL‐6 secretion were enriched in ApoC‐III, disialylated glycans 5402 and 5412 at multiple A1AT glycosites and desialylated A2HSG, and depleted in monosialylated ApoC‐III (ApoC‐III1). HDL from HD+ patients were enriched in SAA but had lower levels of sialylation across glycoproteins. Our results demonstrate that HDL composition, including the site‐specific glycosylations, differentiate between clinical groups, correlate with HDL's ability to modulate LPS‐induced monocyte IL‐6 response, and may be predictive of HDL's ability to protect from infection.Support or Funding InformationThis research project was supported by NIH R01GM049077 (CBL), the UC Davis Clinical and Translational Research Center NIH grant # UL1 TR000002 (AMZ), and by the Burroughs Wellcome Fund and a grant from the NIH 1DP2OD008752 (EM) contracts N01‐DK‐7‐0005 and N01‐DK‐7‐5004 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and a K24DK085153 grant.

Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport.

This study was aimed to investigate the effect of human PON1 overexpression in mice on cholesterol efflux and reverse cholesterol transport. PON1 overexpression in PON1-Tg mice induced a significant 3-fold (p<0.0001) increase in plasma paraoxonase activity and a significant ~30% (p<0.0001) increase in the capacity of HDL to mediate cholesterol efflux from J774 macrophages compared to wild-type mice. It also caused a significant 4-fold increase (p<0.0001) in the capacity of macrophages to transfer cholesterol to apoA-1, a significant 2-fold (p<0.0003) increase in ABCA1 mRNA and protein expression, and a significant increase in the expression of PPARγ (p<0.0003 and p<0.04, respectively) and LXRα (p<0.0001 and p<0.01, respectively) mRNA and protein compared to macrophages from wild-type mice. Moreover, transfection of J774 macrophages with human PON1 also increased ABCA1, PPARγ and LXRα protein expression and stimulates macrophages cholesterol efflux to apo A1. In vivo measurements showed that the overexpression of PON1 significantly increases the fecal elimination of macrophage-derived cholesterol in PON1-Tg mice. Overall, our results suggested that the overexpression of PON1 in mice may contribute to the regulation of the cholesterol homeostasis by improving the capacity of HDL to mediate cholesterol efflux and by stimulating reverse cholesterol transport.

Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

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

TCT-329 Impaired HDL uptake capacity which measure HDL functionality may associate with target lesion revascularization through provoking neoatherosclerosis formation after stent implantation

The importance of HDL functionality on coronary artery disease has been repeatedly demonstrated in recent studies. However, the association between HDL functionality and stent failure has yet to be clarified. Recently, we established a cell-free assay system to evaluate the capacity of HDL to accept

Net cholesterol efflux capacity of HDL enriched serum and coronary atherosclerosis in rheumatoid arthritis

Background/objectivesCardiovascular (CV) risk is increased in patients with rheumatoid arthritis (RA), but not fully explained by traditional risk factors such as LDL and HDL cholesterol concentrations. The cholesterol efflux capacity of HDL may be a better CV risk predictor than HDL concentrations. We hypothesized that HDL's cholesterol efflux capacity is impaired and inversely associated with coronary atherosclerosis in patients with RA. MethodsWe measured the net cholesterol efflux capacity of apolipoprotein B depleted serum and coronary artery calcium score in 134 patients with RA and 76 control subjects, frequency-matched for age, race and sex. The relationship between net cholesterol efflux capacity and coronary artery calcium score and other clinical variables of interest was assessed in patients with RA. ResultsNet cholesterol efflux capacity was similar among RA (median [IQR]: 34% removal [28, 41%]) and control subjects (35% removal [27%, 39%]) (P=0.73). In RA, increasing net cholesterol efflux capacity was not significantly associated with decreased coronary calcium score (OR=0.78 (95% CI 0.51–1.19), P=0.24, adjusted for age, race and sex, Framingham risk score and presence of diabetes). Net cholesterol efflux capacity was not significantly associated with RA disease activity score, C-reactive protein, urinary F2-isoprostanes, or degree of insulin resistance in RA. ConclusionsNet cholesterol efflux capacity is not significantly altered in patients with relatively well-controlled RA nor is it significantly associated with coronary artery calcium score.

Abstract 15: Identification of a High Density Lipoprotein Proteomic Signature Associated With Atherosclerosis Severity in Humans

High density lipoprotein associated cholesterol (HDL-C) has been the traditional biomarker for estimating cardiovascular protection derived from HDL; however, several recent studies have made it clear that HDL-C may not necessarily represent the protective capacity of HDL. The diverse protein and lipid content of HDL is becoming increasingly recognized as the basis for the functional complexity observed in these particles. Proteomics studies have identified 95 consensus proteins consistently found to associate with HDL. For the majority of these proteins, the functional importance of their association with HDL has not yet been determined. In this study, we tested the hypothesis that the protein composition of HDL will have an association with atherosclerosis burden in human subjects. A total of 101 subjects were selected based on atherosclerosis severity as determined by CT-angiography: normal (0% stenosis; n = 31), mild (&lt; 30% stenosis; n = 31), moderate (30 – 49% stenosis; n = 30) and severe (&gt;70% stenosis; n = 9). HDL was separated from plasma by size-exclusion chromatography and isolated from pooled fractions, using a lipid binding resin. HDL bound proteins from each subject were analyzed by electrospray ionization tandem mass spectrometry and a spectral index value (derived from normalized spectrum counts and the number of subjects in which the peptide was detected) was used to examine the association between the HDL proteome and atherosclerosis severity. This analysis identified changes in 14 out of the total of 123 identified proteins. Of those that changed, some displayed clear correlations with disease severity, whereas others were only affected in the severe disease group. Some of these proteins have been previously suggested to play a role in the interaction of HDL and atherosclerosis, such as apoA-IV (+20%; p&lt;0.02) and paraoxonase-1 (-21%; p&lt;0.05). Others may represent new HDL associated biomarkers, such as Ig lambda-3 chain C region (+188%; p&lt;0.01). We are currently developing a novel approach for the analysis of HDL proteome data, which will take into account all identified proteins as a single proteomic signature. This signature may have potential as a simplified metric of HDL composition with a direct connection to functionality.

Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway

Cholesterol efflux capacity associates strongly and negatively with the incidence and prevalence of human CVD. We investigated the relationships of HDL’s size and protein cargo with its cholesterol efflux capacity using APOB-depleted serum and HDLs isolated from five inbred mouse strains with different susceptibilities to atherosclerosis. Like humans, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. HDL’s content of specific proteins strongly correlated with its size and cholesterol efflux capacity, suggesting that its protein cargo regulates its function. Cholesterol efflux capacity with macrophages strongly and positively correlated with retinol binding protein 4 (RBP4) and PLTP, but not APOA1. In contrast, ABCA1-specific cholesterol efflux correlated strongly with HDL’s content of APOA1, APOC3, and APOD, but not RBP4 and PLTP. Unexpectedly, APOE had a strong negative correlation with ABCA1-specific cholesterol efflux capacity. Moreover, the ABCA1-specific cholesterol efflux capacity of HDL isolated from APOE-deficient mice was significantly greater than that of HDL from wild-type mice. Our observations demonstrate that the HDL-associated APOE regulates HDL’s ABCA1-specific cholesterol efflux capacity. These findings may be clinically relevant because HDL’s APOE content associates with CVD risk and ABCA1 deficiency promotes unregulated cholesterol accumulation in human macrophages.

Abstract 14630: Elevated CETP Activity is Associated With Low, Dysfunctional HDL in High Cardiovascular Risk South Asians

Background and Rationale: Low HDL in South Asians (SA) contribute greatly to their high coronary heart disease (CHD) risk relative to European Caucasians (EC), however, the cause of low HDL in SA is unknown. Here we investigated whether cholesteryl-ester transfer protein (CETP) plays a role in mediating low HDL in SA. Methods: Serum was obtained from metabolically well characterized individuals of SA and EC descent (N=244 and 238, respectively) and measured for CETP activity. HDL lipid and protein contents were quantified and HDL size and particle number were measured via NMR. The capacity of HDL to mediate cholesterol efflux was assessed in J774 macrophages with apoB-depleted patient serum. Results: CETP activity was elevated in SA compared with EC (26.5±0.45 vs. 18.5±0.45 pmol/uL/hr, P&lt; 0.0001). HDL from SA was pro-atherogenic - that is, triglyceride-enriched, cholesteryl ester-depleted, reduced in apoAI and smaller in size than in EC (P&lt; 0.05 for all). SA HDL, moreover, showed a reduced capacity to mediate macrophage cholesterol efflux (by 20%, P&lt; 0.0001), even in a subset of younger SA (&lt;40 years, P&lt;0.01). Composition and size changes in HDL were independent predictors of carotid artery intima-media thickness (IMT) in SA (P&lt; 0.05). Conclusions: We have identified for the first time a mechanism to account for low HDL in SA. Elevated CETP in SA was associated with triglyceride-enriched, cholesteryl ester-depleted HDL, smaller in size and reduced in apoA-I content, producing HDL that is less stable in the circulation and less atheroprotective. This was confirmed with the lower relative capacity of HDL from SA to mediate cellular cholesterol efflux and independent correlation of their HDL compositional changes with carotid IMT.

HIV infection induces structural and functional changes in high density lipoproteins

Background and aimsCoronary artery disease is a growing clinical problem in HIV-infected subjects. The increased risk of coronary events in this population has been linked to low levels of HDL, but the effects of HIV infection and anti-retroviral treatment (ART) on HDL structure and function remain unknown. Here, we aimed to determine the composition and function of HDL particles isolated from ART-naive and ART-positive HIV-infected patients. Methods and resultsProteomic profiling revealed decreased levels of paraoxonase (PON) 1 and PON 3 in HDL from HIV patients relative to HDL from uninfected controls (p < 0.0001), and PON activity of HDL from control group (0.13 ± 0.01 U/μl) was significantly higher than PON activity of HDL from HIV-infected untreated subjects (0.12 ± 0.01 U/μl, p = 0.0035), subjects treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (0.11 ± 0.01 U/μl, p < 0.0001), subjects treated with protease inhibitor (PI)-based therapy with detectable viral load (0.11 ± 0.01 U/μl, p < 0.0001), and PI-treated patients with undetectable viral load (0.12 ± 0.01 U/μl, p = 0.0164). Lipidomic profiling uncovered a negative correlation between CD4 T cell counts and particle sphingomyelin, lyso-phosphatidylcholine and ether-linked phosphatidylserine content in the ART-naive (R2 = 0.2611, p < 0.05; R2 = 0.2722, p < 0.05; and R2 = 0.3977, p < 0.05, respectively) but not treated HIV-infected subjects. Functional analysis demonstrated a negative correlation between cholesterol efflux capacity of HDL and viral load in the ART-naive HIV-infected group (R2 = 0.26, p = 0.026). ConclusionsTaken together, these results indicate that HIV infection associates with a number of both protein and lipid compositional changes in HDL particles. Moreover, HIV infection affects cholesterol efflux function of HDL, thus contributing to an increased risk of atherosclerosis in this patient population.