Lipoprotein Particle Distribution Research Articles

Exploring the Interactions between Obesity and Diabetes: Implications for Understanding Metabolic Dysregulation in a Saudi Arabian Adult Population.

The rising prevalence of obesity in Saudi Arabia is a major contributor to the nation's high levels of cardiometabolic diseases such as type 2 diabetes. To assess the impact of obesity on the diabetic metabolic phenotype presented in young Saudi Arabian adults, participants (n = 289, aged 18-40 years) were recruited and stratified into four groups: healthy weight (BMI 18.5-24.99 kg/m2) with (n = 57) and without diabetes (n = 58) or overweight/obese (BMI > 24.99 kg/m2) with (n = 102) and without diabetes (n = 72). Distinct plasma metabolic phenotypes associated with high BMI and diabetes were identified using nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography mass spectrometry. Increased plasma glucose and dysregulated lipoproteins were characteristics of obesity in individuals with and without diabetes, but the obesity-associated lipoprotein phenotype was partially masked in individuals with diabetes. Although there was little difference between diabetics and nondiabetics in the global plasma LDL cholesterol and phospholipid concentration, the distribution of lipoprotein particles was altered in diabetics with a shift toward denser and more atherogenic LDL5 and LDL6 particles, which was amplified in the presence of obesity. Further investigation is warranted in larger Middle Eastern populations to explore the dysregulation of metabolism driven by interactions between obesity and diabetes in young adults.

Differences in metabolomic profiles of APOE4 carrier vs non‐carrier patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease

AbstractBackgroundApolipoprotein E is the major apolipoprotein found in plasma, involved in lipid transport and metabolism. Carrying the ε4 allele of the APOE gene (ApoE4) is a risk factor for developing Alzheimer’s disease (AD) and is associated with altered plasma lipid levels and lipoprotein particle distribution. The AMBAR phase 2b/3 trial is a therapeutic approach for AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma‐exchange procedures with albumin replacement (PE‐Alb) to remove pathological substances from plasma, slowing AD progression. The aim of this study was to assess PE‐Alb differential effects on metabolites across the AMBAR trial between ApoE4 carriers and non‐carriers.Method442 metabolites were quantified in serum samples of 296 ApoE‐genotyped patients included in the AMBAR trial (225 PE‐Alb‐treated and 71 placebo), at 3 time‐points, using high‐throughput UHPLC‐MS (OWL‐Metabolomics, Spain). Data was stratified by ApoE4 carriers (n = 145) and non‐carriers (n = 151) and analyzed through a mixed model for repeated measures. Differences from placebo were assessed through month*treatment group interaction estimates. Reported p‐values were adjusted by Benjamini‐Hochberg procedure.ResultBaseline differences between ApoE4 carriers and non‐carriers were found according to what has been reported in the literature. In ApoE4 carriers, 29 metabolites significantly changed (Adjusted p‐value<0.05) in PE‐Alb‐treated patients compared to placebo at end of study (month 14). Eleven of them, which were in the free Fatty Acids (FA) class (6 monounsaturated‐FA, 3 polyunsaturated‐FA, 2 saturated‐FA), were down regulated. This would agree with the previously reported finding that free‐FA levels increase in blood from AD patients and participate in the pathogenesis of AD by multiple mechanisms. In Non‐carriers, 19 metabolites showed statistically significant change at month 14, 2 of them being downregulated. In both stratifications, most upregulated metabolites were in the Glycerophospholipid class (21/35) which has been reported to be decreased in AD. All other metabolites were in the Glycerolipids (4), Sphingolipids (4), Sterols (3), Bile acids (2) and Amino Acids (1) classes.ConclusionThese results demonstrate modulation of fatty acid metabolism in PE‐Alb‐treated patients from the AMBAR trial in relation to its ApoE genotype. Furthermore, treatment induced positive metabolite changes compared to placebo. These results deserve further investigation.

Lipoproteins and cholesterol homeostasis in paediatric nephrotic syndrome patients.

IntroductionThe aim of this study was to investigate lipoprotein particle distributions and the likelihood of achieving cholesterol homeostasis in the remission phase of nephrotic syndrome (NS) in paediatric patients. We hypothesized that lipoprotein particle distributions moved toward less atherogenic profile and that cholesterol homeostasis was achieved.Materials and methodsThirty-three children, 2 to 9 years old with NS were recruited. Blood sampling took place both in the acute phase and during remission. Serum low-density lipoprotein particles (LDL) and high-density lipoprotein particles (HDL) were separated using non-denaturing polyacrylamide gradient gel (3-31%) electrophoresis. Serum non-cholesterols sterols (NCSs), desmosterol, lathosterol, 7-dehydrocholesterol (7-DHC), campesterol and β-sitosterol were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).ResultsAll patients had desirable serum HDL cholesterol concentrations during remission. The dominant lipoprotein diameters and LDL subclass distribution did not change significantly during follow-up. In contrast, HDL lipoprotein particle distribution shifted towards larger particles. The absolute concentration of desmosterol was significantly lower during remission (P = 0.023). β-sitosterol concentration markedly increased during remission (P = 0.005). Desmosterol/β-sitosterol (P < 0.001) and 7-DHC/β-sitosterol (P = 0.005) ratios significantly declined during disease remission.ConclusionsFavourable changes in the serum lipid profiles, HDL particle subclass distribution and cholesterol metabolism in paediatric patients with NS during remission took place. For the first time, we found that cholesterol homeostasis changed in favour of increased cholesterol absorption during disease remission. Nevertheless, complete cholesterol homeostasis was not achieved during disease remission.

Associations of maternal lipoprotein particle distribution in mid-pregnancy with birth outcomes: a pilot study

BackgroundAn excessive rise in maternal lipids during pregnancy may have detrimental impacts on maternal and fetal health leading to adverse pregnancy outcomes. However, knowledge gaps exist with respect to the association between lipid biomarkers and birth outcomes.MethodsWe conducted a secondary data analysis of healthy pregnant women (N = 25) with mid-pregnancy fasting serum samples collected at 22–28 weeks of gestation and birth outcome data. Serum was analyzed for conventional lipid profile (total-C, HDL-C, LDL-C, and triglycerides) and lipoprotein subclass distribution, including particle number (nM) and size (nm), for very low-density lipoprotein (VLDL)/chylomicron (CM), low density lipoprotein (LDL), and high-density lipoprotein (HDL), by nuclear magnetic resonance spectroscopy.Associations between maternal lipids and birth outcomes, including birth weight (g) and gestational age (weeks), were assessed using multivariable linear regression, adjusted for pre-pregnancy BMI.ResultsAlthough conventional lipids were not associated (p > 0.05) with birth outcomes, every 1-unit increment in large VLDL/CM particles (nM) and VLDL/CM size (nm) was associated with an increase in birth weight (confounder-adjusted β-coefficient, 45.80 g [5.30, 86.20, p = 0.003] and 24.90 g [8.80, 40.90, p = 0.002], respectively). Among the HDL subclass parameters, a 1-unit (nM) increase in the concentration of total HDL-particles was associated with a reduced birth weight (confounder adjusted β-coefficient, -19.40 g [95% confidence interval, -36.70, -2.20]; p = 0.03) after adjustment for maternal pre-pregnancy BMI.ConclusionThe preliminary results of this pilot study suggest that total particle concentrations of VLDL/CM and HDL in mid-pregnancy have divergent associations with birth weight, potentially reflecting the specific roles of these lipoprotein particles with respect to placental function and fetal growth.

Effects of Palm Stearin versus Butter in the Context of Low-Carbohydrate/High-Fat and High-Carbohydrate/Low-Fat Diets on Circulating Lipids in a Controlled Feeding Study in Healthy Humans.

Background. Foods rich in saturated fatty acids (SFAs) have been discouraged by virtue of their cholesterol-raising potential, but this effect is modulated by the food source and background level of carbohydrate. Objective. We aimed to compare the consumption of palm stearin (PS) versus butter on circulating cholesterol responses in the setting of both a low-carbohydrate/high-fat (LC/HF) and high-carbohydrate/low-fat (HC/LF) diet in healthy subjects. We also explored effects on plasma lipoprotein particle distribution and fatty acid composition. Methods. We performed a randomized, controlled-feeding, cross-over study that compared a PS- versus a Butter-based diet in a group of normocholesterolemic, non-obese adults. A controlled canola oil-based ‘Run-In’ diet preceded the experimental PS and Butter diets. All diets were eucaloric, provided for 3-weeks, and had the same macronutrient distribution but varied in primary fat source (40% of the total fat). The same Run-In and cross-over experiments were done in two separate groups who self-selected to either a LC/HF (n = 12) or a HC/LF (n = 12) diet track. The primary outcomes were low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL)-C, triglycerides, and LDL particle distribution. Results. Compared to PS, Butter resulted in higher LDL-C in both the LC/HF (13.4%, p = 0.003) and HC/LF (10.8%, p = 0.002) groups, which was primarily attributed to large LDL I and LDL IIa particles. There were no differences between PS and Butter in HDL-C, triglycerides, or small LDL particles. Oxidized LDL was lower after PS than Butter in LC/HF (p = 0.011), but not the HC/LF group. Conclusions. These results demonstrate that Butter raises LDL-C relative to PS in healthy normocholesterolemic adults regardless of background variations in carbohydrate and fat, an effect primarily attributed to larger cholesterol-rich LDL particles.

59-OR: Lipoprotein Particle Distribution by NMR in Youth with Type 2 Diabetes (T2D) in the TODAY Study

T2D in adolescents is associated with an unfavorable lipid profile, but data on lipoprotein particle size and distribution in this population have yet to be published. The TODAY Study, a randomized treatment trial of T2D in youth, provided the opportunity to evaluate lipoprotein particle distribution and relate lipoprotein particle number and size to HbA1C, need for insulin treatment, gender, race/ethnicity, BMI, and blood pressure (BP). TODAY participants (n=348) with yearly samples available for NMR Lipoprofile assessments (baseline, 12, 24, 36 mos) were included. Baseline participant characteristics (mean±SD) were: age 13.7±2.0 yrs; BMI 34.3±7.6 kg/m2; 62.4% female; 20.7% White, 32.2% Non-Hispanic Black (NHB), 43.7% Hispanic. Analysis demonstrated increasing numbers of LDL, HDL, and VLDL particles over the three yrs (all ps&amp;lt;0.0001) with somewhat weaker trends for decreasing particle size (LDL p=0.0009, HDL p=0.02). HbA1c showed a strong positive correlation with LDL, VLDL, and HDL particle number (all ps&amp;lt;0.005). HbA1c was negatively associated with LDL (p&amp;lt;0.0001) and HDL size (p=0.001) but positively associated with VLDL size (p&amp;lt;0.0001). Need for insulin treatment did not impact these associations. Female subjects had larger HDL particle size than males at baseline (p=0.0004) and throughout (p&amp;lt;0.0001). NHBs had the largest LDL and HDL particle size and smallest VLDL particle size. BMI% and BP showed positive association with LDL, HDL, and VLDL particle numbers but negative association with LDL and HDL size. The preponderance of lipoprotein parameters were strongly associated with TG/HDL ratio and non-HDL-C after adjusting for baseline age, race, gender, BMI%, BP, and need for insulin treatment (p&amp;lt;0.0001). In conclusion, these data demonstrate an atherogenic lipoprotein phenotype in youth with T2D and strong relationships with glycemic control and other cardiac risk factors. Concern regarding premature development of atherosclerosis in youth with T2D is warranted. Disclosure L.E. Katz: None. J.D. Otvos: Employee; Self; LabCorp. K. Drews: None. B. Tesfaldet: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Tolerion, Inc. Other Relationship; Self; Caladrius Biosciences, Inc. S.M. Marcovina: None. S. Mckay: None. R.S. Weinstock: Board Member; Self; JDRF. Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Jaeb Center for Health Research, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61212)

Lipoprotein particles and coronary artery calcium in middle-aged US-White and Japanese men

ObjectiveThis cross-sectional study examined whether contrasting distributions of nuclear magnetic resonance (NMR)-measured lipoproteins contribute to differences in the prevalence of subclinical atherosclerosis measured using coronary artery calcium (CAC) between the...

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...

Utility of Lipoprint® Lipoprotein Subfraction Testing in a Rodent Atherosclerosis Model

Lipid analysis on rodent blood samples has been traditionally constrained by: 1) the need for technically demanding and time‐consuming ultracentrifugation methods requiring large sample volumes and 2) the limited translatability of traditional endpoints (i.e., total High Density Lipoprotein (HDL) or total Low Density Lipoprotein (LDL) cholesterol concentrations) measured using standard clinical chemistry spectrophotometric assays on preclinical studies due to considerable species differences in lipid metabolism and assay cross‐reactivity differences.The Lipoprint® Lipoprotein Subfractions Testing System (Quantimetrix) is a lipid testing option that analyzes lipoprotein subfractions (e.g., Very Low Density Lipoprotein (VLDL), Intermediate Density Lipoprotein (IDL), LDL(1–7), HDL(1–10)) in a small volume serum sample. The technology uses high‐resolution PAGE coupled with digital analysis to provide a profile of the relative distribution of lipoprotein particles within a given sample.We sought to determine if Lipoprint® analysis could be used to investigate alterations in lipid subfractions following administration of a well‐studied pharmaceutical agent in an atherosclerosis rodent preclinical model. Results from the experiments demonstrate the utility of the incorporation of these exploratory lipid subfraction endpoints into this model system in conjunction with conventional total HDL, LDL and triglyceride concentration combined with ex vivo image analysis of plaque burden.

Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial

AimsHigh-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism. Materials and methodsTwenty unmedicated males with prediabetes received 100mg b.i.d. RVX-208 and placebo for 29–33days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry. ResultsRVX-208 treatment for 4weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (p≤0.05 versus placebo), but did not change conventional clinical lipid measures. The concentration of medium-sized HDL particles increased by 11% (P=0.01) and small-sized HDL particles decreased by 10% (P=0.04) after RVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30min later with a more sustained elevation (treatment effect, P=0.003). There was a reduction and delay in total (P=0.001) and oral (P=0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P=0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P=0.016), with no effect on glucose oxidation or total glucose disposal. ConclusionsRVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes.

Lipids and lipoproteins and inflammatory markers in patients with chronic apical periodontitis.

BackgroundSince chronic apical periodontitis (CAP) appears to be a risk factor for coronary heart disease, the aim of the study was to determine the relationship between the size of CAP lesion and inflammatory markers (hsCRP, IL-6, TNF-α), as well as lipids and lipoproteins (LpPLA2, apoAI, apoB level) in blood serum of patients with CAP.MethodsThe patients studied (n = 43) were divided into groups: patients under 50 and over 50 years of age, and a separate subgroup of the oldest age with the largest size of CAP lesions. Apolipoprotein AI (apoAI) above 150 mg/dL and below 150 mg/dL was used as an important criterion for the division of patients into groups. The CAP lesion size was measured using the Kodak digital imaging system software. The control group consisted of clinically healthy volunteers (n = 20) without CAP. Lipids were measured on a Siemens analyzer (Germany), apoAI, apoB, hsCRP levels were determined by immunonephelometric method, using the Health Care Diagnostic Product (Siemens GmbH, Germany), and IL-6, TNF-α and LpPLAG7 assay kits (ELISA, R&D Systems) were used.ResultsThe findings suggested that in patients with CAP and their age increase, the CAP lesion size, the concentration of inflammatory markers and LpPLA2 mass increased. Correlations between the CAP lesion size and LpPLA2 mass and between the CAP lesion size and TG level in patients with apoAI 150 ≤ mg/dL showed increase TG in atherogenic apoB-containing triglyceride-rich lipoprotein and TC in cholesterol-rich lipoprotein. The patients with a low apoAI and high LpPLA2 level can have a higher risk of odontogenic disease and progression of atherosclerosis and coronary heart disease.ConclusionWe have found a positive correlation between apoAI level and the CAP lesion size and a negative correlation between LpPLA2 level and the CAP lesion size. The results suggest that apoAI and LpPLA2 in HDL particles have antiinflammatory action and together can limit the CAP lesion size in patient with a higher apoAI level. The literature data on the distribution of lipoprotein particles in subjects are still insufficient, so this problem requires further studies.

A Double-Blind Randomized Trial of Fish Oil to Lower Triglycerides and Improve Cardiometabolic Risk in Adolescents

To determine the efficacy of 4 g/day fish oil to lower triglycerides and impact lipoprotein particles, inflammation, insulin resistance, coagulation, and thrombosis. Participants (n = 42, age 14 ± 2 years) with hypertriglyceridemia and low-density lipoprotein (LDL) cholesterol <160 mg/dL were enrolled in a randomized, double-blind, crossover trial comparing 4 g of fish oil daily with placebo. Treatment interval was 8 weeks with a 4-week washout. Lipid profile, lipoprotein particle distribution and size, glucose, insulin, high-sensitivity C-reactive protein, interleukin-6, fibrinogen, plasminogen activator inhibitor-1, and thrombin generation were measured. Baseline lipid profile was total cholesterol 194 (5.4) mg/dL (mean [SE]), triglycerides 272 (21) mg/dL, high-density lipoprotein cholesterol 39 (1) mg/dL, and LDL cholesterol 112 (3.7) mg/dl. LDL particle number was 1614 (60) nmol/L, LDL size was 19.9 (1.4) nm, and large very low-density lipoprotein/chylomicron particle number was 9.6 (1.4) nmol/L. Triglycerides decreased on fish oil treatment but the difference was not significant compared with placebo (-52 ± 16 mg/dL vs -16 ± 16 mg/dL). Large very low-density lipoprotein particle number was reduced (-5.83 ± 1.29 nmol/L vs -0.96 ± 1.31 nmol/L; P < .0001). There was no change in LDL particle number or size. There was a trend towards a lower prothrombotic state (lower fibrinogen and plasminogen activator inhibitor-1; .10 > P > .05); no other group differences were seen. In children, fish oil (4 g/day) lowers triglycerides slightly and may have an antithrombotic effect but has no effect on LDL particles.

Flow-mediated dilation, carotid wall thickness and HDL function in subjects with hyperalphalipoproteinemia

Background and aimsThe relationships between very high plasma HDLc and subclinical atherosclerosis are still a matter of debate. Methods and resultsTwenty subjects with primary hyperalphalipoproteinemia (HAL, with HDLc in the highest 10th percentile and absence of overt secondary causes of this condition), aged 30–65 years, were compared with 20 age and sex-matched controls. Lipid determination, lipoprotein particle distribution (Lipoprint®), Cholesterol Efflux Capacity (CEC), plasma adhesion molecule, analyses of CETP, SRB1 and LIPG genes and of different markers of subclinical vascular disease (ankle-brachial index, ABI; carotid intima-media thickness, cIMT; brachial-artery flow mediated dilation, FMD) were performed. Fasting HDLc levels were 40 mg/dl higher in HAL subjects while LDLc concentration was comparable to control group. CETP gene analysis in HAL subjects identified one novel rare Single Nucleotide Polymorphism (SNP, Asp131Asn), possibly damaging, while the common SNP p.Val422Ile was highly prevalent (50% vs. 27.4% in a control population). No rare mutations associated with HAL were found in SR-B1 and LIPG genes. Polyacrylamide gel electrophoresis in HAL subjects disclosed larger and more buoyant HDL particles than in controls, while LDL profile was much more similar. ABI, cIMT and arterial plaques did not differ in cases and controls and the two groups showed comparable FMD at brachial artery examination. Similarly, ABCA1 and ABCG1 HDL-mediated CEC, the most relevant for atheroprotection, did not discriminate between the groups and only ABCG1 pathway seemed somewhat related to arterial reactivity. ConclusionsHDL dimension, function and genetics seem scarcely related to subclinical atherosclerosis and vascular reactivity in middle-aged HAL subjects.

Lifestyle intervention improves lipoprotein particle size and distribution without weight loss in obese Latino adolescents

Childhood obesity is associated with a pro-atherogenic phenotype contributing to increased cardiovascular disease (CVD) risk. This single-arm pilot study examined the effects of a lifestyle intervention on lipoprotein particle size and cholesterol distribution in obese Latino adolescents. Fifteen obese Latino adolescents (15.0 ± 1.0 years) completed a 12-week nutrition education and exercise intervention. Low-density lipoprotein (LDL) particle size and distribution of cholesterol in lipoprotein subclasses were determined via polyacrylamide gel electrophoresis. The intervention resulted in increases in mean LDL particle size (269.3 ± 3.4 to 271.6 ± 2.9 Å, P = 0.0003) and cholesterol in large high-density lipoprotein (HDL) subfractions (22.4 ± 11.2 to 26.8 ± 10.6% area, P = 0.007) along with decreases of cholesterol in small LDL (1.6 ± 2.0 to 0.6 ± 1.2% area, P < 0.01) and HDL subfractions (23.2 ± 9.4 to 19.0 ± 6.7% area, P = 0.05). These improvements were observed independent of changes in weight (90.7 ± 26.2 to 89.9 ± 27.8 kg, P > 0.05) and suggest that lifestyle modification in obese youth may reduce cardiovascular risk by shifting lipoprotein particle size and cholesterol distribution to a less atherogenic phenotype.

Lipoprotein particle distribution and skeletal muscle lipoprotein lipase activity after acute exercise.

BackgroundMany of the metabolic effects of exercise are due to the most recent exercise session. With recent advances in nuclear magnetic resonance spectroscopy (NMRS), it is possible to gain insight about which lipoprotein particles are responsible for mediating exercise effects.MethodsUsing a randomized cross-over design, very low density lipoprotein (VLDL) responses were evaluated in eight men on the morning after i) an inactive control trial (CON), ii) exercising vigorously on the prior evening for 100 min followed by fasting overnight to maintain an energy and carbohydrate deficit (EX-DEF), and iii) after the same exercise session followed by carbohydrate intake to restore muscle glycogen and carbohydrate balance (EX-BAL).ResultsThe intermediate, low and high density lipoprotein particle concentrations did not differ between trials. Fasting triglyceride (TG) determined biochemically, and mean VLDL size were lower in EX-DEF but not in EX-BAL compared to CON, primarily due to a reduction in VLDL-TG in the 70–120 nm (large) particle range. In contrast, VLDL-TG was lower in both EX-DEF and EX-BAL compared to CON in the 43–55 nm (medium) particle range. VLDL-TG in smaller particles (29–43 nm) was unaffected by exercise. Because the majority of VLDL particles were in this smallest size range and resistant to change, total VLDL particle concentration was not different between any of these conditions. Skeletal muscle lipoprotein lipase (LPL) activity was also not different across these 3 trials. However, in CON only, the inter-individual differences in LPL activity were inversely correlated with fasting TG, VLDL-TG, total, large and small VLDL particle concentration and VLDL size, indicating a regulatory role for LPL in the non-exercised state.ConclusionsThese findings reveal a high level of differential regulation between different sized triglyceride-rich lipoproteins following exercise and feeding, in the absence of changes in LPL activity.

Carotid atherosclerosis and lipoprotein particle subclasses in familial hypercholesterolaemia and familial combined hyperlipidaemia

Background and AimsFamilial hypercholesterolaemia (FH) and familial combined hyperlipidaemia (FCH) are common atherogenic disorders with great variability in cardiovascular disease (CVD). No direct atherosclerosis burden comparisons have been performed between FH and FCH in relation to lipoprotein particle distribution. Methods and ResultsRisk factors and three measures of carotid intima-media thickness (IMT) in both sides were determined in 572 FH, 250 FCH and 200 controls. Lipoproteins were assessed by nuclear magnetic resonance (NMR) spectroscopy. Compared with controls, IMT measures were increased in FH and FCH. FCH had the highest adjusted mean–maximum IMT. FH had twice low-density lipoprotein (LDL) particles than controls, but similar LDL subclass size and distribution. FCH subjects also had increased LDL particles and the highest number of small LDL (1519 ± 731 nmol l−1 vs. 887 ± 784 nmol l−1 in FH and 545 ± 409 nmol l−1 in controls). Age, gender, cholesterol/high-density lipoprotein (HDL) ratio, smoking and systolic blood pressure were independently associated with IMT in FH (r2 = 0.38). The same variables, except cholesterol/HDL ratio, were associated with IMT in FCH (r2 = 0.40). Among NMR lipoproteins, only VLDL and chylomicrons increased IMT prediction in FCH by 0.8%. ConclusionFH and FCH subjects show increased carotid atherosclerosis in relation to classical risk factors. Lipoprotein subclasses do not substantially contribute to IMT variability.

Effects of Controlled-Release Alpha Lipoic Acid in Lean, Nondiabetic Patients with Polycystic Ovary Syndrome

The purpose of this study was to determine whether a preparation of controlled-release alpha lipoic acid (CRLA) influences features of the polycystic ovary syndrome (PCOS). We administered CRLA 600 mg twice daily for 16 weeks to six lean, nondiabetic patients with PCOS. Insulin sensitivity was measured by the euglycemic, hyperinsulinemic clamp. Plasma lipids were measured by vertical ultracentrifugation. Oxidative stress markers were measured in serum. At the end of 16 weeks of CRLA treatment, there was a 13.5% improvement in insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp (p < .03). There was also a lowering of triglyceride levels (p < .04) and a shift in the distribution of low-density lipoprotein (LDL) particles toward the larger, more buoyant LDL subclass fraction. Two of the subjects who were not on oral contraception had an increased number of menstrual cycles. Controlled-release alpha lipoic acid treatment, however, was neither associated with an increase in plasma antioxidant capacity nor with a reduction in plasma lipid oxidation products. These data suggest that the CRLA has positive effects on the PCOS phenotype. The effects of CRLA, however, may have been exerted through a mechanism not involving changes in oxidative stress.

Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

Advanced Lipoprotein Testing and Subfractionation Are Not (Yet) Ready for Routine Clinical Use

Standard lipid tests measure the cholesterol or triglyceride content of lipoproteins, expressed as mg/dL (or mmol/L) of cholesterol or triglyceride. A standard lipid panel includes total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These lipids are carried within lipoprotein particles that are heterogeneous in size, density, charge, core lipid composition, specific apolipoproteins, and function.1 A variety of lipoprotein assays have been developed that subfractionate lipoprotein particles according to some of these properties such as size, density, or charge.2 These lipoprotein assays have been proposed for improving assessment of risk of cardiovascular disease (CVD) and for guiding lipid-lowering therapies. They are mostly used today in specialized lipid clinics or research studies, and their general utility for clinical practice is not well delineated.3 In this review, I first provide a summary of current guideline statements that address this topic. Then I give a brief overview of the different laboratory methods available for clinical use and discuss the literature evaluating these methods. Finally, I discuss current limitations to the widespread clinical application of these methods. Response by Superko on p 2404 The Third Adult Treatment Panel of the National Cholesterol Education Program4 and the American Heart Association5 recommend measuring a standard lipid panel in adults and targeting lipid-lowering therapy on the basis of levels of LDL cholesterol, and non-HDL cholesterol in subjects with hypertriglyceridemia. European and Canadian guidelines recommend measuring standard lipids while also emphasizing the total/HDL cholesterol ratio in risk assessment.6,7 Current guidelines do not recommend routine use of advanced lipoprotein tests, mainly because it is unclear how much incremental prognostic information is provided by these tests beyond that available from a standard lipid panel.4,6,7 Recently, an international panel proposed that cardiovascular risk may be more closely related to atherogenic lipoprotein …

LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins

Lipid trafficking in the brain is essential for the maintenance and repair of neuronal membranes, especially after neurotoxic insults. However, brain lipid metabolism is not completely understood. In plasma, LCAT catalyses the esterification of free cholesterol on circulating lipoproteins, a key step in the maturation of HDL. Brain lipoproteins are apolipoprotein E (apoE)-containing, HDL-like particles secreted initially as lipid-poor discs by glial cells. LCAT is synthesized within the brain, suggesting that it may play a key role in the maturation of these lipoproteins. Here we demonstrate that astrocytes are the primary producers of brain LCAT. This LCAT esterifies free cholesterol on nascent apoE-containing lipopoproteins secreted from glia. ApoE is the major LCAT activator in glia-conditioned media (GCM), and both the cholesterol transporter ABCA1 and apoE are required to generate glial LCAT substrate particles. LCAT deficiency leads to the appearance of abnormal approximately 8 nm particles in GCM, and exogenous LCAT restores the lipoprotein particle distribution to the wild-type (WT) pattern. In vivo, complete LCAT deficiency results in a dramatic increase in apoE-HDL and reduced apolipoprotein A-I (apoA-I)-HDL in murine cerebrospinal fluid (CSF). These data show that brain LCAT esterifies cholesterol on glial-derived apoE-lipoproteins, and influences CSF apoE and apoA-I levels.