Small High-density Lipoprotein Research Articles

Paraoxonase 1, HDL Subclasses and Post Surgery Acute Inflammation: A Pilot Study.

High density lipoproteins (HDL) structure and function studies are needed to better understand the heterogeneous nature of the HDL particle, and its interaction with associated proteins such as apolipoprotein A-1 (ApoA-1), paraoxonase 1 (PON1) and the environment. Our study assesses the effects of acute inflammation on PON1 and HDL subclasses in post-surgical colorectal cancer patients. PON1 was measured kinetically through its arylesterase and lactonase activity and HDL sub-classes were measured using Quantimetrix Lipoprint® System. White blood cells (WBC) counts, c-reactive protein (CRP) and serum amyloid A (SAA) levels were also analyzed using standard techniques. Our findings show that baseline PON1 activity is lower in colorectal cancer patients and significant reductions are observed in the acute inflammatory state post-surgery. PON1 changes are also inversely related to inflammatory markers such as SAA and CRP. In addition, our preliminary findings show that small and intermediate HDL decreases post-op Day 1. In conclusion, our study demonstrates the effects of chronic and acute inflammation on PON1. Specifically, PON1 arylesterase and lactonase activity is lower in states of chronic inflammation and further decreased in the acute inflammatory state. Additionally, in our limited sample size, while changes in PON1 and HDL subclasses may be variable in the acute inflammatory period, small HDL decreased with a loss of PON1 activity in the subacute phase.

Association of Dimethylguanidino Valeric Acid With Partial Resistance to Metabolic Health Benefits of Regular Exercise

Metabolic responses to exercise training are variable. Metabolite profiling may aid in the clinical assessment of an individual's responsiveness to exercise interventions. To investigate the association between a novel circulating biomarker of hepatic fat, dimethylguanidino valeric acid (DMGV), and metabolic health traits before and after 20 weeks of endurance exercise training. This study involved cross-sectional and longitudinal analyses of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, a 20-week, single-arm endurance exercise clinical trial performed in multiple centers between 1993 and 1997. White participants with sedentary lifestyles who were free of cardiometabolic disease were included. Metabolomic tests were performed using a liquid chromatography, tandem mass spectrometry method on plasma samples collected before and after exercise training in the HERITAGE study. Metabolomics and data analysis were performed from August 2017 to May 2018. Plasma DMGV levels. The association between DMGV levels and measures of body composition, plasma lipids, insulin, and glucose homeostasis before and after exercise training. Among the 439 participants included in analyses from HERITAGE, the mean (SD) age was 36 (15) years, 228 (51.9%) were female, and the median (interquartile range) body mass index was 25 (22-28). Baseline levels of DMGV were positively associated with body fat percentage, abdominal visceral fat, very low-density lipoprotein cholesterol, and triglycerides, and inversely associated with insulin sensitivity, low-density lipoprotein cholesterol, high-density lipoprotein size, and high-density lipoprotein cholesterol (range of β coefficients, 0.17-0.46 [SEs, 0.026-0.050]; all P < .001, after adjusting for age and sex). After adjusting for age, sex, and baseline traits, baseline DMGV levels were positively associated with changes in small high-density lipoprotein particles (β, 0.14 [95% CI, 0.05-0.23]) and inversely associated with changes in medium and total high-density lipoprotein particles (β, -0.15 [95% CI, -0.24 to -0.05] and -0.19 [95% CI, -0.28 to -0.10], respectively), apolipoprotein A1 (β, -0.14 [95% CI, -0.23 to -0.05]), and insulin sensitivity (β, -0.13; P = 3.0 × 10-3) after exercise training. Dimethylguanidino valeric acid is an early marker of cardiometabolic dysfunction that is associated with attenuated improvements in lipid traits and insulin sensitivity after exercise training. Levels of DMGV may identify individuals who require additional therapies beyond guideline-directed exercise to improve their metabolic health.

Exercise training alters lipoprotein particles independent of brown adipose tissue metabolic activity.

SummaryIntroductionNew strategies for weight loss and weight maintenance in humans are needed. Human brown adipose tissue (BAT) can stimulate energy expenditure and may be a potential therapeutic target for obesity and type 2 diabetes. However, whether exercise training is an efficient stimulus to activate and recruit BAT remains to be explored. This study aimed to evaluate whether regular exercise training affects cold‐stimulated BAT metabolism and, if so, whether this was associated with changes in plasma metabolites.MethodsHealthy sedentary men (n = 11; aged 31 [SD 7] years; body mass index 23 [0.9] kg m−2; VO2 max 39 [7.6] mL min−1 kg−1) participated in a 6‐week exercise training intervention. Fasting BAT and neck muscle glucose uptake (GU) were measured using quantitative [18F]fluorodeoxyglucose positron emission tomography–magnetic resonance imaging three times: (1) before training at room temperature and (2) before and (3) after the training period during cold stimulation. Cervico‐thoracic BAT mass was measured using MRI signal fat fraction maps. Plasma metabolites were analysed using nuclear magnetic resonance spectroscopy.ResultsCold exposure increased supraclavicular BAT GU by threefold (p < 0.001), energy expenditure by 59% (p < 0.001) and plasma fatty acids (p < 0.01). Exercise training had no effect on cold‐induced GU in BAT or neck muscles. Training increased aerobic capacity (p = 0.01) and decreased visceral fat (p = 0.02) and cervico‐thoracic BAT mass (p = 0.003). Additionally, training decreased very low‐density lipoprotein particle size (p = 0.04), triglycerides within chylomicrons (p = 0.04) and small high‐density lipoprotein (p = 0.04).ConclusionsAlthough exercise training plays an important role for metabolic health, its beneficial effects on whole body metabolism through physiological adaptations seem to be independent of BAT activation in young, sedentary men.

Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.

ObjectiveTo identify a plasma metabolomic biomarker signature for migraine.MethodsPlasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.ResultsDecreases in the level of apolipoprotein A1 (β −0.10; 95% confidence interval [CI] −0.16, −0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β −0.10; 95% CI −0.15, −0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β −0.24; 95% CI −0.36, −0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.ConclusionsMetabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

Small HDL, diabetes, and proinflammatory effects in macrophages

Atherosclerosis, an inflammatory disease of the arterial wall, is the commonest cause of cardiovascular disease (CVD) events. Elevated levels of high‐density lipoprotein (HDL) cholesterol are generally believed to protect against CVD and to reduce inflammatory activation of macrophages, a key cell type in lesions of atherosclerosis. However, HDL can also exert proinflammatory effects in macrophages by inducing cholesterol depletion. Because small HDL (7–8.5 nm diameter) is most effective in removing cholesterol from cells by the ABCA1 pathway, we hypothesized that small HDL is the most proinflammatory HDL population. Small‐, medium‐ and large HDL populations were isolated from a human apolipoprotein A‐I transgenic LDL receptor‐deficient mouse model (APOA1Tg;Ldlr−/−). Depletion of cholesterol by HDL increased the ability of toll‐like receptor (TLR) ligands to induce proinflammatory mediators in macrophages. This effect was prevented by cholesterol loading of the macrophages. Small HDL had a significantly stronger effect on Tnfa (3‐fold over LPS alone) and Il1b (2.5‐fold over LPS alone) gene expression than medium or large HDL particles. Inhibition or deletion of the sheddase ADAM17 in macrophages prevented the proinflammatory effects of HDL. Patients with type 1 diabetes mellitus (T1DM) exhibit an increased risk of CVD despite having normal or high HDL‐cholesterol. To investigate the effect of diabetes on HDL subpopulations, we crossed a virally‐induced mouse model of T1DM (Ldlr−/−;GpTg) with the human APOA1Tg;Ldlr−/− mouse. The mice (APOA1Tg;Ldlr−/−;GpTg, n=8–10) were injected with a liver‐specific adeno‐associated virus driving expression of human cholesteryl ester transfer protein (hCETP) to mimic human physiology. Diabetic mice had an increased HDL particle concentration (~2‐fold) associated with a significant increase in serum HDL cholesterol efflux capacity through both ABCA1 and ABCG1, compared with non‐diabetic mice. The largest increase was in the small HDL particle concentration (15 μM vs 6 μM in non‐diabetic mice). Moreover, resident peritoneal macrophages from diabetic mice exhibited increased cytokine gene expression, as compared with non‐diabetic littermates. Our findings demonstrate that higher levels of small HDL, as observed in a mouse model of diabetes, can exacerbate inflammatory activation in non‐lipid loaded macrophages in an ADAM17‐dependent manner. We have found similar changes in HDL concentration and function in humans with T1DM, suggesting that our mouse model might provide novel insights into CVD risk in T1DM patients.Support or Funding Informationfunded in part by the National Institutes of Health, grants DP3DK108209, P01HL092969, P30 DK017047, and P01HL128203This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension

BackgroundAberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.ObjectiveTo investigate the relationship between circulating lipoprotein subclasses and...

Characteristics of Coronary Artery Disease Patients Who Have a Polymorphism in the Cholesterol Ester Transfer Protein (CETP) Gene.

Cholesterol ester transfer protein (CETP) is responsible for the transformation of high density lipoprotein (HDL) to low density lipoprotein (LDL) and is a risk factor for atherosclerosis. Our study investigated the association of the rs5883 CETP gene polymorphism with HDL and LDL levels, in 45 coronary artery disease patients and 45 control patients. CETP gene polymorphism was detected using Real Time-Polymerase Chain Reaction (RT-PCR). Lipoprotein levels were measured using Quantimetrix system. There were lack of associaition regarding CETP polymorphism in atherosclerosis and HDL and LDL levels (p>0.05) BMI was higher among coronary artery disease patients (CADP) compared to the control group (28.97±6.38, 26.52±4.39 respectively, p<0.03). Frequency of CADP (82.6 %, n=19) who were taking treatment was higher (17.4 %, n=4) (p<0.00). The frequencies of hypertension and type-2 diabetes were higher among CADP (p<0.00). Families of CADP have more CADP (p<0.02). Small HDL particle levels were higher in the control group (p<0.00). In Turkey, BMI, and frequencies of hypertension and type-2 diabetes were higher among CADP than among healthy controls. Furthermore, the genotypes of the rs5883 CETP gene polymorphism did not differ between CADP and healthy controls.

Patients With Systemic Lupus Erythematosus Show an Increased Arterial Stiffness That is Predicted by IgM Anti-β2 -Glycoprotein I and Small Dense High-Density Lipoprotein Particles.

To investigate the metabolic and immunologic factors associated with the presence of central arterial stiffness as measured by the augmentation index (AIx). We conducted a cross-sectional study of 69 female patients with systemic lupus erythematosus (SLE) compared with a control group of 34 healthy women. The anthropometrical variables, the vascular studies, and the analytic data were obtained the same day. The AIx was assessed by peripheral arterial tonometry. The analysis of lipoprotein populations was performed using nuclear magnetic resonance (NMR) spectroscopy. Arterial stiffness was increased in patients with SLE compared with control subjects (mean ± SD 20.30 ± 21.54% versus 10.84 ± 11.51%; P = 0.0021). Values for the AIx were correlated with the Framingham risk score (r = 0.481, P < 0.001), carotid intima-media thickness (r = 0.503, P < 0.001), systolic blood pressure (r = 0.270, P < 0.001), and age (r = 0.365, P < 0.001). Patients receiving antimalarial drugs had a lower AIx (mean ± SD 11.74 ± 11.28% versus 24.97 ± 20.63%; P = 0.024). The AIx was correlated with the atherogenic lipoproteins analyzed by NMR. The immunologic variables associated with the AIx were C4 (r = 0.259, P = 0.046) and IgM anti-β2 -glycoprotein I (IgM anti-β2 GPI) (r = 0.284, P = 0.284). In the multivariate analysis, age (β = 0.347, 95% confidence interval [95% CI] 0.020-0.669, P = 0.035), IgM β2 GPI (β = 0.321, 95% CI 0.024-0.618, P = 0.035) and small dense high-density lipoprotein (HDL) particles (β = 1.288, 95% CI 0.246-2.329, P = 0.017) predicted the AIx. SLE patients had increased arterial stiffness compared with healthy control subjects. Arterial stiffness was decreased in patients treated with antimalarial drugs. Age, IgM β2 GPI, and the number of small dense HDL particles predicted the AIx.

Small HDL subclass is associated with coronary plaque stability: An optical coherence tomography study in patients with coronary artery disease

The role of high-density lipoprotein (HDL) subclasses in atherosclerotic diseases remains an open question. Previous clinical trials have attempted to explore the predictive effect of HDL subspecies on cardiovascular risk. However, no studies have assessed the connections between these subclasses and characteristics of plaque microstructure. To investigate the relationship of HDL subclasses and coronary plaque stability assessed by optical coherence tomography (OCT). Morphological characteristics of 160 nontarget lesions from 85 patients with coronary artery disease were assessed by OCT. HDL subclass profiles were analyzed using nondenaturing polyacrylamide gel electrophoresis. The plasma levels of small HDL subclass (percentage or concentration) were found to be positively associated with fibrous cap thickness (r=0.232, P=.007; r=0.243, P=.005) and negatively with maximum lipid arc (r=-0.240, P=.005; r=-0.252, P=.003) and lipid core length (r=-0.350, P<.001; r=-0.367, P<.001). Multivariate logistic regression analysis showed the small HDL subclass (percentage or concentration) (odds ratio [OR]: 0.457, 95% confidence interval [CI]: 0.214-0.974, P=.043; OR: 0.438, 95% CI: 0.204-0.938, P=.034) to be an independent factor in predicting OCT-detected thin-cap fibroatheroma of nontarget lesions. High levels of small HDL are associated with coronary nontarget plaque stability. Our findings suggest that the small HDL subtype might represent the atheroprotective activity of HDL.

Associations between epicardial adipose tissue, subclinical atherosclerosis and high-density lipoprotein composition in type 1 diabetes

BackgroundThe pathophysiology of cardiovascular complications in people with type 1 diabetes (T1DM) remains unclear. An increase in epicardial adipose tissue (EAT) and alterations in the composition of high-density lipoprotein (HDL) are associated with coronary artery disease, but information on its relationship in T1DM is very limited. Our aim was to determine the association between EAT volume, subclinical atherosclerosis, and HDL composition in type 1 diabetes.MethodsSeventy-two long-term patients with T1DM without clinical atherosclerosis were analyzed. EAT volume and subclinical atherosclerosis were measured using cardiac computed tomography angiography. EAT was adjusted according to body surface to obtain an EAT index (iEAT). HDL composition was determined.ResultsThe mean iEAT was 40.47 ± 22.18 cc/m2. The bivariate analysis showed positive associations of the iEAT with gender, age, hypertension, dyslipidemia, smoking, body mass index, waist circumference, insulin dose, and triglyceride (P < 0.05). The iEAT correlated positively with small HDL, increased content of apolipoprotein (apo)A-II and apoC-III, and decreased content of apoE and free cholesterol. Multiple linear regression showed that age, apoA-II content in HDL, and waist circumference were independently associated with the iEAT. Fifty percent of the patients presented subclinical atherosclerotic lesions. These patients had a higher iEAT, and their HDL contained less cholesterol and more apoA-II and lipoprotein-associated phospholipase A2 than patients without subclinical atherosclerosis.ConclusionAlterations in the composition of HDL in TIDM are associated with increased iEAT and the presence of subclinical atherosclerosis. We propose that these abnormalities of HDL composition could be useful to identify T1DM patients at highest cardiovascular risk.

Association between proprotein convertase subtilisin/kexin 9 (PCSK9) and lipoprotein subclasses in children with type 1 diabetes mellitus: Effects of glycemic control

Background and aimsDyslipidemia in type 1 diabetes mellitus (T1DM) is characterised by altered distributions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses. Recent studies suggested that proprotein convertase subtilisin/kexin 9 (PCSK9) may contribute to the development of dyslipidemia in T1DM. In this cross-sectional study, we investigated the association between PCSK9 and lipoprotein subclasses in young T1DM patients, with respect to glycemic control. MethodsPlasma PCSK9 and lipoprotein subclasses were determined in 207 patients with T1DM (106 boys and 101 girls), aged 13.9 ± 3.0 years and treated by intensive insulin therapy. ResultsPlasma PCSK9 levels significantly increased with worsening of glycemic control (p < 0.001). T1DM patients with poor glucoregulation had the highest proportion of small, dense LDL (sdLDL) and smaller HDL particles, as well. PCSK9 was positively associated with markers of glucose homeostasis and serum lipid parameters only in patients with suboptimal/poor glucoregulation. In well-controlled T1DM, plasma PCSK9 level was inversely associated with a relative proportion of sdLDL particles (p < 0.01) and this association remained significant in multivariate analysis. In T1DM patients with suboptimal/poor glycemic control, PCSK9 was positively associated with the proportion of the smallest HDL3c particles (p < 0.001), but negatively with HDL size (p < 0.05). ConclusionsThe extent of achieved metabolic control modifies the association between PCSK9 and lipoprotein subclasses in T1DM. Further investigations are needed to reveal whether the observed effects of glycemic control on PCSK9 and sdLDL levels have causal consequences on CVD risk in young patients with T1DM.

Consumption of regular-fat vs reduced-fat cheese reveals gender-specific changes in LDL particle size - a randomized controlled trial

BackgroundRegular-fat cheese does not seem to increase low density lipoprotein cholesterol (LDL-C) concentrations compared to reduced-fat cheese. However, plasma LDL-C concentrations do not reflect levels and size of LDL particles, which might be a better predictor of cardiovascular risk.MethodsThe aim was to compare the effects of regular-fat cheese vs reduced-fat cheese and carbohydrate-rich foods on LDL particle size distribution in adults with ≥ 2 metabolic syndrome (MetS) risk factors. The study was part of a 12 weeks’ randomized controlled trial in which subjects had been randomly allocated to 1 of 3 intervention groups; regular-fat cheese (REG), reduced-fat cheese (RED) or a no-cheese/carbohydrate (CHO) group. Subjects in the REG and RED groups consumed 80 g cheese/d per 10 MJ, whereas subjects in the CHO consumed bread and jam corresponding to 90 g/d and 25 g/d per 10 MJ, respectively. Fasting blood samples at wk. 0 (baseline) and wk. 12 were analyzed for LDL particle size distribution and cholesterol content using nuclear magnetic resonance (NMR) spectroscopy.ResultsA total of 85 subjects [mean ± SD age: 54.0 ± 12.8 y; BMI: 28.7 ± 3.6 kg/m2] completed the study. Overall, regular-fat cheese did not impact lipoprotein particle number and size differently than reduced-fat cheese. In men (n = 23), the REG diet decreased total LDL particle number (LDL-P, − 223.2 ± 91.1 nmol/l, P = 0.01) compared with the RED diet. The reduction was primarily in the medium-sized LDL fraction (− 128.5 ± 51.8 nmol/l, P = 0.01). In women (n = 62), the REG diet increased the concentration of cholesterol in the small high density lipoprotein (HDL) particles compared with the CHO diet (2.9 ± 1.0 mg/dl, P = 0.006).ConclusionOverall, regular-fat cheese did not alter LDL particle size distribution compared to reduced-fat cheese after a 12 wk. intervention in subjects with ≥2 MetS risk factors. However, our results suggest that lipoprotein response to cheese intake is gender-specific. This warrants further investigation.Trial registrationThis trial was registered at Clinicaltrials.gov as NCT0261471. Registered 30 November 2015 - Retrospectively registered.

Relationship between dietary quality, determined by DASH score, and cardiometabolic health biomarkers: A cross-sectional analysis in adults

The relationship between dietary patterns and cardiometabolic disease is of increasing interest. However, limited data regarding the association between dietary quality and biomarkers of cardiometabolic health exist. Therefore the aim of this work was to examine potential associations between dietary quality, assessed using the Dietary Approaches to Stop Hypertension (DASH) dietary quality score, adiposity and biomarkers of glucose homeostasis, lipoprotein metabolism and inflammation in a cross-sectional sample of 1493 men and women. Anthropometric measurements included BMI, hip and waist circumference (WC). Serum acute-phase reactants, adipocytokines, pro-inflammatory cytokines and white blood cell (WBC) counts were determined. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance (NMR) spectroscopy. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Higher dietary quality was associated with lower BMI (P<0.05), WC (P<0.001), tumour necrosis factor α (TNF-α), interleukin 6 (IL-6), WBC and plasminogen activator inhibitor-1 (PAI-1) concentrations (P<0.01) and reduced insulin resistance (P<0.05). In addition less small low density lipoprotein (LDL) and small high density lipoprotein (HDL) particles and less large very low density lipoprotein (VLDL) particles were observed among those with better dietary quality (P<0.001). Individuals in the top DASH quartile had a 54% and 48% lower likelihood of central obesity and metabolic syndrome (MetS), respectively, than those in the lowest DASH quartile (P<0.05). Our data suggest that higher quality diet is associated with improved adiposity measures and a less insulin resistant, pro-inflammatory, pro-thrombotic and pro-atherogenic cardiometabolic profile which may impact on central obesity and MetS risk. These findings, which may be of clinical and public health significance in terms of dietary approaches to promote cardiometabolic health, warrant further examination.

Dietary Inflammatory Index and Biomarkers of Lipoprotein Metabolism, Inflammation and Glucose Homeostasis in Adults.

Accumulating evidence identifies diet and inflammation as potential mechanisms contributing to cardiometabolic risk. However, inconsistent reports regarding dietary inflammatory potential, biomarkers of cardiometabolic health and metabolic syndrome (MetS) risk exist. Our objective was to examine the relationships between a food frequency questionnaire (FFQ)-derived dietary inflammatory index (DII®), biomarkers of lipoprotein metabolism, inflammation and glucose homeostasis and MetS risk in a cross-sectional sample of 1992 adults. Energy-adjusted DII (E-DII) scores derived from an FFQ were calculated. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance (NMR) spectroscopy. Serum acute-phase reactants, adipocytokines, pro-inflammatory cytokines and white blood cell (WBC) counts were determined. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Our data indicate that a more pro-inflammatory diet, reflected by higher E-DII scores, was associated with potentially pro-atherogenic lipoprotein profiles characterised by increased numbers of large very low density lipoprotein (VLDL), small dense low density lipoprotein (LDL) and high density lipoprotein (HDL) particles and less large LDL and HDL particles (all p < 0.001). Inflammatory profiling identified a range of adverse phenotypes among those with higher E-DII scores, including higher complement component C3 (C3), C-reactive protein (CRP), (both p < 0.05), interleukin 6 (IL-6) and tumour necrosis factor (TNF)-α concentrations, higher WBC counts and neutrophil to lymphocyte ratio (NLR) and lower adiponectin levels (all p < 0.001). MetS risk was increased among those with higher E-DII scores (OR 1.37, 95% CI (1.01, 1.88), p < 0.05), after adjusting for potential confounders. In conclusion, habitual intake of a more pro-inflammatory diet is associated with unfavourable lipoprotein and inflammatory profiles and increased MetS risk.

Pathophysiology of Diabetic Dyslipidemia

Accumulating clinical evidence has suggested serum triglyceride (TG) is a leading predictor of atherosclerotic cardiovascular disease, comparable to low-density lipoprotein (LDL)-cholesterol (C) in populations with type 2 diabetes, which exceeds the predictive power of hemoglobinA1c. Atherogenic dyslipidemia in diabetes consists of elevated serum concentrations of TG-rich lipoproteins (TRLs), a high prevalence of small dense low-density lipoprotein (LDL), and low concentrations of cholesterol-rich high-density lipoprotein (HDL)2-C. A central lipoprotein abnormality is an increase in large TG-rich very-low-density lipoprotein (VLDL)1, and other lipoprotein abnormalities are metabolically linked to increased TRLs. Insulin critically regulates serum VLDL concentrations by suppressing hepatic VLDL production and stimulating VLDL removal by activation of lipoprotein lipase. It is still debated whether hyperinsulinemia compensatory for insulin resistance is causally associated with the overproduction of VLDL. This review introduces experimental and clinical observations revealing that insulin resistance, but not hyperinsulinemia stimulates hepatic VLDL production. LDL and HDL consist of heterogeneous particles with different size and density. Cholesterol-depleted small dense LDL and cholesterol-rich HDL2 subspecies are particularly affected by insulin resistance and can be named “Metabolic LDL and HDL,” respectively. We established the direct assays for quantifying small dense LDL-C and small dense HDL(HDL3)-C, respectively. Subtracting HDL3-C from HDL-C gives HDL2-C. I will explain clinical relevance of measurements of LDL and HDL subspecies determined by our assays. Diabetic kidney disease (DKD) substantially worsens plasma lipid profile thereby potentiated atherogenic risk. Finally, I briefly overview pathophysiology of dyslipidemia associated with DKD, which has not been so much taken up by other review articles.

Relation between high density lipoprotein particles concentration and cardiovascular events: a meta-analysis

BackgroundTrails aimed at raising high density lipoprotein(HDL) cholesterol concentration failed to make better cardiovascular outcomes. HDL particles may be better biomarkers reflecting properties of HDL. This meta-analysis was conducted to evaluate the relation between blood HDL particles level and cardiovascular events.MethodsPubMed and other databases were searched for eligible studies and NewCastle-Ottawa Quality Assessment Scale(NOS) was used to assess the quality of included studies. A random or fixed-effect model was applied to calculate the pooled hazard ratio(HR).ResultsTwelve studies were finally included. The pooled HR(95%confidence interval) for per standard deviation(SD) increment and top quartile versus bottom quartile were 0.79(0.72,0.86) and 0.65(0.57,0.75), respectively. Subgroup analysis suggested that HR was significantly lower in subjects with a cardiovascular disease(CVD) history than that of people without established CVD. Subclass analysis indicated that HRs for per SD increment of small(0.85) and medium(0.84) HDL particles were significantly lower than that of large HDL particles(0.96).ConclusionsHDL particle level in blood was inversely related to CVD events, indicating that HDL particles maybe a protective factor in patients with CVD, thus making HDL particles a potential biomarker and therapy target.

Association between apolipoprotein E genotypes and panic disorder in Turkish population

Aim: In this study, we aimed to investigate possible interactions among the apolipoprotein E (ApoE) and panic disorder (PD), taking into account serum cholesterol levels and subfractions.Methods: ApoE genotyping was performed by real-time polymerase chain reaction in DNA samples of PD patient group (n = 45) and healthy control group (n = 50). The serum lipid levels, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) subfraction analysis were examined.Results: There was a significant difference of ApoE genotypes in patient and control groups. The E3/E3 genotypes lower whereas E4 allele carriers were significantly higher in PD group ApoE4allele carriers had 3.2-fold higher risk of PD. PD group had significantly lower LDL and HDL levels. In spite of the decreased levels of total LDL, antiatherogenic large LDL subgroup was significantly lower in a patient with PD. Antiatherogenic large HDL and Intermediate HDL levels were lower, while atherogenic small HDL subfraction was significantly higher in PD group. Furthermore, Apo E3/E3 genotype carriers had significantly higher large LDL, HDL, large HDL, intermediate HDL level, and also had highest HDL between all the groups. ApoE4 allele carriers while they had highest atherogenic small HDL level.Conclusion: E4 allele can be associated with PD as an eligible risk factor, the E3/E3 could be a risk-reducing factor for PD. Patients with PD not only had lower LDL and HDL levels but also they have higher atherogenic LDL and HDL subfractions. Also, E3/E3 genotype carriers had convenient but ApoE4 carriers had atherogenic plasma cholesterol levels and subfractions.

Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure

During acute-phase response (APR), there is a dramatic increase in serum amyloid A (SAA) in plasma high density lipoproteins (HDL). Elevated SAA leads to reactive AA amyloidosis in animals and humans. Herein, we employed apolipoprotein A-II (ApoA-II) deficient (Apoa2−/−) and transgenic (Apoa2Tg) mice to investigate the potential roles of ApoA-II in lipoprotein particle formation and progression of AA amyloidosis during APR. AA amyloid deposition was suppressed in Apoa2−/− mice compared with wild type (WT) mice. During APR, Apoa2−/− mice exhibited significant suppression of serum SAA levels and hepatic Saa1 and Saa2 mRNA levels. Pathological investigation showed Apoa2−/− mice had less tissue damage and less inflammatory cell infiltration during APR. Total lipoproteins were markedly decreased in Apoa2−/− mice, while the ratio of HDL to low density lipoprotein (LDL) was also decreased. Both WT and Apoa2−/− mice showed increases in LDL and very large HDL during APR. SAA was distributed more widely in lipoprotein particles ranging from chylomicrons to very small HDL in Apoa2−/− mice. Our observations uncovered the critical roles of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt consideration of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles.

Comprehensive Metabolic Profiling Reveals a Lipid-Rich Fingerprint of Free Thyroxine Far Beyond Classic Parameters.

Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular patterns associated with alterations in thyroid hormones levels remain to be explored in detail. A number of recent studies took great advantage of metabolomics profiling to outline the metabolic actions of thyroid hormones in humans. Among 952 participants in the Study of Health in Pomerania, data on serum free thyroxine (FT4) and thyrotropin and comprehensive nontargeted metabolomics data from plasma and urine samples were available. Linear regression analyses were performed to assess the association between FT4 or thyrotropin and metabolite levels. After accounting for major confounders, 106 of 613 plasma metabolites were significantly associated with FT4. The associations in urine were minor (12 of 587). Most of the plasma metabolites consisted of lipid species, and subsequent analysis of highly resolved lipoprotein subclasses measured by proton nuclear magnetic resonance spectroscopy revealed a consistent decrease in several of these species (e.g., phospholipids) and large low-density lipoprotein and small high-density lipoprotein particles. The latter was unique to men. Several polyunsaturated and saturated fatty acids displayed an association with FT4 in women only. A random forest-based variable selection approach using phenotypic characteristics revealed higher alcohol intake in men and an adverse thyroid state and menopause in women as the putative mediating factors. In general, our observations have confirmed the lipolytic and lipogenic effect of thyroid hormones even in the physiological range and revealed different phenotypic characteristics (e.g., lifestyle differences) as possible confounders for sex-specific findings.

Biomarkers of Cardiovascular Risk in Haemodialysis Patients.

All stages of chronic kidney disease (CKD) are associated with increased risks of atherosclerosis and cardiovascular morbidity and mortality. According to studies, levels of copeptin, growth differentiation factor-15 (GDF-15) and heart fatty-acid binding protein (h-FABP) are increased in dialysis patients. This study included 50 patients (19 women, 31 men) chronically undergoing haemodialysis. The concentration of markers such as: copeptin, GDF-15, h-FABP, troponin and serum creatine kinase MB (CKMB) was measured with the use of ELISA tests. Serum concentration of 10 high-density lipoprotein (HDL) subfractions and 7 low-density lipoprotein (LDL) subfractions was analysed with the use of Lipoprint™ system (Quantimetrix Corp.). In this study, we observed higher copeptin level, lower percentage share of cholesterol HDL4 subfraction and higher percentage share of small HDL particles subfraction in HD patients with diabetes mellitus than in those without diabetes. We also found significantly lower percentage share of cholesterol HDL5 subfraction in patients with GDF-15 > 3rd quartile (Q3) compared with those with GFD-15 ≤ Q3. Finally, it was observed that the percentage share of cholesterol HDL5 subfraction was significantly lower in patients with h-FABP > Q3, and the share of intermediate HDL subfractions was significantly lower in haemodialysis (HD) patients with h-FABP > 75 percentile. The fact that increased level of one biomarker correlated with higher values of other markers may suggest that their concentration depends on the severity of disease. The obtained results also suggest that the measurement of copeptin may support the diagnosis of cardiovascular problems in dialysis patients.