Lipoprotein Lipid Research Articles

J-Edited DIffusional Proton Nuclear Magnetic Resonance Spectroscopic Measurement of Glycoprotein and Supramolecular Phospholipid Biomarkers of Inflammation in Human Serum.

Proton nuclear magnetic resonance (NMR) N-acetyl signals (Glyc) from glycoproteins and supramolecular phospholipids composite peak (SPC) from phospholipid quaternary nitrogen methyls in subcompartments of lipoprotein particles) can give important systemic metabolic information, but their absolute quantification is compromised by overlap with interfering resonances from lipoprotein lipids themselves. We present a J-Edited DIffusional (JEDI) proton NMR spectroscopic approach to selectively augment signals from the inflammatory marker peaks Glyc and SPCs in blood serum NMR spectra, which enables direct integration of peaks associated with molecules found in specific compartments. We explore a range of pulse sequences that allow editing based on peak J-modulation, translational diffusion, and T2 relaxation time and validate them for untreated blood serum samples from SARS-CoV-2 infected patients (n = 116) as well as samples from healthy controls and pregnant women with physiological inflammation and hyperlipidemia (n = 631). The data show that JEDI is an improved approach to selectively investigate inflammatory signals in serum and may have widespread diagnostic applicability to disease states associated with systemic inflammation.

Influence of hot red pepper oil in broiler diets on blood, antioxidant, immunological parameters and intestinal bacteria counts

The present study aimed to examine the impacts of supplementing hot red pepper oil (HRPO) to broiler diets. One hundred and twenty Arbor Acres chicks were divided randomly into four experimental groups as three supplementation levels of HRPO (0.25, 0.5 and 1.0 mL/kg diet) and the control group. Results showed that HRPO supplementation exhibited significantly (p < 0.001) higher red blood cells (RBCs) count, hemoglobin (Hb) and packed cells volume (PCV) percentage, while insignificant effects were shown for white blood cells (WBCs) count or its differentiation. Diets supplemented with different levels of HRPO influenced significantly (p < 0.001) the total protein (TP), albumin (Alb) and glucose (Glo) values of the studied birds. Results also indicated that different levels of HRPO supplementations significantly (p < 0.01) decreased total lipid, triglycerides (Trig), cholesterol (Cho) and low-density lipoprotein (LDL), but did not affect high density lipoprotein (HDL) values. Data revealed that supplementing broiler diets with different levels of HRPO enhanced their liver function. The bactericidal activity index was significantly increased (p < 0.02) compared with control. HRPO supplemented groups had beneficial effects (p < 0.02) on cecal microbiota count. It could be concluded that dietary HRPO supplementation could improve the general internal health status of Arbor Acres broiler chicks.

Lipid Transport in Brown Adipocyte Thermogenesis.

Non-shivering thermogenesis is an energy demanding process that primarily occurs in brown and beige adipose tissue. Beyond regulating body temperature, these thermogenic adipocytes regulate systemic glucose and lipid homeostasis. Historically, research on thermogenic adipocytes has focused on glycolytic metabolism due to the discovery of active brown adipose tissue in adult humans through glucose uptake imaging. The importance of lipids in non-shivering thermogenesis has more recently been appreciated. Uptake of circulating lipids into thermogenic adipocytes is necessary for body temperature regulation and whole-body lipid homeostasis. A wide array of circulating lipids contribute to thermogenic potential including free fatty acids, triglycerides, and acylcarnitines. This review will summarize the mechanisms and regulation of lipid uptake into brown adipose tissue including protein-mediated uptake, lipoprotein lipase activity, endocytosis, vesicle packaging, and lipid chaperones. We will also address existing gaps in knowledge for cold induced lipid uptake into thermogenic adipose tissue.

Co-Morbidly of Malaria and Typhoid Perturbs Lipid Homeostasis in Humans

Introduction: Malaria and typhoid diseases have remained endemic in low-income countries, including Nigeria. Aims: This study investigated the impact of malaria concurrently occurring with typhoid on plasma, erythrocytes, and lipoproteins lipid profile. Materials and Methods: Cholesterol, triacylglycerol (TAG) phospholipids (PLs), and non-esterified fatty acids (NEFAs) were determined spectrophotometrically in controls and patients presenting at the Out-Patient Clinic of the State Hospital, Abeokuta, Nigeria. Results: The presence of either or both parasitic infections provoked dyslipidaemia when compared with the controls. Dyslipidaemia was characterised by significant (P &lt; 0.05) decreased plasma, erythrocytes, high density lipoprotein (HDL), and low density lipoprotein (LDL) cholesterol; however very LDL (VLDL) cholesterol increased. While hypertriglyceridemia was observed in plasma, hypotriglyceridemia was observed in the erythrocytes of the patients. In HDL, hypertriglyceridemia was observed in malaria-infected patients whereas hypotriglyceridemia was observed in typhoid-infected and co-infection subjects. Malaria and/or typhoid induced phospholipidaemia in plasma and erythrocytes, but provoked decreased HDL-phospholipids (PLs) only in malaria-infected patients. Malaria and/or typhoid elicited decreased LDL+VLDL-PLs. While increased plasma NEFAs concentration was observed in malaria-infected patients; malaria and co-infection resulted in decreased erythrocytes NEFAs. Malaria and/or typhoid caused decreased cholesterol/phospholipids molar ratio in plasma, erythrocytes, and HDL. Conclusion: The findings of this study indicate that parasitic protozoa and bacterial infections produce a plethora of effects on lipid metabolism, ranging from up-/down-regulation of certain lipid metabolites. These may be early biochemical events in the induction of atherosclerosis by parasitic infections.

Profiling the metabolome of patients with dementia in the UK Biobank

AbstractBackgroundThere is increasing interest in early metabolic changes in dementia, which may reflect the effects of genetic determinants of dementia, medical history and co‐morbidity, environmental risk factors, and aging. We studied the relation of blood‐based metabolites to the risk of dementia.MethodThe analyses are conducted in 121,389 participants of the UK Biobank (UKB) and include over 1172 incident dementia patients who developed dementia during the follow‐up. The metabolome was characterized using Nuclear Magnetic Resonance of the Nightingale Health platform. The platform covers 249 metabolic measures, including small molecules, fatty acids and detailed lipoprotein lipids. We integrated metabolic data measured before dementia onset with genetic data to determine whether the metabolites associations reflect causal pathways or rather consequences of the disease process. After log transformation of metabolites, scaling, and quality control, data were analysed using Cox‐regression. We adjusted for age, sex, BMI, technical variables ethnicity, smoking, alcohol, education, metabolic and neuropsychiatric medication and APOE genotypes.ResultWe identified 36 novel metabolites that are significantly associated with incident dementia (FDR&lt;0.05), with positive associations of ketone bodies to the future risk of dementia and negative associations of fatty acids, various amino acids, and cholesterol subfractions. The metabolic pattern is remarkably similar for incident patients with Alzheimer disease and vascular dementia and overlaps substantially with the metabolic profile identified for incident Parkinson’s disease. We found evidence that a number of metabolites may mediate the association between the APOE e2 and APOE e4 variants and dementia.ConclusionOur findings suggest that changes in the metabolism that occur before the onset of disease are associated to the future risk of dementia.

Abstract 11198: Role of Different Lipid Parameters and Lipoproteins on Coronary Microvascular Dysfunction in the Young

Aim: Young with coronary microvascular dysfunction (CMD) have increased cardiovascular morbidity. Particularly, Asian patients with CMD are considerably younger than their Western peers. Blood lipids are traditionally considered risk factors for myocardial infarction (MI) of the elderly. However, little is known about CMD in the young. The purpose of our study was to test the associations between lipids and lipoprotein particles and CMD in the young. Methods: A cross-sectional study was conducted from 2014 to 2020, 1868 young participants were included. CMD was defined as angina but no obstructive coronary disease. All participants had baseline laboratory testing. Lipid parameters, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), small dense low density lipoprotein cholesterol (sd LDL-C), high-density lipoprotein (HDL), non-HDL, TC/HDL ratio, TG/HDL ratio and LDL/HDL ratio were measured. Both low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) subfractions were measured using the Quantimetrix Lipoprint System. Logistic regression analysis was performed to determine associated factors for CMD. Results: Very low-, intermediate-, small dense-, and low- density lipoprotein particles were positively associated with CMD. HDL particles were inversely associated with CMD apart from small HDL. Cholesterol in large HDL was inversely associated with CMD (odds ratio [OR] = 0.75), whereas cholesterol in small HDL was not (OR = 1.08). TG within all lipoproteins, including most HDL particles, were positively associated with CMD. In multiple logistic regression analyses, non-HDL [OR = 1.56 (1.16-1.87)], sd LDL-C [OR = 1.80 (1.21-2.27)], TC [OR = 1.41 (1.25-1.93)], TC/HDL [OR = 1.26 (1.15-1.68)] were significantly associated with CMD. Conclusions: Lipids and lipoproteins showed similar associations with CMD. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with CMD. Non-HDL, sd LDL-C, TC, and TC/HDL were significantly associated with CMD than others. This result should be considered in future clinical lipid-lowering trials and a routine screening for CMD in the young.

Impact of combined consumption of fish oil and probiotics on the serum metabolome in pregnant women with overweight or obesity.

BackgroundIf a pregnant woman is overweight, this can evoke metabolic alterations that may have health consequences for both mother and child.MethodsPregnant women with overweight/obesity (n = 358) received fish oil+placebo, probiotics+placebo, fish oil+probiotics or placebo+placebo from early pregnancy onwards. The serum metabolome was analysed from fasting samples with a targeted NMR-approach in early and late pregnancy. GDM was diagnosed by OGTT.FindingsThe intervention changed the metabolic profile of the women, but the effect was influenced by their GDM status. In women without GDM, the changes in nine lipids (FDR<0.05) in the fish oil+placebo-group differed when compared to the placebo+placebo-group. The combination of fish oil and probiotics induced changes in more metabolites, 46 of the lipid metabolites differed in women without GDM when compared to placebo+placebo-group; these included reduced increases in the concentrations and lipid constituents of VLDL-particles and less pronounced alterations in the ratios of various lipids in several lipoproteins. In women with GDM, no differences were detected in the changes of any metabolites due to any of the interventions when compared to the placebo+placebo-group (FDR<0.05).InterpretationFish oil and particularly the combination of fish oil and probiotics modified serum lipids in pregnant women with overweight or obesity, while no such effects were seen with probiotics alone. The effects were most evident in the lipid contents of VLDL and LDL only in women without GDM.FundingState Research Funding for university-level health research in the Turku University Hospital Expert Responsibility Area, Academy of Finland, the Diabetes Research Foundation, the Juho Vainio Foundation, Janssen Research & Development, LLC.

Lipoprotein size is a main determinant for the rate of hydrolysis by exogenous LPL in human plasma

LPL is a key player in plasma triglyceride metabolism. Consequently, LPL is regulated by several proteins during synthesis, folding, secretion, and transport to its site of action at the luminal side of capillaries, as well as during the catalytic reaction. Some proteins are well known, whereas others have been identified but are still not fully understood. We set out to study the effects of the natural variations in the plasma levels of all known LPL regulators on the activity of purified LPL added to samples of fasted plasma taken from 117 individuals. The enzymatic activity was measured at 25°C using isothermal titration calorimetry. This method allows quantification of the ability of an added fixed amount of exogenous LPL to hydrolyze triglyceride-rich lipoproteins in plasma samples by measuring the heat produced. Our results indicate that, under the conditions used, the normal variation in the endogenous levels of apolipoprotein C1, C2, and C3 or the levels of angiopoietin-like proteins 3, 4, and 8 in the fasted plasma samples had no significant effect on the recorded activity of the added LPL. Instead, the key determinant for the LPL activity was a lipid signature strongly correlated to the average size of the VLDL particles. The signature involved not only several lipoprotein and plasma lipid parameters but also apolipoprotein A5 levels. While the measurements cannot fully represent the action of LPL when attached to the capillary wall, our study provides knowledge on the interindividual variation of LPL lipolysis rates in human plasma.

Fat metabolism is associated with telomere length in six population-based studies.

Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold Pmeta = 6.5 × 10-4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 × 10-4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 × 10-4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.

Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

Dyslipidemia and cardiovascular complications are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis up to hepatocellular carcinoma. Lipoprotein(a) (Lp(a)) has been associated with cardiovascular risk and metabolic abnormalities, but its impact on the severity of liver damage in patients with NAFLD remains to be clarified. Circulating Lp(a) levels were assessed in 600 patients with biopsy‐proven NAFLD. The association of Lp(a) with liver damage was explored by categorizing serum Lp(a) into quartiles. The receiver operating characteristic curve was used to analyze the accuracy of serum Lp(a) in hepatic fibrosis prediction. Hepatic expression of lipoprotein A (LPA) and of genes involved in lipid metabolism and fibrogenic processes were evaluated by RNA sequencing in a subset of patients with NAFLD for whom Lp(a) dosage was available (n = 183). In patients with NAFLD, elevated Lp(a) levels were modestly associated with circulating lipids, carotid plaques, and hypertension (P < 0.05). Conversely, patients with low serum Lp(a) displayed insulin resistance (P < 0.05), transaminase elevation (P < 0.05), and increased risk of developing severe fibrosis (P = 0.007) and cirrhosis (P = 0.002). In addition, the diagnostic accuracy of Lp(a) in predicting fibrosis increased by combining it with transaminases (area under the curve fibrosis stage 4, 0.87; P < 0.0001). Hepatic LPA expression reflected serum Lp(a) levels (P = 0.018), and both were reduced with the progression of NAFLD (P < 0.05). Hepatic LPA messenger RNA levels correlated with those of genes involved in lipoprotein release, lipid synthesis, and fibrogenesis (P < 0.05). Finally, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, apolipoprotein E (ApoE) rs445925, and proprotein convertase subtilisin/kexin type 9 (PCSK9) rs7552841, known variants that modulate circulating lipids, may influence serum Lp(a) levels (P < 0.05). Conclusion: Circulating Lp(a) combined with transaminases may represent a novel noninvasive biomarker to predict advanced fibrosis in patients with NAFLD.

High-density lipoprotein lipid peroxidation in association with presence of coronary artery disease and atrial fibrillation in a large cross-sectional study

Abstract Background The function of high-density lipoprotein (HDL) cholesterol may play a more important role in the prevention of cardiovascular disease compared to the concentration of the HDL. Cardiovascular diseases such as coronary artery disease (CAD) and atrial fibrillation (AF) have been linked to impaired HDL function. Purpose The aim of the present study is to assess a biochemical measure of the antioxidant function of HDL and its association with presence of CAD and AF. Methods Patients admitted for elective cardiac catheterization were recruited in this cross-sectional study. Out of 1231 participants that were included in the analyses, 727 patients had confirmed CAD (CAD group), 369 patients had no CAD (no CAD group) and 129 persons were included as a control group. HDL function was measured in sera by determination of HDL-lipid peroxidation content (HDLox) assessed by a validated fluorometric cell-free biochemical assay and was normalized for the levels of HDL cholesterol (normalized HDLox/HDL-C ratio or nHDLox; no units). Results are expressed as median with interquartile range. Associations of nHDLox with presence of CAD and AF were assessed by univariate and multivariate analyses. Results Participants in the CAD group had higher levels of nHDLox (0.80, 0.61–1.03) compared to the no CAD (0.70, 0.55–0.93) and control (0.66, 0.55–1.03, no units, p&amp;lt;0.001) group. Out of 1206 participants, 233 (19%) had AF and 973 (81%) had no AF. Patients with AF have also higher nHDLox (0.82, 0.60–10.03) compared to persons without AF (0.73, 0.58–0.98, p=0.03). In univariate analysis nHDLox was associated with CAD (p&amp;lt;0.001). In multivariate analysis adjusted for age, gender, CAD, BMI and hypertension, nHDLox was a strong independent predictor of atrial fibrillation (p=0.015) but was not an independent predictor of CAD (p&amp;gt;0.05) Conclusions Reduced antioxidant function of HDL (increased HDLox measured by a biochemical assay), a metric of HDL function, is increased in patients with atherosclerosis and manifested CAD and is also associated with the presence of atrial fibrillation independent of the presence of CAD. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Medical School of Brandenburg-MHB Fontane

An impact of lipid profile and lipid lowering drugs on \u226570\u2009year olds of an upper socioeconomic class: a retrospective cohort study

BackgroundLife expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival.MethodsThis was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013–2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed.ResultsOverall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found.ConclusionsThis analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.

High-Density Lipoprotein 3 Cholesterol and Primary Open-Angle Glaucoma: Metabolomics and Mendelian Randomization Analyses

We hypothesized that the effect of blood lipid-related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG. Cross-sectional study. Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n= 8503). All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid-related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis. Primary open-angle glaucoma. Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61-0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84-0.99, P= 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG. Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.

Effects of apolipoprotein B on the lifespan and risks of major disease including type 2 diabetes: a mendelian randomization analysis using outcomes in first-degree relatives

In brief: Using a multivariable Mendelian randomization approach, genetic data on lipoprotein lipid levels and disease outcomes indicated that higher Apolipoprotein B (ApoB) levels increase the risks of coronary heart disease, stroke and T2DM, and shorten longevity. ApoB is emerging as a more sensitive measure of disease risks posed by lipoprotein than the conventionally used LDL-C.

DLp/HDL-BGBP and MTP Cloning and Expression Profiles During Embryonic Development in the Mud Crab Scylla paramamosain.

Lipids are the main energy source for embryonic development in oviparous animals. Prior to the utilization and catabolism, lipids are primarily transported from the yolk sac to embryonic tissues. In the present study, cDNA encoding a circulatory large lipid transfer protein (LLTP) superfamily member, the precursor of large discoidal lipoprotein (dLp) and high-density lipoprotein/β-1,3-glucan-binding protein (HDL-BGBP), named dLp/HDL-BGBP of 14,787 bp in length, was cloned from the mud crab Scylla paramamosain. dLp/HDL-BGBP was predicted to encode a 4,831 amino acids (aa) protein that was the precursor of dLp and HDL-BGBP, which were both detected in hemolymph by liquid chromatography–mass spectrometry (LC-MS/MS) analysis. For the intracellular LLTP, three microsomal triglyceride transfer protein (MTP) cDNAs of 2,905, 2,897, and 3,088 bp in length were cloned from the mud crab and were predicted to encode MTP-A of 881 aa, MTP-B of 889 aa, and MTP-C of 919 aa, respectively, which were different merely in the N-terminal region and shared an identical sequence of 866 aa. During embryonic development, the expression level of dLp/HDL-BGBP consecutively increased from the early appendage formation stage to the eye pigment-formation stage, which indicated that HDL-BGBP is probably the scaffolding protein for yolk lipid. For the MTP gene, MTP-C accounted for ~70% of MTP mRNA from the blastocyst stage to the nauplius stage, as well as the pre-hatching stage; MTP-C and MTP-A expression levels were comparable from the early appendage formation stage to the late eye pigment-formation stage; MTP-A was extremely low in blastocyst and gastrula stages; MTP-B was expressed at a relatively low-level throughout embryo development. The variations in the expression profiles among MTP transcripts suggested that MTP might play roles in the lipid droplet maturation and lipoprotein assembly during embryonic development.

Associations of Endogenous Hormones With HDL Novel Metrics Across the Menopause Transition: The SWAN HDL Study.

Novel metrics of high-density lipoprotein (HDL) (subclasses, lipid content, and function) may improve characterization of the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of estradiol (E2) and follicle-stimulating hormone (FSH). We tested associations of endogenous E2 and FSH with novel HDL metrics and assessed whether these associations varied by time relative to FMP. This study was a longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study, using a community-based cohort of 463 women, baseline mean age 50.2 (2.7) years. The main outcome measures were HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL particles (HDL-P), HDL size, and HDL cholesterol (HDL-C). In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC, and HDL-Tg, but negatively with medium HDL-P (P values < 0.05). The positive association between E2 and HDL-Tg was stronger 2 years post-FMP than before, (interaction P = 0.031). FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle (P values < 0.05). Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause (interaction P values < 0.05). Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future.

Liver-humanized mice fed a NASH-diet are an advanced model to study cardiometabolic diseases

Background and Aims: Conventional mouse models of diet-induced cardiometabolic diseases, e.g., atherosclerosis and nonalcoholic steatohepatitis (NASH), are limited to recapitulate the full pathology of human disease. Conversely, dietary challenge in liver-humanized mice (LHM), i.e., mice repopulated with human hepatocytes, can be more relevant to study cardiometabolic diseases as LHM exhibit a human-like lipoprotein and liver lipid metabolism. Nevertheless, we have previously reported LHM to be resistant to high-fat/high-sucrose diet. Here, we aimed to investigate whether LHM developed cardiometabolic diseases when challenged with a high-fat/high-fructose/high-cholesterol diet (NASH-diet).

Effects of Low Molecular Weight and Unfractionated Heparin on Lipoprotein Lipase and Lipid Profile in haemodialysis patients

Introduction: In haemodialysis patients, mortality from cardiovascular disease is much greater than in the general population. The current study aimed to evaluate the effects of two different types of heparin, low molecular weight heparins (LMWH) and high molecular weight heparin (HMWH), on lipid profile in patients undergoing haemodialysis.Material &amp; Methods: A total of 60 patients on haemodialysis were selected from two main hospitals of Lahore, Pakistan and were divided into two major groups based on the type of heparin used. A 5 ml blood sample was taken from the dialysis machine to get the serum and was kept frozen at -20ºC for analysis of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein. Comparison of lipoprotein lipase activity between groups were evaluated by using the student t-test. A P-value of ? 0.05 was considered statistically significant.Results: Gender wise distribution of study population (n=60) was 67% (n=40) males and 33% (n=20) females. The age distribution of individuals varied from 39-43 years. Moreover, use of HMWH was high in males (73%) as compared to female (27%) with an average age of 39 ± 12 years where duration of haemodialysis was 4.44 ± 2.83. A significant difference in LPL activity related to different times in all patients was observed. A clearer difference observed in case of LDL where LPL activity was markedly different in both groups. Our data showed that individuals using LMWH had less chances of dyslipidaemia as compared to those using HMWH.Conclusion: LMWH is a useful and safe anticoagulant during haemodialysis as compared to HMWH.

Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity.

The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very-low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR-B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid-lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.

CD36 Activation Enhances Hydrogen Peroxide Generation in Human Platelets

Cardiovascular disease remains the leading cause of death in the United States and thrombosis following atherosclerotic plaque rupture represents a significant portion of this mortality. Our lab and others have previously shown that oxidized lipids in low density lipoprotein (LDL) particles (oxLDL) serve as a “danger” signal that is recognized by CD36, a scavenger receptor of the innate immune system, found on platelets, and other vascular cells, that promotes platelet hyper-reactivity and thrombogenesis. Recently published data from our lab suggests that oxLDL-CD36 signaling in platelets involves generation of reactive oxygen species (ROS) that are important signaling pathway regulators and contribute to the sustained activation of the redox-sensitive MAPK, ERK5. This pathway is an important contributor to platelet activation and thrombosis. It is not well understood how CD36-dependent ROS generation maintains platelets under hyperlipidemic conditions in a “hypersensitive” state. Our hypothesis is that oxLDL acting through CD36 stimulates specific hydroperoxide species to modulate platelet signaling pathways. Using reverse-phase HPLC to detect 7-hydroxycoumarin (COH), the stable fluorescent product of the reaction between hydroperoxides and coumarin boronic acid (CBA), we selectively measured intracellular hydroperoxide generation in washed human platelets. Platelets showed a dose-dependent increase in COH accumulation of 70 ± 20%, 81 ± 13%, and 84 ± 16% after stimulation with oxLDL 25 μg/mL, 50 μg/mL, or 100 μg/mL, respectively (p=0.0115, p<0.01, p<0.01). Equivalent doses of native LDL produced no significant increase in COH accumulation. Platelets also showed a time-dependent increase in COH with maximal accumulation after 60 minutes of 50 μg/mL oxLDL stimulation (p<0.001). Previously published functional aggregometry data suggested that PEG-catalase, an enzyme that promotes hydrogen peroxide (H2O2) breakdown, prevents oxLDL-stimulated platelet activation and aggregation. Here we showed that pre-treatment of platelets with PEG-catalase blunted oxLDL-stimulated COH accumulation by 42 ± 8.6% (p=0.0106). In addition to H2O2, CBA reacts with peroxynitrite, but inhibition of platelet nitric oxide synthase with L-NG-Nitroarginine methyl ester (L-NAME) did not alter COH generation after oxLDL treatment when compared to oxLDL alone. Since CD36 signaling activates platelets through “non-classical” pathways, we examined how classic platelet agonists affected oxLDL-stimulated hydroperoxide generation. Treatment with collagen-related peptide (CRP) showed no significant increase in COH accumulation, but co-stimulation with oxLDL and CRP showed a 185 ± 26.4% increase in COH accumulation, as compared to oxLDL alone (p<0.0001), suggesting a synergistic effect between the oxLDL-CD36 and collagen-GPVI signaling pathways. This effect was not observed after thrombin or ADP treatment. Further studies are necessary to elucidate how oxLDL-stimulated hydroperoxide generation affects platelet signaling. Taken together our data suggests that oxLDL specifically generates H2O2 in platelets to promote a hyper-sensitive state and collagen-GPVI signaling may enhance this effect promoting thrombosis in pro-atherogenic conditions. Since mice and humans lacking CD36 do not demonstrate a bleeding diathesis and form normal thrombi, we reason that targeting CD36-mediated redox mechanisms has clinical potential to reduce the risk of atherothrombosis without compromising normal physiological hemostasis responses, unlike current anti-platelet agents in clinical use. DisclosuresNo relevant conflicts of interest to declare.