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Recent genetic data can offer important insights into the roles of lipoprotein subfractions and particle sizes in preventing coronary artery disease (CAD), as previous observational studies have often reported conflicting results. In this study, we first used the LD score regression to estimate the genetic correlation of 77 subfraction traits with traditional lipid profile and identified 27 traits that may involve distinct genetic mechanisms. We then used Mendelian randomization (MR) to estimate the causal effect of these traits on the risk of CAD. In univariable MR, the concentration and content of medium high-density lipoprotein (HDL) particles showed a protective effect against coronary artery disease. The effect was not attenuated in multivariable MR that adjusted for traditional lipid profile. The multivariable MR analyses also found that small HDL particles and smaller mean HDL particle diameter may have a protective effect. We identified four genetic markers for HDL particle size and CAD.

Background and aims Thyroid dysfunction is related to several lipid abnormalities. There is no consensus about concentration of high-density lipoprotein (HDL) in different studies. The aim of this report is to evaluate HDL particle (HDL-P) subfractions across a spectrum of thyroid functions in a Brazilian population. Methods Individuals were divided into three groups by baseline thyroid function (subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism). HDL-P subfractions were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy. To examine the association between HDL-P subfractions and thyroid function, we used univariate and multivariate linear regression models adjusted for demographic characteristics, comorbidities, lifestyle factors, and traditional lipid measurement (HDL-C, LDL-C and triglycerides). Results Of 3304 participants, 54.1% were women, 51.2% white, with mean age 50.6 ± 8.7 years. HDL-C and triglycerides levels (p = 0.032 and p = 0.016, respectively) were higher in the SC hypothyroid group. There were no statistically significant differences in total cholesterol levels and LDL-C levels. In univariate analysis, small HDL-P subfractions were significantly lower in subclinical hypothyroidism (p = 0.026) whereas intermediate HDL-P were higher in subclinical hyperthyroidism (p = 0.049), compared to euthyroidism. After adjustment for demographic data, SC hypothyroidism was still statistically associated with lower levels of small HDL-P. After adjusting for comorbidities, lifestyle factors, and traditional lipid measurements, SC hypothyroidism had an established association with lower levels of small HDL-P while SC hyperthyroidism was associated with lower levels of large HDL-P. Conclusions In this large cohort from a Brazilian population, subclinical hypothyroidism was associated with lower small HDL-P subfractions, and subclinical hyperthyroidism with lower large HDL-P subfractions and higher intermediate HDL-P subfractions.

The prevalence of atherosclerosis is increased in type 1 diabetes despite normal-to-high HDL-cholesterol levels. The cholesterol efflux capacity (CEC) of HDL is a better predictor of cardiovascular events than static HDL-cholesterol. This cross-sectional study addressed the hypothesis that impaired HDL function contributes to enhanced CVD risk within type 1 diabetes. We compared HDL particle size and concentration (by NMR), total CEC, ATP-binding cassette subfamily A, member 1 (ABCA1)-dependent CEC and ABCA1-independent CEC (by determining [3H]cholesterol efflux from J774-macrophages to ApoB-depleted serum), and carotid intima–media thickness (CIMT) in 100 individuals with type 1 diabetes (37.6 ± 1.2 years; BMI 26.9 ± 0.5 kg/m2) and 100 non-diabetic participants (37.7 ± 1.1 years; 27.1 ± 0.5 kg/m2). Compared with non-diabetic participants, total HDL particle concentration was lower (mean ± SD 31.01 ± 8.66 vs 34.33 ± 8.04 μmol/l [mean difference (MD) −3.32 μmol/l]) in participants with type 1 diabetes. However, large HDL particle concentration was greater (9.36 ± 3.98 vs 6.99 ± 4.05 μmol/l [MD +2.37 μmol/l]), resulting in increased mean HDL particle size (9.82 ± 0.57 vs 9.44 ± 0.56 nm [MD +0.38 nm]) (p

HDL efflux capacity and HDL particle size are associated with atherosclerotic CVD (ASCVD) events in middle-aged individuals; however, it is unclear whether these associations are present in older adults. We sampled 402 Chicago Healthy Aging Study participants who underwent a dedicated carotid MRI assessment for lipid-rich necrotic core (LRNC) plaque. We measured HDL particle size, HDL particle number, and LDL particle number with NMR spectroscopy, as well as HDL efflux capacity. We quantified the associations between HDL particle size and HDL efflux using adjusted linear regression models. We quantified associations between the presence of LRNC and HDL and LDL particle number, HDL particle size, and HDL efflux capacity using adjusted logistic regression models. HDL efflux capacity was directly associated with large (β = 0.037, P < 0.001) and medium (β = 0.0065, P = 0.002) HDL particle concentration and inversely associated with small (β = −0.0049, P = 0.018) HDL particle concentration in multivariable adjusted models. HDL efflux capacity and HDL particle number were inversely associated with prevalent LRNC plaque in unadjusted models (odds ratio: 0.5; 95% confidence interval: 0.26, 0.96), but not after multivariable adjustment. HDL particle size was not associated with prevalent LRNC. HDL particle size was significantly associated with HDL efflux capacity, suggesting that differences in HDL efflux capacity may be due to structural differences in HDL particles. Future research is needed to determine whether HDL efflux is a marker of ASCVD risk in older populations.

Purpose of review In the last 2 years, significant advances in the understanding of HDL particle structure and the associations between particle structure, function, and atherosclerosis have been made. We will review and provide clinical and epidemiological context to these recent advances. Recent findings Several recent studies have analyzed the associations between HDL particle size distribution, number, and particle function and specific environmental, behavioral, and pharmacologic exposures. Detailed phenotyping of HDL-associated protein complements, particularly apolipoproteins, strongly suggests structural subspecies of HDL exist with differential associations with HDL function and ASCVD risk. Summary The recent data on biological and structural variation in HDL suggests the existence of relatively discrete particle species, which share a similar structure and function. We propose that the classical taxonomy that clusters HDL particles by cholesterol content is incomplete. Detailed phenotyping of HDL subspecies in clinical and epidemiological research may yield insights into new risk markers and biochemical pathways that could provide targets for atherosclerotic cardiovascular disease (ASCVD) therapy and prevention in the future.

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.

Background:As Mendelian Randomization (MR) studies showed no effect of variants altering HDL-cholesterol (HDL-C) levels concerning Cardiovascular Disease (CVD) and novel therapeutic interventions aiming to raise HDL-C resulted to futility, the usefulness of HDL-C is unclear.Objective:As the role of HDL-C is currently doubtful, it is suggested that the atheroprotective functions of HDLs can be attributed to the number of HDL particles, and their characteristics including their lipid and protein components. Scientific interest has focused on HDL function and on the causes of rendering HDL particles dysfunctional, whereas the relevance of HDL subclasses with CVD remains controversial.Methods:The present review discusses changes in quality as much as in quantity of HDL in pathological conditions and the connection between HDL particle concentration and cardiovascular disease and mortality. Emphasis is given to the recently available data concerning the cholesterol efflux capacity and the parameters that determine HDL functionality, as well as to recent investigations concerning the associations of HDL subclasses with cardiovascular mortality.Results:MR studies or pharmacological interventions targeting HDL-C are not in favor of the hypothesis of HDL-C levels and the relationship with CVD. The search of biomarkers that relate with HDL functionality is needed. Similarly, HDL particle size and number exhibit controversial data in the context of CVD and further studies are needed.Conclusion:There is no room for the old concept of HDL as a silver bullet,as HDL-C cannot be considered a robust marker and does not reflect the importance of HDL particle size and number. Elucidation of the complex HDL system, as well as the finding of biomarkers, will allow the development of any HDL-targeted therapy.

BACKGROUND: Fish oil enriched in omega-11 long-chain monounsaturated fatty acids (LCMUFA; C20:1 and C22:1 isomers combined) have shown lipid-lowering and atheroprotective effects in animal models. OBJECTIVE: To perform a first-in-human trial of LCMUFA-rich saury fish oil supplementation to test its safety and possible effect on plasma lipids. METHODS: A double-blind, randomized cross-over clinical trial was carried out in 30 healthy normolipidemic adults (BMI

Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoprotein to supply fatty acids, and its deficiency leads to hypertriglyceridemia, thereby inducing metabolic syndrome (MetSyn). Nordihydroguaiaretic acid (NDGA) has been recently reported to inhibit LPL secretion by endoplasmic reticulum (ER)-Golgi redistribution. However, the role of NDGA on dyslipidemia and MetSyn remains unclear. To address this question, leptin receptor knock out (KO)-db/db mice were randomly assigned to three different groups: A normal AIN76-A diet (CON), a Western diet (WD) and a Western diet with 0.1% NDGA and an LPL inhibitor, (WD+NDGA). All mice were fed for 12 weeks. The LPL inhibition by NDGA was confirmed by measuring the systemic LPL mass and adipose LPL gene expression. We investigated whether the LPL inhibition by NDGA alters the metabolic phenotypes. NDGA led to hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. More strikingly, the supplementation of NDGA increased the percentage of high density lipoprotein (HDL)small (HDL3a+3b+3c) and decreased the percentage of HDLlarge (HDL2a+2b) compared to the WD group, which indicates that LPL inhibition modulates HDL subclasses. was NDGA increased adipose inflammation but had no impact on hepatic stress signals. Taken together, these findings demonstrated that LPL inhibition by NDGA aggravates metabolic parameters and alters HDL particle size.

Dyslipidemia may influence enzymes and transfer proteins needed to the lipoprotein particle remodeling. Calculated indices and evaluation of lipoprotein particle size have widely been used to predict cardiovascular risk. The aim of this study was to evaluate HDL particle size and LDL particle size estimate based on TG/HDL-C as well as apoB/apoA-I ratio as possible marker and atherogenic indices, respectively, of cardiovascular disease risk in the presence of dyslipidemia. We evaluated 100 individuals of both gender, without treatment with lipid-lowering drugs, 27 normolipidemic and 73 dyslipidemic, such as isolated hypercholesterolemia (n = 16), isolated hypertriglyceridemia (n = 17), low HDL-C (n = 26) and mixed dyslipidemia (n = 14). The HDL particle size did not differ between groups. The TG/HDL-C ratio was higher in groups with isolated hypertriglyceridemia (4.2 ± 1.5), low HDL-C (5.2 ± 3.1) and mixed dyslipidemia (5.3 ± 1.6). The apoB/apoA-I ratio was increased in all groups of dyslipidemia (apoB/apoA-I > 0.5) when compared to normolipidemic (apoB/apoA-I = 0.5, p

Background Alterations in plasma lipoprotein subclass distribution affect the risk for coronary artery disease (CAD). However, it is unclear whether the determination of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) phenotypes may or may not improve the ability to predict CAD development. Methods Polyacrylamide gradient (3-31%) gel electrophoresis was used to simultaneously determine size and distribution of lipoprotein subclasses in 181 CAD patients and 178 controls. Results Mean LDL and HDL subclass sizes were significantly smaller in patients than in controls (p lt 0.001). Multivariate logistic regression analysis showed that small dense LDL particles were independent CAD risk predictors (OR = 2.867, p lt 0.01), even when adjusted for other traditional risk factors, while small HDL particles lost their significance after adjustment (OR = 2.071, p = 0.054). The area under the ROC curve for LDL (0.671) and HDL (0.643) particle size measurement demonstrated low clinical accuracy when compared to the combination of traditional lipid risk factor measurements. Conclusions CAD is associated with the predominance of smaller LDL and HDL particles. However, simultaneous determination of these two lipoprotein phenotypes provides no additional power in discriminating CAD and non-CAD subjects, beyond that obtained by the traditional risk factors.

Objectives: We determined the frequencies of apolipoprotein E (apo E) alleles and examined the effect of apo E polymorphism on lipoprotein particle sizes in Serbian healthy, middle-aged individuals. Design and methods: We performed apo E phenotype by immunobloting method in 183 men and 143 women (mean years: 56.3 +/- 10.60 and 54.9 +/- 10.31, respectively). Plasma lipid and apolipoprotein levels were measured by routine laboratory methods. LDL and HDL particle sizes were determined by nondenaturing polyacrylamide gradient (3-31%) gel electrophoresis. Results: The apo E allele frequencies were epsilon 2-4.9%, epsilon 3-86.5%, and epsilon 4-8.6%. Men with epsilon 4 allele had lower HDL-C and Apo AI concentrations than epsilon 3 men. The epsilon 2 allele men had the smallest LDL particles, highest percent of subjects with LDL phenotype B and highest TG/HDL-C ratio. Women with epsilon 2 allele had lowest concentration of apo B. The epsilon 4 allele women had smallest HDL particles and highest percent of the subjects with small-sized HDL phenotype. Conclusions: This study showed gender-related effect of apo E polymorphism on lipoprotein particle size. In men, possession of the 62 allele is associated with small LDL particles, whereas in women, epsilon 4 allele is associated with small HDL particles. Differences in gender-related influence of apo E polymorphism on LDL and HDL particle sizes could be clinically useful in strategy for reduction of coronary disease risk in middle-aged men and women.

Since the development of coronary heart disease (CAD) is affected by a specific pattern of plasma high density lipoprotein (HDL) effects it may be useful to know whether this occurs already in childhood. In this study we evaluated particle size distribution of HDL by gradient gel electrophoresis and the determination of cholesterol esterification rate (FER HDL ) in plasma depleted of apo B lipoproteins in 221 children (108 boys and 113 girls) aged 4 months to 20 years. Total plasma- (TC), low-density lipoprotein- (LDL-C) and HDL(HDL-C) cholesterol, HDL unesterified cholesterol (HDL-UC) and plasma triglycerides (TG) were also measured. There were no significant gender and age differences with respect to the plasma TC. LDL-TC and TG but concentration of HDL-TC increased with age. Post-pubertal girls had significantly higher relative concentrations of HDL 2b compared to boys (30.4% vs 17.2%), while HDL 3b,c was lower in post-pubertal girls (8.7% vs. 16.5 %). FER HDL correlated inversely with HDL 2b and positively with MDL 3b,c particles and was significantly higher in boys of the post-pubertal group compared to girls (16.9%/h vs 12.5%/h). While in girls there was a positive correlation between age and HDL-C, HDL-UC and the relative concentration of HDL 2b no significant correlation were observed in boys. In girls the increase in TC showed a significant correlation with a simultaneous increase in HDL-C, HDL-UC and HDL 2b . In boys TC correlated significantly with changes in TG only. When HDL 2b and HDL 3b,c cholesterol levels are calculated from HDL-C concentration and per cent distribution the differences between males and females are further emphasized. These data indicate that HDL particle size distribution is age- and gender-dependent.

Objective— High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD. Methods and Results— Altogether, 148 members of Finnish low-HDL families and 133 healthy control subjects participated in our study. HDL particle size was significantly smaller in affected family members (HDL ≤10th Finnish age-sex specific percentile) compared with unaffected family members and control subjects (9.1±0.04 nm versus 9.5±0.05 nm, P P 2b particles as well as preβ-HDL concentration were significantly decreased among the affected family members. Mean IMT was significantly higher in the affected family members than in the control subjects (0.85±0.01 mm versus 0.79±0.01 mm; P 2b , systolic blood pressure, and preβ-HDL were significant independent determinants of mean IMT. Conclusions— The decreased levels of HDL 2b and preβ-HDL reflect the potentially efflux-deficient HDL subspecies profile in the affected low-HDL family members. Decreased HDL particle size caused by the decrease of plasma concentration of HDL 2b and decreased preβ-HDL levels correlate with increased IMT.

Atherosclerosis begins in childhood. Protection from atherosclerosis is provided by high-density lipoprotein (HDL), a heterogeneous particle, which includes several subclasses differing in size, density and apolipoprotein content. The objective of this study was to document the relevance of assessing HDL particle size as another feature of dyslipidemia related to the develpment of atheosclerosis during childhood. For that purpose, HDL particle size in 268 community-based children (137 boys and 131 girls), 7–13 years old, was measured by gradient gel electrophoresis, and relationships of HDL particle size to plasma lipids parameters and the anthropometric indices were analyzed. There was no gender difference in HDL particle diameter. The results of analysis revealed significant positive correlations between HDL particle diameter and HDL-cholesterol level (r=0.363, p

It is thought that apolipoprotein A-I (apoA-I) spontaneously exchanges between high-density lipoprotein (HDL)-bound and lipid-free states, which is relevant to the occurrence of preβ-HDL particles in plasma. To improve our understanding of the mechanistic basis for this phenomenon, we performed kinetic and thermodynamic analyses for apoA-I exchange between discoidal HDL-bound and lipid-free forms using fluorescence-labeled apoA-I variants. Gel filtration experiments demonstrated that addition of excess lipid-free apoA-I to discoidal HDL particles promotes exchange of apoA-I between HDL-associated and lipid-free pools without alteration of the steady-state HDL particle size. Kinetic analysis of time-dependent changes in NBD fluorescence upon the transition of NBD-labeled apoA-I from HDL-bound to lipid-free state indicates that the exchange kinetics are independent of the collision frequency between HDL-bound and lipid-free apoA-I, in which the lipid binding ability of apoA-I affects the rate of association of lipid-free apoA-I with the HDL particles and not the rate of dissociation of HDL-bound apoA-I. Thus, C-terminal truncations or mutations that reduce the lipid binding affinity of apoA-I strongly impair the transition of lipid-free apoA-I to the HDL-bound state. Thermodynamic analysis of the exchange kinetics demonstrated that the apoA-I exchange process is enthalpically unfavorable but entropically favorable. These results explain the thermodynamic basis of the spontaneous exchange reaction of apoA-I associated with HDL particles. The altered exchangeability of dysfunctional apoA-I would affect HDL particle rearrangement, leading to perturbed HDL metabolism.

HDL-increasing drugs such as fenofibrate and niacin have failed to decrease the cardiovascular risk in patients with type 2 diabetes. Drug-mediated quantitative and qualitative HDL modifications could be involved in these negative results. To evaluate the quantitative and qualitative effects of niacin and fenofibrate on HDL in patients with type 2 diabetes, a prospective, randomised controlled intervention trial was conducted. Thirty type 2 diabetic patients with low HDL were randomised to receive either fenofibrate (FFB) or niacin broken vertical bar laropiprant (ERN/LPR) as an add-on to simvastatin treatment for 12 weeks according to a crossover design. At the basal point and after each intervention period, physical examinations and comprehensive standard biochemical determinations and HDL metabolomics were performed. Thirty nondiabetic patients with normal HDL were used as a basal control group. ERN/LRP, but not FFB, significantly increased HDL cholesterol. Neither ERN/LRP nor FFB reversed the HDL particle size or particle number to normal. ERN/LRP increased apoA-I but not apoA-II, whereas FFB produced the opposite effect. FFB significantly increased Pre beta 1-HDL, whereas ERN/LRP tended to lower Pre beta 1-HDL. CETP and LCAT activities were significantly decreased only by ERN/LRP. PAF-AH activity in HDL and plasma decreased with the use of both agents. Despite their different actions on antioxidant parameters, none of the treatments induced detectable antioxidant improvements. ERN/LRP and FFB had strikingly different effects on HDL quantity and quality, as well as on HDL cholesterol concentrations. When prescribing HDL cholesterol increasing drugs, this differential action should be considered. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

A low plasma HDL-cholesterol concentration is an important risk factor for coronary heart disease (CHD) and is often accompanied by increased triglyceride concentrations. Women have generally higher HDL-cholesterol and lower triglyceride concentrations and concomitantly are at lower risk of CHD than men. As HDL particle size is a new and potentially important marker of CHD risk, we have examined the potential gender difference in HDL particle size, assessed by nondenaturing 4–30% polyacrylamide gradient gel electrophoresis, in a sample of men (n=231) and women (n=183). Overall, men were characterized by a less favorable lipoprotein–lipid profile, which was accompanied by smaller HDL particle size compared to women. However, when men and women were matched for HDL particle size and compared for their metabolic profile, it was found that both genders were characterized by similar plasma lipoprotein–lipid profile despite the fact that women were characterized by higher levels of total body fat but lower waist girth than men. In summary, HDL particle size is a strong marker of the gender-related difference in the determination of the metabolic risk profile.

Background Apolipoprotein (apo) A‐I is a major high‐density lipoprotein ( HDL ) protein that causes cholesterol efflux from peripheral cells through the ATP ‐binding cassette transporter A1 ( ABCA 1), thus generating HDL and reversing the macrophage foam cell phenotype. Pre‐β 1 HDL is the smallest subfraction of HDL , which is believed to represent newly formed HDL , and it is the most active acceptor of free cholesterol. Furthermore it has a possible protective function against cardiovascular disease ( CVD ). We developed a novel apoA‐I mimetic peptide without phospholipids (Fukuoka University ApoA‐I Mimetic Peptide, FAMP ). Methods and Results FAMP type 5 ( FAMP 5) had a high capacity for cholesterol efflux from A172 cells and mouse and human macrophages in vitro, and the efflux was mainly dependent on ABCA 1 transporter. Incubation of FAMP 5 with human HDL or whole plasma generated small HDL particles, and charged apoA‐I‐rich particles migrated as pre‐β HDL on agarose gel electrophoresis. Sixteen weeks of treatment with FAMP 5 significantly suppressed aortic plaque formation (scrambled FAMP , 31.3±8.9% versus high‐dose FAMP 5, 16.2±5.0%; P HDL ‐mediated cholesterol efflux capacity from the mice. Conclusions A newly developed apoA‐I mimetic peptide, FAMP , has an antiatherosclerotic effect through the enhancement of the biological function of HDL . FAMP may have significant atheroprotective potential and prove to be a new therapeutic tool for CVD .

Apolipoprotein A-II (apoA-II) is the second major apolipoprotein following apolipoprotein A-I (apoA-I) in HDL. ApoA-II has multiple physiological functions and can form senile amyloid fibrils (AApoAII) in mice. Most circulating apoA-II is present in lipoprotein A-I/A-II. To study the influence of apoA-I on apoA-II and AApoAII amyloidosis, apoA-I-deficient (C57BL/6J.Apoa1−/−) mice were used. Apoa1−/− mice showed the expected significant reduction in total cholesterol (TC), HDL cholesterol (HDL-C), and triglyceride (TG) plasma levels. Unexpectedly, we found that apoA-I deficiency led to redistribution of apoA-II in HDL and an age-related increase in apoA-II levels, accompanied by larger HDL particle size and an age-related increase in TC, HDL-C, and TG. Aggravated AApoAII amyloidosis was induced in Apoa1−/− mice systemically, especially in the heart. These results indicate that apoA-I plays key roles in maintaining apoA-II distribution and HDL particle size. Furthermore, apoA-II redistribution may be the main reason for aggravated AApoAII amyloidosis in Apoa1−/− mice. These results may shed new light on the relationship between apoA-I and apoA-II as well as provide new information concerning amyloidosis mechanism and therapy.

Small LDL and HDL particle size are characteristic of a proatherogenic lipoprotein profile. Aerobic exercise increases these particle sizes. Although visceral adipose tissue (VAT) has been strongly linked with dyslipidemia, the importance of intermuscular adipose tissue (IMAT) to dyslipidemia and exercise responses is less well understood. We measured exercise-associated changes in thigh IMAT and VAT and examined their relationships with changes in LDL and HDL particle size. Sedentary, dyslipidemic, overweight subjects ( n = 73) completed 8–9 mo of aerobic training. Linear regression models were used to compare the power of IMAT change and VAT change to predict lipoprotein size changes. In men alone ( n = 40), IMAT change correlated inversely with both HDL size change ( r = −0.42, P = 0.007) and LDL size change ( r = −0.52, P < 0.001). That is, reduction of IMAT was associated with a shift toward larger, less atherogenic lipoprotein particles. No significant correlations were observed in women. After adding VAT change to the model, IMAT change was the only significant predictor of either HDL size change ( P = 0.034 for IMAT vs. 0.162 for VAT) or LDL size change ( P = 0.004 for IMAT vs. 0.189 for VAT) in men. In conclusion, in overweight dyslipidemic men, exercise-associated change in thigh IMAT was inversely correlated with both HDL and LDL size change and was more predictive of these lipoprotein changes than was change in VAT. Reducing IMAT through aerobic exercise may be functionally related to some improvements in atherogenic dyslipidemia in men.

Objectives: Small, dense LDL particles are associated with an increased risk of coronary heart disease (CHD), and there is growing evidence that small HDL subclasses are less protective than the larger ones. Very limited information is available about the lipoprotein subclasses among populations living in South-East European region, and none for Serbia. Design and methods: We analyzed the distributions of LDL and HDL subclasses and their relationships with Framingham risk scores (FRS) in 229 Serbian middle-aged asymptomatic individuals. By use of non-denaturing gradient gel electrophoresis, we determined the diameters of LDL and HDL subtractions in a single run. Results: Comparing to women, men had smaller LDL and HDL particles (P lt 0.001, and P lt 0.05, respectively), higher frequency of LDL B phenotype (P lt 0.005), and significant reduction of HDL2b in favor of HDL2a subclasses (P lt 0.05). The observed gender-related differences disappeared after the age of 60. We found a significant association of the small LDL particles with high FRS values (P lt 0.005). A notable incidence of risk lipoprotein phenotypes (LDL B-9.2%; small-sized HDL-9.9%) was found among subjects that were categorized as "low-risk", requiring no further intervention, according to FRS. Conclusion: Measurement of LDL, and possibly HDL particle size could provide further insight into individual CHD risk, and enable them to benefit from targeted preventive measures.

OBJECTIVE: Dyslipidaemia in obesity is characterized by hypertriglyceridaemia, low HDL-C levels, small, dense HDL particles and increased phospholipid transfer protein (PLTP) activity. METHODS: In the present study, we investigated PLTP activity and HDL particle size in 16 morbidly obese, middle-aged women, who underwent Swedish Adjustable Gastric Banding surgery. Study subjects were tested within 2 months before and 1 y after surgery. PLTP activity was determined by exogenous substrate assay and HDL particle size by gradient gel electrophoresis, respectively. RESULTS: Pronounced weight loss after gastric banding surgery resulted in a significant decrease of PLTP activity from 8.42±2.04 to 7.43±2.21 μmol/ml/h (P=0.02). The size of HDL2 particles increased signficantly from 14.04±0.86 to 14.28±0.64 nm (P=0.02) after body weight reduction, while no change in HDL3 particle size was apparent. DISCUSSION: Our results suggest that dyslipidaemia in obesity is—at least partially—reversible by weight loss. We hypothesize that reduction of PLTP activity and increase of HDL particle size are important component factors in converting the atherogenic lipoprotein profile of obese subjects into a less atherogenic profile with weight loss.

A diet restricted in saturated fat and cholesterol is recommended for subjects with elevated LDL cholesterol concentrations before and during drug therapy. Gender differences in lipoprotein subspecies response to such diets have not been studied in detail. We examined the effects of a diet low in total fat, saturated fat and cholesterol (Therapeutic Lifestyle Changes, TLC, diet: 26% of energy as fat, 4% as saturated fat, and 45 mg cholesterol/4.2 MJ), compared with an average American diet (AAD: 35% of energy as fat, 14% as saturated fat, and 147 mg cholesterol/4.2 MJ), on plasma lipoprotein subspecies in men and women. Each diet period lasted 6 wk. Body weight was kept constant during each diet period. Men (n = 19) and postmenopausal women (n = 14) >40 y old with moderate hypercholesterolemia participated in this study. Plasma lipoprotein concentrations were assessed by standardized methodology, and lipoprotein sizes were determined by gradient gel electrophoresis and NMR spectroscopy. The TLC diet resulted in greater reductions in total cholesterol and plasma apolipoprotein B concentrations in men than in women (-19% vs. -12%, P < 0.05, and -18% vs. -9%, P < 0.05, respectively). Postprandial triacylglycerol and LpAI:AII concentrations were reduced in men, but not in women (-15% vs. 8%, P < 0.05, and -9% vs. -2%, respectively, P < 0.05). Similar decreases in LpAI concentrations and LDL and HDL particle size were observed in men and women. These data are consistent with the concept that middle aged/elderly men may have a more favorable lipoprotein response to a low fat, low cholesterol diet than postmenopausal women.

Background Obesity is associated with an atherogenic lipid profile characterized by a predominance of small LDL and HDL particles. Weight loss, by dietary restriction or exercise, increases LDL particle size. Whether these interventions can augment HDL size in conjunction with LDL size remains unknown. Objective This study compared the effects of alternate day fasting (ADF), calorie restriction (CR), and endurance exercise on LDL and HDL particle size in overweight and obese subjects. Methods In a 12-week parallel-arm trial, adult subjects (n = 60) were randomized to 1 of 4 groups: 1) ADF (75% energy restriction for 24-h alternated with ad libitum feeding for 24-h), 2) CR (25% energy restriction every day), 3) exercise (moderate intensity training 3 x/week), or 4) control. Results Body weight was reduced (P < 0.001) by ADF, CR, and exercise (5.2 ± 1.1%, 5.0 ± 1.4%, 5.1 ± 0.9%, respectively). Plasma LDL cholesterol decreased (P < 0.05) with ADF (10 ± 4%) and CR (8 ± 4%), whereas HDL cholesterol increased (P < 0.05) with exercise (16 ± 5%). Integrated LDL particle size was augmented (P = 0.01) by ADF and CR. The proportion of small LDL particles decreased (P = 0.04) with ADF only, and the proportion of large HDL particles increased (P = 0.03) with exercise only. Conclusion These results indicate that dietary restriction increases LDL particle size, while endurance training augments HDL particle size, with minimal weight loss. None of these interventions concomitantly increased both LDL and HDL particle size, however.

Low plasma levels of HDL cholesterol have been as- sociated with an increased risk of coronary heart disease. HDL particles are heterogeneous with respect to size and apolipo- protein content. The objective of the present study was to develop a method to generate lipid-stainable calibrators that would allow the assessment of HDL particle size from whole plasma, using polyacrylamide gradient gel electrophoresis (PAGGE). Lipid-stainable HDL calibrators were obtained by subjecting isolated red blood cells to hemolysis either by freezing at � 20 or � 80 � C overnight or by rapid exposure to liquid nitrogen and mixing of the hemolysis products with plasma aliquots. All three methods were highly reproducible in producing Sudan black lipid-stainable HDL calibrators ranging from 75 to 200 A. The assessment of HDL particle size with these lipid-stainable HDL calibrators was also highly reproducible, with a coeffi- cient of variation below 5.5%. These lipid-stainable HDL calibrators simplify the assessment of HDL particle size by PAGGE using whole plasma, without the need for costly, time- consuming ultracentrifugation procedures. —Perusse, M., A. Pascot, J-P. Despres, C. Couillard, and B. Lamarche. A new method for HDL particle sizing by polyacrylamide gradient gel electrophoresis using whole plasma. J. Lipid Res. 2001. 42: 1331- 1334.