Lipoprotein Particle Size Research Articles

Plant-based diet indices and lipoprotein particle subclass profiles: A cross-sectional analysis of middle- to older-aged adults

Background and aimsPlant-based diets (PBDs) are associated with favourable lipid profiles and cardiometabolic outcomes. However, limited data regarding PBD indices (PDIs) and lipoprotein subclasses exist. We examined overall PDI, healthful PDI (hPDI) and unhealthful PDI (uPDI) associations with lipid and lipoprotein profiles. MethodsThis cross-sectional analysis includes 1,986 middle- to older-aged adults from the Mitchelstown Cohort. The PDI, hPDI and uPDI scores were calculated from validated food frequency questionnaires. Higher PDI, hPDI and uPDI scores indicate a more PBD, healthful PBD and unhealthful PBD, respectively. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance spectroscopy. Relationships between PDIs and lipid and lipoprotein profiles were examined via correlation and regression analyses adjusted for covariates. ResultsIn fully adjusted regression analyses, higher PDI scores were associated with lower high-density lipoprotein (HDL) cholesterol concentrations and more triglyceride-rich lipoprotein and small very low-density lipoprotein (VLDL) particles. Higher hPDI scores were negatively associated with non-HDL cholesterol concentrations, large VLDL and small HDL particles, the Lipoprotein Insulin Resistance Index (LP-IR) score and VLDL particle size. Higher uPDI scores were associated with lower HDL cholesterol and greater triglyceride concentrations and more medium and large VLDL, total LDL, small LDL and total non-HDL particles, less large LDL and large HDL particles, a greater LP-IR score, greater VLDL particle size and smaller LDL and HDL particle size. ConclusionsThis study provides novel evidence regarding associations between PBD quality and lipoprotein subclasses. A more unhealthful PBD was robustly associated with a more pro-atherogenic lipoprotein profile.

Associations of lipoprotein subclasses with risk of all-cause and cardiovascular disease mortality in individuals with type 2 diabetes: A prospective cohort study.

Although lipoproteins are well-established risk factors for cardiovascular disease (CVD) mortality, conventional measurements failed to identify lipoprotein particle sizes. This study aimed to investigate associations of lipoprotein subclasses categorized by particle sizes with risk of all-cause and CVD mortality in individuals with type 2 diabetes. This study included 6575 individuals with type 2 diabetes from the UK Biobank. Concentrations of very low-, low-, intermediate- and high-density lipoprotein [very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), intermediate-density lipoprotein and high-density lipoprotein (HDL)] particles in 14 subclasses and lipid constituents within each subclass were measured by quantitative nuclear magnetic resonance. Multivariable-adjusted Cox proportional-hazard regression models were used to estimate the hazard ratio (HR) for per standard deviation increment of log-transformed lipoprotein subclasses with risk of mortality. All p-values were adjusted by the false discovery rate method. During a median follow-up of 11.4 years, 943 deaths were documented, including 310 CVD deaths. Small HDL particles were inversely associated with CVD mortality, with HR (95% CI) of 0.78 (0.69, 0.87), whereas very large and large HDL particles were positively associated with CVD mortality with HR (95% CI) of 1.28 (1.12, 1.45) and 1.19 (1.05, 1.35), respectively. A similar pattern was observed for all-cause mortality [small HDL particle (HR, 95% CI): 0.79, 0.74-0.85; large HDL particle: 1.15, 1.07-1.24; very large HDL particle: 1.26, 1.17-1.36]. For VLDL and LDL, very small VLDL particle was positively, while medium LDL particle was inversely associated with all-cause mortality, but not associated with CVD mortality. The pattern of association with all-cause and CVD mortality for cholesterol and triglyceride within lipoprotein particles was similar to those for lipoprotein particles themselves. The associations between lipoprotein particles, particularly HDL particles, with all-cause and CVD mortality among patients with type 2 diabetes were significantly varied by particle sizes, highlighting the importance of particle size as a lipoprotein metric in mortality risk discrimination.

The LDL-C/ApoB ratio predicts cardiovascular and all-cause mortality in the general population

BackgroundGenerally, low-density lipoprotein (LDL) particle size can be inferred from the LDL cholesterol concentration to total apolipoprotein B concentration ratio (LDL-C/ApoB ratio, hereinafter called LAR), which is a good predictor of cardiovascular disease. However, the predictive ability of LAR for mortality risk in the general population is still unclear. This study aimed to explore the association between LAR and cardiovascular as well as all-cause mortality among American adults.MethodsThe present study was a secondary analysis of existing data from the National Health and Nutrition Examination Survey (NHANES). The final analysis included 12,440 participants from 2005 to 2014. Survival differences between groups were visualized using Kaplan‒Meier curves and the log-rank test. The association of LAR with cardiovascular and all-cause mortality was evaluated using multivariate Cox regression and restricted cubic spline analysis. Age, sex, coronary artery disease, diabetes, lipid-lowering medication use and hypertriglyceridemia were analyzed in subgroup analyses.ResultsThe median age in the study cohort was 46.0 years [interquartile range (IQR): 31.0–62.0], and 6,034 (48.5%) participants were male. During the follow-up period, there were 872 (7.0%) all-cause deaths and 150 (1.2%) cardiovascular deaths. Compared with individuals without cardiovascular events, those who experienced cardiovascular deaths had a lower LAR (1.13 vs. 1.25) (P < 0.001). The adjusted Cox regression model indicated that lower LAR was an independent risk factor for both cardiovascular [hazard ratio (HR) = 0.304, 95% confidence interval (CI): 0.114–0.812] and all-cause mortality (HR = 0.408, 95% CI: 0.270–0.617). Moreover, a significant age interaction was observed (P for interaction < 0.05), and there was a strong association between LAR and mortality among participants over 65 years of age. Further analysis showed an inverse association between LAR and both cardiovascular and all-cause mortality.ConclusionsLAR can independently predict cardiovascular and all-cause mortality in the general population.

Association between triglyceride-glucose index and low-density lipoprotein particle size in korean obese adults

BackgroundSmall dense low-density lipoprotein cholesterol (sdLDL-C) is the lipoprotein marker among the various lipoproteins that is most strongly related to atherosclerosis. Insulin resistance (IR) can alter lipid metabolism, and sdLDL-C is characteristic of diabetic dyslipidemia. Therefore, this study sought to inspect the relationship between the triglyceride-glucose (TyG) index and mean low-density lipoprotein (LDL) particle size.MethodsIn this study, a total of 128 adults participated. The correlation coefficients between various lipoproteins and the TyG index were compared using Steiger’s Z test and the Spearman correlation. The independent link between the TyG index and mean LDL particle size was demonstrated by multiple linear regression analysis. To identify the TyG index cutoff value for the predominance of sdLDL particles, receiver operating characteristic curves were plotted.ResultsMean LDL particle size correlated more strongly with the TyG index than did very low-density lipoprotein, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Regression analysis demonstrated that mean LDL particle size had a strong association with the TyG index (β coefficient = -0.038, P-value < 0.001). The TyG index optimal cutoff value for sdLDL particle predominance and the corresponding area under the curve (standard error: 0.028, 95% confidence interval: 0.842–0.952) were 8.72 and 0.897, respectively, which were close to the cutoff value of diabetes risk in Koreans.ConclusionsMean LDL particle size is more strongly correlated with the TyG index than do other lipid parameters. After correcting for confounding variables, mean LDL particle size is independently linked with the TyG index. The study indicates that the TyG index is strongly related to atherogenic sdLDL particles predominance.

The benefits of measuring the size and number of lipoprotein particles for cardiovascular risk prediction: A systematic review and meta-analysis

ObjectiveCardiovascular risk (CVR) is conventionally calculated by measuring the total cholesterol content of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). The purpose of this systematic review was to assess the CVR associated with LDL and HDL particle size and number as determined by nuclear magnetic resonance (NMR) spectroscopy. Material and methodsA literature search was performed using the electronic databases MEDLINE and Scopus. All cohort and case–control studies published before January 1, 2019 that met the following inclusion criteria were included: HDL-P, LDL-P, HDL-Z and/or LDL-Z measured by NMR spectroscopy; cardiovascular event as an outcome variable; risk of cardiovascular events expressed as odds ratios or hazard ratios; only adult patients. A meta-analysis was performed for each exposure variable (4 for LDL and 5 for HDL) and for each exposure measure (highest versus lowest quartile and 1-standard deviation increment). ResultsThis review included 24 studies. Number of LDL particles was directly associated with CVR: risk increased by 28% with each standard deviation increment. LDL particle size was inversely and significantly associated with CVR: each standard deviation increment corresponded to an 8% risk reduction. CVR increased by 12% with each standard deviation increase in number of small LDL particles. HD, particle number and size were inversely associated with CVR. ConclusionLarger particle size provided greater protection, although this relationship was inconsistent between studies. Larger number of LDL particles and smaller LDL particle size are associated with increased CVR. Risk decreases with increasing number and size of HDL particles.

Sex-specific responses in glucose-insulin homeostasis and lipoprotein-lipid components after high-dose supplementation with marine n-3 PUFAs in abdominal obesity: a randomized double-blind crossover study.

Clinical studies on effects of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) on lipoprotein-lipid components and glucose-insulin homeostasis have shown conflicting results, which may partly be explained by differential responses in females and males. However, we have lacked data on sexual dimorphism in the response of cardiometabolic risk markers following increased consumption of n-3 or n-6 PUFAs. To explore sex-specific responses after n-3 (EPA + DHA) or n-6 (LA) PUFA supplementation on circulating lipoprotein subfractions, standard lipids, apolipoproteins, fatty acids in red blood cell membranes, and markers of glycemic control/insulin sensitivity among people with abdominal obesity. This was a randomized double-blind crossover study with two 7-week intervention periods separated by a 9-week washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we measured lipoprotein particle subclasses, standard lipids, apolipoproteins, fatty acid profiles, and markers of glycemic control/insulin sensitivity. The between-sex difference in relative change scores was significant after n-3 for total high-density lipoproteins (females/males: -11%*/-3.3%, p = 0.036; *: significant within-sex change), high-density lipoprotein particle size (+2.1%*/-0.1%, p = 0.045), and arachidonic acid (-8.3%*/-12%*, p = 0.012), and after n-6 for total (+37%*/+2.1%, p = 0.041) and small very-low-density lipoproteins (+97%*/+14%, p = 0.021), and lipoprotein (a) (-16%*/+0.1%, p = 0.028). Circulating markers of glucose-insulin homeostasis differed significantly after n-3 for glucose (females/males: -2.1%/+3.9%*, p = 0.029), insulin (-31%*/+16%, p < 0.001), insulin C-peptide (-12%*/+13%*, p = 0.001), homeostasis model assessment of insulin resistance index 2 (-12%*/+14%*, p = 0.001) and insulin sensitivity index 2 (+14%*/-12%*, p = 0.001), and quantitative insulin sensitivity check index (+4.9%*/-3.4%*, p < 0.001). We found sex-specific responses after high-dose n-3 (but not n-6) supplementation in circulating markers of glycemic control/insulin sensitivity, which improved in females but worsened in males. This may partly be related to the sex differences we observed in several components of the lipoprotein-lipid profile following the n-3 intervention. https://clinicaltrials.gov/, identifier [NCT02647333].

Proatherogenic changes in lipoprotein particles associated with a high triglyceride to high-density lipoprotein cholesterol ratio in youths.

A high triglyceride (TG) to high-density lipoprotein cholesterol (HDL) ratio (TG/HDL) predicts atherosclerosis and cardiovascular events. This study examined whether a proatherogenic distribution of plasma lipoprotein subclasses is associated with a high TG/HDL ratio in youths with obesity. Lipoprotein particle concentration and size were measured by proton nuclear magnetic resonance in a multiethnic cohort of 592 adolescents with overweight/obesity (age 13 ± 3 years, 58% females, BMI z score 2.1 ± 0.8) who were phenotyped with a 3-hour oral glucose tolerance test and abdominal magnetic resonance imaging. The highest TG/HDL quartile showed a higher particle concentration of very low-density lipoprotein (VLDL; +178%, p < 0.0001), intermediate-density lipoprotein (+338%, p < 0.0001), and low-density lipoprotein (LDL; +42%, p < 0.0001), compared with the lowest quartile. The prevalence of large VLDL, very small LDL, and small HDL progressively increased across TG/HDL quartiles. The TG/HDL ratio correlated positively with the average particle size of VLDL (r=0.37, p < 0.0001) and negatively with particle size of both LDL (r=-0.51, p < 0.0001) and HDL (r=-0.69, p < 0.0001). These associations were independent of sex, age, race/ethnicity, body mass, fasting plasma glucose, and insulin sensitivity. In youths with obesity, an elevated TG/HDL ratio is associated with high concentrations of proatherogenic lipoprotein subclasses. This phenotype may explain the increased cardiovascular risk associated with a high TG/HDL ratio.

Contribution of APOE Genetic Variants to Dyslipidemia.

apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE. However, more investigation is required to elucidate the significance of rarer variants of apoE.

Classification of Common Food Lipid Sources Regarding Healthiness Using Advanced Lipidomics: A Four-Arm Crossover Study.

Prospective studies have failed to establish a causal relationship between animal fat intake and cardiovascular diseases in humans. Furthermore, the metabolic effects of different dietary sources remain unknown. In this four-arm crossover study, we investigated the impact of consuming cheese, beef, and pork meat on classic and new cardiovascular risk markers (obtained from lipidomics) in the context of a healthy diet. A total of 33 young healthy volunteers (23 women/10 men) were assigned to one out of four test diets in a Latin square design. Each test diet was consumed for 14 days, with a 2-week washout. Participants received a healthy diet plus Gouda- or Goutaler-type cheeses, pork, or beef meats. Before and after each diet, fasting blood samples were withdrawn. A reduction in total cholesterol and an increase in high density lipoprotein particle size were detected after all diets. Only the pork diet upregulated plasma unsaturated fatty acids and downregulated triglycerides species. Improvements in the lipoprotein profile and upregulation of circulating plasmalogen species were also observed after the pork diet. Our study suggests that, within the context of a healthy diet rich in micronutrients and fiber, the consumption of animal products, in particular pork meat, may not induce deleterious effects, and reducing the intake of animal products should not be regarded as a way of reducing cardiovascular risk in young individuals.

Role of food matrix in modulating dairy fat induced changes in lipoprotein particle size distribution in a human intervention

BackgroundIntake of dairy fat within the matrix of cheese lowered circulating LDL cholesterol concentration to a greater extent than the same components consumed separately as butter, protein, and calcium. However, circulating LDL cholesterol is not indicative of concentration or size of LDL particles (LDL-P), which are recognized as more sensitive risk markers of CVD. ObjectivesThis was an exploratory analysis to investigate the role of the food matrix on lipoprotein particle size distribution, after a dairy fat intervention, in overweight adults aged ≥50 y. MethodsLipoprotein particle size distribution was measured in fasting EDTA blood samples taken at week 0 (baseline) and at week 6, using NMR. In total, 127 participants (BMI ≥ 25 kg/m2, aged ≥50 y) received ∼42 g dairy fat in 1 of 4 treatments: group A, 120 g full-fat cheddar cheese (FFCC); group B, reduced-fat cheese plus butter (RFC+B); group C, butter, calcium caseinate powder, and calcium supplement (CaCO3) (BCC); or group D, 120 g FFCC (as per group A) but after a 6-wk washout period during which they excluded cheese before intervention. ResultsTotal VLDL and chylomicron particles (VLDL/CM-P) decreased after intervention. There was a strong correlation between reduced VLDL/CM-P and a reduction in small proatherogenic VLDL-P (r = 0.888, P < 0.001). Reductions in total LDL-P were associated with a reduction in small LDL-P and, to a lesser extent, with large LDL-P. There was a significant main effect of treatment for change in intermediate-density lipoprotein particles (IDL-P) after the intervention (P = 0.023) between groups B and D (−46.86 ± 30.38 and 40.69 ± 32.72 nmol/L, respectively). HDL particle (HDL-P) parameters (diameter, concentration, or size distribution) were not affected by diet. ConclusionsOur findings indicate that reductions in LDL cholesterol observed with dairy fat consumption are driven by reductions in LDL-P concentration. A trend toward a less atherogenic profile was observed, but there was no clear effect of the individual food matrices.This trial was registered at ISRCTN as ISRCTN86731958.

The benefits of measuring the size and number of lipoprotein particles for cardiovascular risk prediction: A systematic review and meta-analysis

ObjectiveCardiovascular risk (CVR) is conventionally calculated by measuring the total cholesterol content of high-density lipoproteins (HDL) and low-density lipoproteins (LDL). The purpose of this systematic review was to assess the CVR associated with LDL and HDL particle size and number as determined by nuclear magnetic resonance (NMR) spectroscopy. Material and methodsA literature search was performed using the electronic databases MEDLINE and Scopus. All cohort and case–control studies published before January 1, 2019 that met the following inclusion criteria were included: HDL-P, LDL-P, HDL-Z and/or LDL-Z measured by NMR spectroscopy; cardiovascular event as an outcome variable; risk of cardiovascular events expressed as odds ratios or hazard ratios; only adult patients. A meta-analysis was performed for each exposure variable (4 for LDL and 5 for HDL) and for each exposure measure (highest versus lowest quartile and 1-standard deviation increment). ResultsThis review included 24 studies. Number of LDL particles was directly associated with CVR: risk increased by 28% with each standard deviation increment. LDL particle size was inversely and significantly associated with CVR: each standard deviation increment corresponded to an 8% risk reduction. CVR increased by 12% with each standard deviation increase in number of small LDL particles. HD, particle number and size were inversely associated with CVR. ConclusionLarger particle size provided greater protection, although this relationship was inconsistent between studies. Larger number of LDL particles and smaller LDL particle size are associated with increased CVR. Risk decreases with increasing number and size of HDL particles.

Lipoprotein Insulin Resistance Index: A Simple, Accurate Method for Assessing Insulin Resistance in South Asians.

Identification of insulin resistance (IR) in South Asians, who are at a higher risk for type 2 diabetes, is important. Lack of standardization of insulin assays limits the clinical use of insulin-based surrogate indices. The lipoprotein insulin resistance index (LP-IR), a metabolomic marker, reflects the lipoprotein abnormalities observed in IR. The reliability of the LP-IR index in South Asians is unknown. We evaluated the predictive accuracy of LP-IR compared with other IR surrogate indices in South Asians. In a cross-sectional study (n = 55), we used calibration model analysis to assess the ability of the LP-IR score and other simple surrogate indices (Homeostatic Model Assessment of Insulin Resistance, Quantitative insulin sensitivity check index, Adipose insulin resistance index, and Matsuda Index) to predict insulin sensitivity (SI) derived from the reference frequently sampled intravenous glucose tolerance test. LP-IR index was derived from lipoprotein particle concentrations and sizes measured by nuclear magnetic resonance spectroscopy. Predictive accuracy was determined by root mean squared error (RMSE) of prediction and leave-one-out cross-validation type RMSE of prediction (CVPE). The optimal cut-off of the LP-IR index was determined by the area under the receiver operating characteristic curve (AUROC) and the Youden index. The simple surrogate indices showed moderate correlations with SI (r = 0.53-0.69, P < .0001). CVPE and RMSE were not different in any of the surrogate indices when compared with LP-IR. The AUROC was 0.77 (95% CI 0.64-0.89). The optimal cut-off for IR in South Asians was LP-IR >48 (sensitivity: 75%, specificity: 70%). The LP-IR index is a simple, accurate, and clinically useful test to assess IR in South Asians.

Alzheimer’s Disease Patients, Especially ApoE4 Carriers, Have Significantly Reduced High‐density Lipoprotein Particle Size Revealed by Negative‐stained Transmission Electron Microscopy

AbstractBackgroundHigh density lipoproteins (HDL) are protective against a wide array of diseases and have recently also been found to be associated with reduced risk of Alzheimer’s Disease (AD). However, the amount of circulating HDL‐cholesterol does not correlate closely with function, explaining only about 40% of the variance in HDL’s ability to perform its primary role of cholesterol efflux. HDL particle composition, size and structure are important determinants of functional capacity, however little is known about HDL particle physical characteristics in AD patients, in particular whether there are apolipoprotein E (APOE) genotype‐dependent effects.MethodPlasma samples from a total of 172 APOE genotyped patients, n = 37 ApoE3/E3 and n = 34 ApoE3/E4 with diagnosed AD, n = 22 ApoE3/E3 and n = 18 ApoE3/E4 with diagnosed MCI, and n = 44 ApoE/E3 and n = 39 ApoE3/E4 age‐ and sex‐matched non‐AD controls were obtained from the UC Davis Alzheimer’s Disease Research Center biobank. HDL particles were isolated from plasma by sequential density‐adjusted ultracentrifugation followed by size‐exclusion chromatography. The size of HDL from each patient was characterized using negative‐stained transmission electron microscopy (NS‐TEM) followed by computational particle size analysis.ResultOn average, 34 TEM micrographs were obtained, and over 33,000 individual particles were selected and analyzed from each HDL sample using pre‐determined image quality and image selection criteria. The average particle size were compared between AD patients and controls stratified by APOE genotype. The mean particle diameter of HDL from MCI and AD patients was smaller compared to the control group (8.28 +/‐ 0.587, 8.30 +/‐ 0.662 vs. 8.84 +/‐ 0.587, respectively). The differences remained statistically significant when stratified by genotype. Both MCI and AD group had smaller HDL particle size compared to the control group in the ApoE3/E3 genotype (8.37 +/‐ 0.452, 8.48 +/‐ 0.613 vs. 8.90 +/‐ 0.602, respectively), and in the ApoE3/E4 genotype (8.17 +/‐ 0.707, 8.11 +/‐ 0.667 vs. 8.80 +/‐ 0.582, respectively).ConclusionThese results reveal that patients with Alzheimer’s dementia and mild cognitive impairment have disrupted HDL particle distribution, with smaller average HDL particle size, highlighting the need for further studies of lipoprotein metabolism in AD.

Association of physical activity with metabolic profile from adolescence to adulthood.

Physical activity benefits cardiometabolic health, but little is known about its detailed links with serum lipoproteins, amino acids, and glucose metabolism at young age. We therefore studied the association of physical activity with a comprehensive metabolic profile measured repeatedly in adolescence. The cohort is derived from the longitudinal Special Turku Coronary Risk Factor Intervention Project. At ages 13, 15, 17, and 19 years, data on physical activity were collected by a questionnaire, and circulating metabolic measures were quantified by nuclear magnetic resonance metabolomics from repeatedly assessed serum samples (age 13: n=503, 15: n=472, 17: n=466, and 19: n=361). Leisure-time physical activity (LTPA;MET h/wk) was directly associated with concentrations of polyunsaturated fatty acids, and inversely with the ratio of monounsaturated fatty acids to total fatty acids (-0.006SD; [-0.008, -0.003]; p < 0.0001). LTPA was inversely associated with very-low-density lipoprotein (VLDL) particle concentration (-0.003SD; [-0.005, -0.001]; p=0.002) and VLDL particle size (-0.005SD; [-0.007, -0.003]; p < 0.0001). LTPA showed direct association with the particle concentration and size of high-density lipoprotein (HDL), and HDL cholesterol concentration (0.004SD; [0.002, 0.006]; p < 0.0001). Inverse associations of LTPA with triglyceride and total lipid concentrations in large to small sized VLDL subclasses were found. Weaker associations were seen for other metabolic measures including inverse associations with concentrations of lactate, isoleucine, glycoprotein acetylation, and a direct association with creatinine concentration. The results remained after adjusting for body mass index and proportions of energy intakes from macronutrients. Physical activity during adolescence is beneficially associated with the metabolic profile including novel markers. The results support recommendations on physical activity during adolescence to promote health and possibly reduce future disease risks.

Sugar-Sweetened Beverage Consumption and Plasma Lipoprotein Cholesterol, Apolipoprotein, and Lipoprotein Particle Size Concentrations in US Adults

Prospective cohort studies have found a relation between sugar-sweetened beverage (SSB) consumption (sodas and fruit drinks) and dyslipidemia. There is limited evidence linking SSB consumption to emerging features of dyslipidemia, which can be characterized by variation in lipoprotein particle size, remnant-like particle (RLP), and apolipoprotein concentrations. To examine the association between SSB consumption and plasma lipoprotein cholesterol, apolipoprotein, and lipoprotein particle size concentrations among US adults. We examined participants from the Framingham Offspring Study (FOS; 1987-1995, n = 3047) and the Women's Health Study (1992, n = 26,218). Concentrations of plasma LDL cholesterol, apolipoprotein B (apoB), HDL cholesterol, apolipoprotein A1 (apoA1), triglyceride (TG), and non-HDL cholesterol, as well as total cholesterol:HDL cholesterol ratio and apoB:apoA1 ratio, were quantified in both cohorts; concentrations of apolipoprotein E, apolipoprotein C3, RLP-TG, and RLP cholesterol (RLP-C) were measured in the FOS only. Lipoprotein particle sizes were calculated from nuclear magnetic resonance signals for lipoprotein particle subclass concentrations (TG-rich lipoprotein particles [TRL-Ps]: very large, large, medium, small, and very small; LDL particles [LDL-Ps]: large, medium, and small; HDL particles [HDL-Ps]: large, medium, and small). SSB consumption was estimated from food frequency questionnaire data. We examined the associations between SSB consumption and all lipoprotein and apoprotein measures in linear regression models, adjusting for confounding factors such as lifestyle, diet, and traditional lipoprotein risk factors. SSB consumption was positively associated with LDL cholesterol, apoB, TG, RLP-TG, RLP-C, and non-HDL cholesterol concentrations and total cholesterol:HDL cholesterol and apoB:apoA1 ratios; and negatively associated with HDL cholesterol and apoA1 concentrations (P-trend range: <0.0001 to 0.008). After adjustment for traditional lipoprotein risk factors, SSB consumers had smaller LDL-P and HDL-P sizes; lower concentrations of large LDL-Ps and medium HDL-Ps; and higher concentrations of small LDL-Ps, small HDL-Ps, and large TRL-Ps (P-trend range: <0.0001 to 0.001). Higher SSB consumption was associated with multiple emerging features of dyslipidemia that have been linked to higher cardiometabolic risk in US adults.

High-Density Lipoprotein Particle Size and Function Predict Cardiovascular Events in Patients With CKD

High-Density Lipoprotein Particle Size and Function Predict Cardiovascular Events in Patients With CKD

APOE Genotypes Modulate Inflammation Independently of Their Effect on Lipid Metabolism

The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.

Variant APOL1 protein in plasma associates with larger particles in humans and mouse models of kidney injury.

BackgroundGenetic variants in apolipoprotein L1 (APOL1), a protein that protects humans from infection with African trypanosomes, explain a substantial proportion of the excess risk of chronic kidney disease affecting individuals with sub-Saharan ancestry. The mechanisms by which risk variants damage kidney cells remain incompletely understood. In preclinical models, APOL1 expressed in podocytes can lead to significant kidney injury. In humans, studies in kidney transplant suggest that the effects of APOL1 variants are predominantly driven by donor genotype. Less attention has been paid to a possible role for circulating APOL1 in kidney injury.MethodsUsing liquid chromatography-tandem mass spectrometry, the concentrations of APOL1 were measured in plasma and urine from participants in the Seattle Kidney Study. Asymmetric flow field-flow fractionation was used to evaluate the size of APOL1-containing lipoprotein particles in plasma. Transgenic mice that express wild-type or risk variant APOL1 from an albumin promoter were treated to cause kidney injury and evaluated for renal disease and pathology.ResultsIn human participants, urine concentrations of APOL1 were correlated with plasma concentrations and reduced kidney function. Risk variant APOL1 was enriched in larger particles. In mice, circulating risk variant APOL1-G1 promoted kidney damage and reduced podocyte density without renal expression of APOL1.ConclusionsThese results suggest that plasma APOL1 is dynamic and contributes to the progression of kidney disease in humans, which may have implications for treatment of APOL1-associated kidney disease and for kidney transplantation.

Effects of Gestational Diabetes Mellitus on Cholesterol Metabolism in Women with High-Risk Pregnancies: Possible Implications for Neonatal Outcome.

Metabolic disorders in pregnancy, particularly gestational diabetes mellitus (GDM), are associated with an increased risk for adverse pregnancy outcome and long-term cardiometabolic health of mother and child. This study analyzed changes of serum cholesterol synthesis and absorption markers during the course of high-risk pregnancies, with respect to the development of GDM. Possible associations of maternal lipid biomarkers with neonatal characteristics were also investigated. The study included 63 women with high risk for development of pregnancy complications. Size and proportions of small low-density (LDL) and high-density lipoprotein (HDL) particles were assessed across trimesters (T1–T3), as well as concentrations of cholesterol synthesis (lathosterol, desmosterol) and absorption markers (campesterol, β-sitosterol). During the study, 15 women developed GDM, while 48 had no complications (non-GDM). As compared to the non-GDM group, women with GDM had significantly higher triglycerides in each trimester, while having a lower HDL-C level in T3. In addition, they had significantly lower levels of β-sitosterol in T3 (p < 0.05). Cholesterol synthesis markers increased across trimesters in both groups. A decrease in serum β-sitosterol levels during the course of pregnancies affected by GDM was observed. The prevalence of small-sized HDL decreased in non-GDM, while in the GDM group remained unchanged across trimesters. Newborn’s size in the non-GDM group was significantly higher (p < 0.01) and inversely associated with proportions of both small, dense LDL and HDL particles (p < 0.05) in maternal plasma in T1. In conclusion, high-risk pregnancies affected by GDM are characterized by altered cholesterol absorption and HDL maturation. Advanced lipid testing may indicate disturbed lipid homeostasis in GDM.

The relative importance of particle count, type, and size of ApoB-containing lipoproteins in risk of myocardial infarction

Abstract Background An accumulating body of evidence suggests that the number of apolipoprotein B-containing particles (ApoB-P) is more predictive of cardiovascular risk than their lipid content. However, it is unclear if this association is consistent across different lipoprotein types and sizes. Purpose We aimed to evaluate if particle type and size are associated with incident myocardial infarction (MI) beyond ApoB-P count. Moreover, we aimed to determine if the risk associated with lipoprotein(a) is additive to that of ApoB-P. Methods This prospective cohort study included 96,126 participants without prior history of stroke, coronary or peripheral artery disease or use of lipid-lowering medication from the UK Biobank. Count and size of VLDL, IDL, LDL, and HDL, as well as ApoB level and total ApoB-P count were measured in non-fasting plasma samples by nuclear magnetic resonance platform. Lipoprotein(a) was measured by immunoturbidimetric assay. We explored associations between these lipoprotein markers and incident MI using Cox proportional hazard models adjusted sequentially for clinical covariates, HDL count and size, and ApoB-P. Results Over a median follow-up of 12.1 years, 1702 participants had incident MI. In unadjusted models, 1-SD increases in ApoB-P count, ratio of VLDL to (LDL+IDL) particle counts, VLDL size and lipoprotein(a) were associated with a higher risk of MI, while LDL size was associated with a lower risk of MI (Table 1). When adjusting for clinical covariates and lipid parameters, only ApoB-P and lipoprotein(a) remained significantly associated with a higher risk of MI (HR: 1.40 [1.32; 1.48] and 1.20 [1.14; 1.27], respectively). Adjusted restricted cubic splines confirmed findings from linear trend Cox models (Figure 1). ApoB-P count was highly correlated with ApoB level (r=0.99), and replication of analyses replacing one for another revealed no change in results. Conclusion The risk of MI is independently associated with the total particle count of all ApoB-P, and not the size or type of these lipoproteins. ApoB level can be used as a very accurate surrogate of ApoB-P count in the clinical setting. Lipoprotein(a) is associated with MI risk independently of total particle count, and therefore, the combination of ApoB and lipoprotein(a) may provide the optimal clinical evaluation of lipid-mediated MI risk. Funding Acknowledgement Type of funding sources: None.