Large HDL Research Articles

Haptoglobin Phenotype Modulates Lipoprotein-Associated Risk for Preeclampsia in Women With Type 1 Diabetes.

The incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease. To investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks. Multicenter prospective study of T1DM pregnancy. Pregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks' gestation (mean ± SD). Hp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE. Hp phenotype did not predict PE, but lipoprotein associations with subsequent PE were confined to women with Hp 2-2, in whom the following associations with PE were observed: increased low-density lipoprotein (LDL) cholesterol, LDL particle concentration, apolipoprotein B (APOB), triacylglycerol/high-density lipoprotein (HDL) cholesterol ratio, and APOB/apolipoprotein AI (APOA1) ratio; decreased HDL cholesterol, APOA1, large HDL particle concentration, and peripheral lipoprotein lipolysis (all P < 0.05). In women with one or two Hp-1 alleles, no such associations were observed. In women with T1DM, although Hp phenotype did not predict PE risk, lipoprotein-related risks for PE were limited to those with the Hp 2-2 phenotype. Hp phenotype may modulate PE risk in diabetes.

Differences in Response to Egg Intake Result in Distinct Lipoprotein Profiles While Plasma Concentrations of Carotenoids and Choline Are Not Affected (P08-102-19)

ObjectivesIt has been demonstrated that some individuals (approximately 1/3 of the population) can be classified as hyper-responders to dietary cholesterol. The objective of this study was to evaluate whether the response to dietary cholesterol (provided by eggs) would affect lipoprotein metabolism and the bioavailability of lutein, zeaxanthin and choline, nutritional components present in eggs. MethodsWe recruited 36 healthy subjects who underwent a two-week washout period in which they consumed zero eggs. Participants were then fed 3 eggs (540 additional mg of dietary cholesterol) for 4 weeks. Plasma lipids were measured by use of an automated chemical clinical analyzer; the number of large and small LDL and HDL particles were measured by Nuclear Magnetic Resonance. Plasma lutein and zeaxanthin were determined by use of HPLC and plasma choline by use of LSM spectroscopy. We classified the normal response to dietary cholesterol as 2.2 mg/dL for each additional 100 mg of dietary cholesterol. Therefore, those individuals who had >12 mg/dL increase in plasma cholesterol after the intervention (n = 12) were considered hyper-responders while the other 24 subjects who presented changes in plasma cholesterol ranging from −16 to 9 mg/dL were considered hypo-responders. ResultsCompared to zero eggs, hyper-responders had significant increases in plasma total, LDL and HDL cholesterol (P < 0.001) with no changes in the LDL/HDL ratio. They also had higher concentrations of large LDL (P < 0.01) with no changes in small LDL. In contrast no changes in plasma total LDL or HDL cholesterol or large LDL were observed in hypo-responders after the consumption of 3 eggs/day. Interestingly, both hypo and hyper-responders had significant increases in large HDL particles (12%), plasma lutein (17%), zeaxanthin (30%) and choline (12%) (P < 0.001) compared to zero egg intake. ConclusionsThese results suggest that egg intake increases the bioavailability of carotenoids and choline present in eggs independently of plasma cholesterol response to dietary cholesterol. Further, the observed increases in large HDL in all individuals could be associated with HDL being a major transporter of lutein and zeaxanthin in plasma. Funding SourcesThe Esperance Family and the Egg Nutrition Center.

Infusions of Large Synthetic HDL Containing Trimeric apoA-I Stabilize Atherosclerotic Plaques in Hypercholesterolemic Rabbits

BackgroundAmong strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic high-density lipoprotein (sHDL). MethodsNew Zealand rabbits underwent a perivascular injury at both carotids and were randomly allocated into 2 protocols: (1) a single-dose study, where rabbits were treated with a single infusion of sHDL containing a trimeric form of human apoA-I (TN-sHDL, 200 mg/kg) or with Placebo; (2) a multiple-dose study, where 4 groups of rabbits were treated 5 times with Placebo or TN-sHDL at different doses (8, 40, 100 mg/kg). Plaque changes were analysed in vivo by intravascular ultrasound. Blood was drawn from rabbits for biochemical analyses and cholesterol efflux capacity evaluation. ResultsIn both protocols, atheroma volume in the Placebo groups increased between the first and the second intravascular ultrasound evaluation. A stabilization or a slight regression was instead observed vs baseline in the TN-sHDL-treated groups (P < 0.005 vs Placebo after infusion). TN-sHDL treatment caused a sharp rise of plasma-free cholesterol levels and a significant increase of total cholesterol efflux capacity. Histologic analysis of carotid plaques showed a reduced macrophage accumulation in TN-sHDL-treated rabbits compared with Placebo (P < 0.05). ConclusionsOur results demonstrate that acute and subacute treatments with TN-sHDL are effective in stabilizing atherosclerotic plaques in a rabbit model. This effect appears to be related to a reduced intraplaque accumulation of inflammatory cells. Besides recent failures in proving its efficacy, sHDL treatment remains a fascinating therapeutic option for the reduction of cardiovascular risk.

CETP genotype and concentrations of HDL and lipoprotein subclasses in African-American men.

Aim: To assess the association between theCETP Taq1B and I405V polymorphisms with levels of lipoprotein subclasses in African-American (AA) men with and without Type 2diabetes (T2DM). Patients & methods: AA men, over 30 years of age, with (n=54) or without T2DM (n=50), and not receiving lipid-lowering agents, underwent advanced lipid analysis and genotyping. Results & conclusion: In the total patient population Taq1B B2-allele carriers had significantly higher levels of large HDL subclasses (HDL-2b [p=0.017] and HDL-L [p=0.019]), lower levels of small-HDL subclasses (HDL-3a [p =0.004] and HDL-3b [p=0.031]), and lower levels of LDL subclasses (LDL-IVa [p=0.012] and LDL-IIIb [p=0.009]). The only significant genotype-diabetes interaction occurred with the HDL-2a subclass (p=0.015). No statistically significant associations were seen with I405V genotype. Our observations of lower levels of small-HDL and higher levels of large-HDL suggest that a potentially important HDL subclass-CETP relationship exists.

Evacetrapib reduces preβ-1 HDL in patients with atherosclerotic cardiovascular disease or diabetes

Background and aimsCholesteryl ester transfer protein (CETP) inhibitor-mediated induction of HDL-cholesterol has no effect on the protection from cardiovascular disease (CVD). However, the mechanism is still unknown. Data on the effects of this class of drugs on subclasses of HDL are either limited or insufficient. In this study, we investigated the effect of evacetrapib, a CETP inhibitor, on subclasses of HDL in patients with atherosclerotic cardiovascular disease or diabetes. MethodsBaseline and 3-month post-treatment samples from atorvastatin 40 mg plus evacetrapib 130 mg (n = 70) and atorvastatin 40 mg plus placebo (n = 30) arms were used for this purpose. Four subclasses of HDL (large HDL, medium HDL, small HDL, and preβ-1 HDL) were separated according to their size and quantified by densitometry using a recently developed native polyacrylamide gel electrophoresis (PAGE) system. ResultsRelative to placebo, while evacetrapib treatment dramatically increased large HDL and medium HDL subclasses, it significantly reduced small HDL (27%) as well as preβ-1 HDL (36%) particles. Evacetrapib treatment reduced total LDL, but also resulted in polydisperse LDL with LDL particles larger and smaller than the LDL subclasses of the placebo group. ConclusionEvacetrapib reduced preβ-1 HDL and small HDL in patients with ASCVD or diabetes on statin. Preβ-1 HDL and medium HDL are negatively interrelated. The results could give a clue to understand the effect of CETP inhibitors on cardiovascular outcomes.

Dietary unsaturated fat increases HDL metabolic pathways involving apoE favorable to reverse cholesterol transport.

HDL that contains apolipoprotein E (apoE) is a subspecies especially active in steps in reverse cholesterol transport, a process that brings cholesterol from peripheral cells to the liver. Here, we studied the effect of dietary unsaturated fat compared with carbohydrate on the metabolism of HDL containing apoE. We enrolled 9 adults who were overweight or obese and had below-average HDL-cholesterol in a crossover study of a high-fat diet, primarily unsaturated, and a low-fat, high-carbohydrate diet. A metabolic tracer study was performed after each diet period. Dietary fat increased the secretion, metabolism, and clearance of HDL subspecies containing apoE. Dietary fat increased the rate of clearance of large cholesterol-rich HDL containing apoE and increased their conversion to small HDL containing apoE, indicating selective cholesterol ester delivery to the liver. The high-unsaturated-fat diet did not affect the metabolism of HDL lacking apoE. HDL containing apoE is a diet-responsive metabolic pathway that renders HDL more biologically active in reverse cholesterol transport. This may be a mechanism by which unsaturated fat protects against coronary heart disease. Protein-based HDL subspecies such as HDL containing apoE may be used to identify additional atheroprotective treatment targets not evident in the total HDL-cholesterol measurement. ClinicalTrials.gov NCT01399632. NIH and the National Center for Advancing Translational Science.

MENOPAUSAL STAGE INFLUENCES LIPOPROTEIN SUBCLASS PROFILE IN HABITUALLY ACTIVE WOMEN

Menopause is associated with increased cardiovascular disease risk, in part due to worsening cholesterol profile with advancing menopausal stage. The effect of menopausal stage on lipoprotein cholesterol, lipoprotein particle size and number in active midlife women has not been evaluated.PURPOSETo evaluate differences in lipoprotein subclass concentrations between highly‐fit, habitually active women at distinct menopausal stages.METHODSWomen (40–65 yr) were healthy habitually active highly‐fit pre‐, peri‐, and postmenopausal women (PRE, n = 10, VO2peak = 47.0 ± 2.4 ml/kg/min, PERI, n = 12, VO2peak = 49.1 ± 2.4 ml/kg/min, and POST, n = 13, VO2peak = 43.8 ± 1.8 ml/kg/min). Menopausal stage was defined using the STRAW+10 criteria. Particle subclass concentrations and mean particle sizes (were measured using nuclear magnetic resonance spectroscopy (LabCorp). Calculated lipids (total triglyceride, total VLDL and chylomicron triglyceride, and total HDL cholesterol) were also analyzed. Blood samples for lipoprotein particle analysis were collected during days 1–6 of the menstrual cycle for PRE. ANOVAs with Holm‐Sidak post hoc testing were used to determine differences between groups for each lipid outcome. Nonparametric tests were employed if assumptions were not met. Data are presented as mean ± SEM.RESULTSThere was a significant effect of menopause stage on total HDL cholesterol (p = 0.010) with greater HDL cholesterol in POST (88.5 ± 2.2 mg/dl) vs. PRE (72.2 ± 5.7 mg/dl, p = 0.032) and total HDL particle concentration (p = 0.010) with significantly greater total HDL particle concentration in POST (40.2 ± 1.1 μmol/L) compared with PRE (34.9 ± 1.5 μmol/L, p = 0.023) and POST compared with PERI (PERI, 35.5 ± 1.3 μmol/L, p = 0.033). There was a trend for an effect of menopausal status on large HDL particle concentration (p = 0.072) with progressively greater large HDL particle concentration with each advancing stage (PRE 12.1 ± 1.1 μmol/L, PERI, 14.0 ± 1.2 μmol/L, POST, 15.5 ± 0.6 μmol/L). There was no significant effect of menopausal stage on medium or small HDL particle concentration or HDL size (all p&gt;0.05). There was an effect of menopausal stage on large LDL particle concentration (p = 0.039) with greater concentration of large LDL particles in PRE (479 ± 52.6 nmol/L) vs. POST (663 ± 47.5 nmol/L, p = 0.034) but no effect of menopausal stage on small LDL, IDL, or total LDL particle concentration, or LDL size (all p&gt;0.05). There was no effect of menopausal status on any VLDL &amp; chylomicron particle concentration or VLDL size (all p&gt;0.05).CONCLUSIONThese data indicate that in healthy, highly fit women, advancing menopausal stage does not have a negative effect on many lipoprotein particle concentrations. Habitual physical activity may eliminate or potentially reverse some of the negative consequences of menopause on lipids.Support or Funding InformationFunding Sources: American College of Sports Medicine Foundation Doctoral Student Research Grant (Serviente), National Institute on Aging Grant T32‐AG049676 (Pennsylvania State University), University of Massachusetts Amherst Provost's Undergraduate Research Fellowship (Chalvin).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract MP41: A Diet High in Carbohydrate and Low in Fat Alters the HDL Proteome and Metabolism of 9 HDL Proteins in Humans

Introduction: When dietary carbohydrate replaces fat, HDL cholesterol (HDL-C) and the primary HDL protein apolipoprotein A1 (apoA1) decrease. The proportion in plasma of large HDL2 decreases while small HDL3 increases. These findings suggest that diet affects metabolically important attributes of HDL that produce the size changes. We studied in humans the effect of dietary carbohydrate and unsaturated fat on the HDL proteome and metabolism of 9 HDL proteins across 5 HDL sizes. Methods and Results: Twelve participants were placed on a healthy, controlled diet high in unsaturated fat (HF) or high in carbohydrate (HC) in a randomized crossover design. At the end of each 4-week diet period, subjects were infused with a stable isotope tracer (D3-Leu) in order to label all newly synthesized HDL proteins. Blood samples were collected and tracer was followed for 70 hrs post-infusion. ApoA1-HDL was isolated by immunoaffinity purification, separated into 5 HDL particle sizes, and prepared for analysis by mass spectrometry. We used label free quantification to characterize the HDL proteome. The proteome composition and distribution across the 5 HDL sizes were remarkably conserved in all subjects on both diets. Diet altered the abundance of several proteins on the major HDL sizes alpha2 and alpha3. The HC diet increased proteins involved in lipid metabolism (apoC3, apoA2) and decreased antioxidant (PON1, PON3) and protease inhibitor (SERPINA3, SERPING1) proteins. We also monitored the metabolism of 9 proteins that likely affect HDL metabolism - apoA1, apoA2, apoA4, apoC3, apoE, apoJ, apoL1, apoM and LCAT. We used parallel reaction monitoring and XPI software to measure the amount of D3-Leu tracer over time in these 9 proteins across the 5 HDL sizes. We found that the HC diet increased apoA2 and apoJ and decreased apoA1 pool sizes on large HDL. The HC diet also increased apoM turnover in large HDL, and apoA1, apoA2, and apoE turnover across the HDL size range. Conclusions: Dietary carbohydrate when it replaces unsaturated fat alters the HDL proteome and metabolism of several HDL proteins on specific HDL sizes. Carbohydrate increases the abundance of proteins involved in lipid metabolism, decreases antioxidant and protease inhibitor proteins, and accelerates turnover of apoA1, apoA2, apoE, and apoM. This study suggests that diet modulates HDL function by affecting HDL composition and the metabolism of major HDL proteins.

The Protective Role of Adiponectin for Lipoproteins in End-Stage Renal Disease Patients: Relationship with Diabetes and Body Mass Index.

Cardiovascular disease (CVD) events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. The number and severity of CVD events remain inappropriate and difficult to explain by considering only the classic CVD risk factors. Our aim was to clarify the changes and the relationship of lipoprotein subfractions with other CVD risk factors, namely, body mass index (BMI) and adipokines, inflammation and low-density lipoprotein (LDL) oxidation, and the burden of the most prevalent comorbidities, diabetes mellitus (DM) and hypertension (HT). We studied 194 ESRD patients on dialysis and 22 controls; lipid profile, including lipoprotein subpopulations and oxidized LDL (oxLDL), C-reactive protein (CRP), adiponectin, leptin, and paraoxonase 1 activity were evaluated. Compared to controls, patients presented significantly lower levels of cholesterol, high-density lipoprotein cholesterol (HDLc), LDLc, oxLDL, and intermediate and small HDL and higher triglycerides, CRP, adiponectin, large HDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein- (IDL) B. Adiponectin levels correlated positively with large HDL and negatively with intermediate and small HDL, oxLDL/LDLc, and BMI; patients with DM (n = 17) and with DM+HT (n = 70), as compared to patients without DM or HT (n = 69) or only with HT (n = 38), presented significantly higher oxLDL, oxLDL/LDLc, and leptin and lower adiponectin. Obese patients (n = 45), as compared to normoponderal patients (n = 81), showed lower HDLc, adiponectin, and large HDL and significantly higher leptin, VLDL, and intermediate and small HDL. In ESRD, the higher adiponectin seems to favor atheroprotective HDL modifications and protect LDL particles from oxidative atherogenic changes. However, in diabetic and obese patients, adiponectin presents the lowest values, oxLDL/LDLc present the highest ones, and the HDL profile is the more atherogenic. Our data suggest that the coexistence of DM and adiposity in ESRD patients on dialysis contributes to a higher CVD risk, as showed by their lipid and adipokine profiles.

Effects of weight change on HDL-cholesterol and its subfractions in over 28,000 men and women

Changes in body mass index (ΔBMI) have well-established relationships to changes in high-density lipoprotein (ΔHDL)-cholesterol concentrations; however, their relationships to ΔHDL subfractions are less well understood. Assess the associations between ΔHDL and ΔBMI in a very large cohort. Age and sex-adjusted Δapo A1 concentrations were measured within 10 HDL subfractions in 14,121 women and 13,969 men using two-dimensional HDL-mapping. Significance was identified at .01<P≤.05 (*), .001<P≤.01 (†), .0001<P≤.001 (‡), and P≤.0001 (§). ΔBMI was significantly associated with Δα-1 (very large HDL, slope ± SE, females: -0.39±0.07§; males: -0.51±0.05§), Δα-3 (medium HDL, females: 0.18±0.04§; males: 0.19±0.04§), and Δα-4 (small HDL, females: 0.14±0.03§; males: 0.15±0.04§ mg/dL per kg/m2). As a percent of baseline, the changes in α-1 per ΔBMI were nearly twice as great as the changes in HDL-cholesterol per ΔBMI in both males (-1.53% vs -0.77%) and females (-0.79% vs -0.42%). HDL-cholesterol decreased significantly in healthy-weight patients who became overweight, overweight patients who became class I or class II obese, class I obese patients who became class II obese, and class II obese patients who became class III. In contrast, HDL-cholesterol increased in class III obese patients who became class II or class I, class II obese patients who became class I or overweight, class I patients who became overweight or healthy weight, overweight patients who became healthy weight, and healthy weight patients who became underweight. Weight change significantly affects HDL-cholesterol concentrations throughout the obesity spectrum. ΔBMI's effect on Δα-1 was nearly twice as great as its effect on HDL-cholesterol.

U HDL-cholesterolu již zřejmě neplatí "čím výše, tím lépe"

It is very well known from the old epidemiological population studies, that HDL-cholesterol (HDL-C) was in a negative association with coronary events risk. New studies have occurred during the last 10 years that the mentioned association has in fact the U-shaped curve, i.e. lower and higher levels of HDL-C then the optimal one are in an exponential increasing risk. The association of high HDL-C levels with cardiovascular risk is not explained clearly. There might be a hypothesis concerning a change of function of large HDL particles riched of cholesterol esters, which become to be cholesterol donors for the arteries. Key words: cardiovascular risk - HDL-cholesterol - HDL particles.

Weight loss achieved by bariatric surgery modifies high-density lipoprotein subfractions and low-density lipoprotein oxidation towards atheroprotection

ObjectivesWeight loss achieved by laparoscopic adjustable gastric banding (LAGB) induces an increase in high-density lipoprotein cholesterol (HDLc) but a small effect on low-density lipoprotein (LDL), although changes in their quality (size and composition) are uncertain. Our aim was to study the impact of weight loss, achieved 13-months after LAGB, on inflammation and dyslipidemia, focusing on HDL and LDL subfractions, and oxidized LDL (oxLDL). Design & methodsWe evaluated standard lipid profile, HDL and LDL subfractions, oxLDL, interleukin (IL)-6 and C-reactive protein (CRP), in twenty obese patients, before (T0) and 13-months after LAGB (T1), and in seventeen healthy controls. ResultsAt T1, patients showed lower body weight (12% median weight loss) and anthropometric indices; reduction in TG, atherogenic indices, oxLDL, oxLDL/LDL ratio, CRP and IL-6, and enhancement in HDLc; an increase in large HDL and intermediate HDL subfractions, and a decrease in small HDL subfraction; LDL subfractions were not modified. Percentual change (%Δ) of oxLDL, from T0 to T1, correlated significantly and positively with %Δ of small HDL subfraction and with %Δ of body mass index. ConclusionsWeight loss induced atheroprotective changes on inflammation, and lipid profile, enhancing larger HDL, the more atheroprotective subfraction, reducing the less protective subclass, small HDL, and reducing oxLDL and oxLDL/LDL ratio. Quality of lipoproteins appears useful cardiovascular risk biomarkers, deserving further studies.

Paradox of hypercholesterolaemia in highly trained, keto-adapted athletes

ObjectiveA growing number of ultra-endurance athletes have switched to a very low-carbohydrate/high-fat eating pattern. We compared markers of cholesterol and the lipoprotein profile in a group of elite ultra-runners consuming...

Metabolomic profiling implicates adiponectin as mediator of a favorable lipoprotein profile associated with NT-proBNP

BackgroundThe N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is an important biomarker for the diagnosis of heart failure. Apart from this and only recently recognized, NT-proBNP levels associate with higher HDL- and lower LDL-cholesterol levels comprising a favorable blood lipid profile. To further examine this observation, the lipoprotein profile in relation to NT-proBNP was examined in-depth by proton nuclear magnetic resonance spectroscopy (1H-NMR). We complemented this investigation with a state-of-the-art untargeted metabolomics approach.MethodsLipoprotein particles were determined by 1H-NMR spectroscopy in 872 subjects without self-reported diabetes from the population-based Study of Health in Pomerania (SHIP)-TREND with available NT-proBNP measurements. Comprehensive metabolomics data for plasma and urine samples were obtained. Linear regression models were performed to assess the associations between serum concentrations of NT-proBNP and the metabolites/lipoprotein particles measured in plasma or urine.ResultsAn increase in serum NT-proBNP was associated with a benefical lipoprotein profile, including a decrease in VLDL, IDL and LDL-particles along with an increase in large HDL particles. These findings were replicated in a second independent cohort. Serum concentrations of NT-proBNP showed significant inverse associations with seven plasma metabolites while associations with 39 urinary metabolites, mostly comprising amino acids and related intermediates, were identified. Mediation analyses revealed adiponection as mediating factor for the associations observed with lipoproteins particles.ConclusionsMost of the metabolic changes associated with NT-proBNP implicate significant influence on the blood lipid profile besides vasodilatory and the diuretic action of BNP signaling. Our data suggest that the more favorable lipoprotein profile as associated with elevated NT-proBNP concentrations in mainly cardiac healthy individuals might relate to adiponectin signaling indicating even indirect cardio-protective effects for NT-proBNP.

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.

Genetically-determined CETP concentration decreases large HDL and increases small VLDL without affecting LDL

Genetically-determined CETP concentration decreases large HDL and increases small VLDL without affecting LDL

Slim Body Weight Is Highly Associated With Enhanced Lipoprotein Functionality, Higher HDL-C, and Large HDL Particle Size in Young Women.

There has been no information about the correlations between body weight distribution and lipoprotein metabolism in terms of high-density lipoproteins-cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP). In this study, we analyzed the quantity and quality of HDL correlations in young women (21.5 ± 1.2-years-old) with a slim (n = 21, 46.2 ± 3.8 kg) or plump (n = 30, 54.6 ± 4.4 kg) body weight. Body weight was inversely correlated with the percentage of HDL-C in total cholesterol (TC). The plump group showed 40% higher body fat (26 ± 3 %) and 86% more visceral fat mass (VFM, 1.3 ± 0.3 kg) than the slim group, which showed 18 ± 2% body fat and 0.7 ± 0.2 kg of VFM. Additionally, the plump group showed 20% higher TC, 58% higher triglyceride (TG), and 12% lower HDL-C levels in serum. The slim group showed 34% higher apoA-I but 15% lower CETP content in serum compared to the plump group. The slim group showed a 13% increase in particle size and 1.9-fold increase in particle number with enhanced cholesterol efflux activity. Although the plump group was within a normal body mass index (BMI) range, its lipid profile and lipoprotein properties were distinctly different from those of the slim group in terms of CETP mass and activity, HDL functionality, and HDL particle size.

Circulating Metabolites and the Risk of Type 2 Diabetes—A Prospective Study of 10,938 Young Adults from Four Finnish Cohorts

Background: Advances in metabolomics have allowed high-throughput metabolic profiling of large population samples. We aimed to identify circulating lipids and metabolites predictive of the risk for type 2 diabetes in young adults. Methods: Nuclear magnetic resonance metabolomics was used to quantify 229 metabolic measures in 10,938 individuals from four Finnish cohorts (mean age 35 years, range 24-45). Associations between baseline metabolites and diabetes onset during 7-15 years of follow-up (330 incident cases) were assessed by logistic regression adjusted for sex, baseline age and glucose. Findings: Out of 229 metabolic measures, 174 were associated with risk for incident diabetes in meta-analysis of the four cohorts (P&amp;lt;0.001; range of odds ratios (OR) per 1-SD: 0.41-1.85). Among the strongest biomarkers were increased concentrations of branched-chained and aromatic amino acids (OR: 1.54-1.74) and triglycerides in very-low-density lipoproteins (VLDL; OR 1.78), and lower levels of omega-6 fatty acids (OR 0.61) and free cholesterol within large high-density lipoprotein (HDL; OR 0.41). A biomarker score was derived in three of the cohorts, comprised of phenylalanine, free cholesterol in large HDL, and the ratio of cholesterol esters to total lipids in large VLDL. When validated in the fourth cohort, those in the upper quartile of the biomarker score had considerably higher 15-year-risk for diabetes compared to those in the lowest quartile (OR 16.1). Interpretation: Metabolic aberrations across multiple molecular pathways are predictive of the long-term risk of type 2 diabetes in young adults. Comprehensive metabolic profiling may facilitate targeting preventive interventions at young asymptomatic individuals at increased risk for type 2 diabetes. Disclosure A.V. Ahola-Olli: None. L. Mustelin: Employee; Self; Nightingale Health Ltd. M. Kalimeri: Employee; Self; Nightingale Health Oy. J. Kettunen: Other Relationship; Self; Nightingale Ltd. J.J. Jokelainen: None. J. Auvinen: None. K.S. Puukka: None. A.S. Havulinna: None. T. Lehtimäki: None. M. Kähönen: None. V. Salomaa: Other Relationship; Self; Novo Nordisk Inc.. M. Perola: None. M. Jarvelin: None. M. Ala-Korpela: None. P. Wurtz: Employee; Self; Nightingale Health. Stock/Shareholder; Self; Nightingale Health.

Abstract 166: Effects of Dietary Unsaturated Fat and Carbohydrate on the HDL Proteome and Metabolism of 9 HDL Proteins Across 6 HDL Size Fractions in Humans

Introduction: When dietary carbohydrate replaces fat, HDL-C and apoA1 decrease. The proportion in plasma of large HDL2 decreases while small HDL3 increases. These findings suggest that diet affects metabolically important attributes of HDL that produce the size changes. We studied in humans the effect of dietary carbohydrate and unsaturated fat on the HDL proteome and metabolism of 9 HDL proteins across 6 HDL sizes. Methods and Results: Twelve participants were placed on a controlled high unsaturated fat (HF) or high carbohydrate (HC) diet in a randomized crossover design. At the end of each 4-week diet period, subjects were infused with D3-Leu tracer, and blood was collected for 70 hrs. ApoA1-HDL was prepared by immunoaffinity purification, separated into 6 sizes α0, α1, α2, α3, preβ, and &lt;preβ by ND-PAGE, and in-gel trypsinized for mass spectrometry. We used label free quantification to characterize the HDL proteome. The proteome composition and distribution across the 6 HDL sizes were remarkably conserved in all subjects on both diets. Diet altered the abundance of several proteins on the major HDL sizes α2 and α3. The HC diet increased proteins involved in lipid metabolism (apoC3, apoC1, apoC2-C4) and acute phase response (SAA1, 4), and decreased antioxidant (PON1, 3) and protease inhibitor (SERPINA3, G1) proteins. We also monitored the metabolism of 9 proteins that likely affect HDL metabolism – apoA1, apoA2, apoA4, apoC3, apoE, apoM, apoJ, apoL1, and LCAT. We used high resolution parallel reaction monitoring and XPI software to measure tracer enrichment in these 9 proteins across the 6 HDL sizes. We found that the HC diet increased apoA2 and decreased apoA1 and apoA4 pool sizes on large HDL. The HC diet increased apoA1 and apoE turnover on large α1 and α2 and 3, respectively. Conclusions: Dietary carbohydrate when it replaces unsaturated fat alters the HDL proteome and metabolism of several HDL proteins on specific HDL sizes. Carbohydrate increases the abundance of proteins involved in lipid metabolism and the acute phase response, decreases antioxidant and protease inhibitor proteins, and enhances turnover of apoE and apoA1. This study suggests that diet modulates HDL function by affecting HDL composition and the metabolism of major HDL proteins.

Abstract 549: Improvement in Large Density HDL Particle Number by NMR is Associated with Reduction in Coronary Soft Plaque Burden by Coronary Computed Tomography Angiography in Psoriasis

Background: Patients with psoriasis (PSO), a chronic inflammatory disease associated with dysfunctional lipoprotein profile and accelerated risk of MI, have increased burden of subclinical atherogenesis by coronary computed tomography angiography (CCTA). Large HDL particle (l-HDLp) number by NMR has been shown to associate negatively with cardiovascular (CV) events independent of traditional lipoprotein levels. We hypothesize that increase in l-HDLp would inversely associate with soft plaque volume (PV) as well as non-calcified coronary burden (NCB). Methods: Consecutive treatment naïve PSO patients (n= 92 arteries) underwent CCTA (320 detector row, Toshiba) at baseline and one-year. Soft plaque volume and non-calcified burden were assessed using a semi-automated software (QAngio, Medis). Lipoprotein profiling and cholesterol efflux capacity was done by NMR. Results: Patients were middle aged and at low CV risk by traditional risk scores (Table 1). With improvement of PSO severity at one year and no change in traditional CV risks, l-HDLp increased (5.8 ± 0.4 vs. 6.3 ± 0.5, p=0.007) concurrently with cholesterol efflux capacity (0.95 ± 0.02 vs 1.01 ± 0.02, p=0.003). PV reduced at one-year (3.7 ± 1.2 vs. 2.9 ± 1.1 mm 3 , p=0.01), as well as NCB (1.20 ± 0.06 vs. 1.07 ± 0.06 mm 2 , p&lt;0.001). Coronary burden was inversely associated with l-HDLp beyond traditional CV risk factors (β = -0.47, p&lt;0.001). Conclusions: Increase in l-HDLp was inversely associated with coronary plaque burden possibly through improvement in HDL function via cholesterol efflux capacity, suggesting a role for NMR lipoprotein profiling in assessment of CVD in chronic inflammatory states.