Lipoprotein Lipid Research Articles

Lipoproteins and lipoprotein lipid composition are associated with stages of dysglycemia and subclinical coronary atherosclerosis

BackgroundDyslipidaemia in patients with diabetes contributes to the risk of atherosclerotic cardiovascular disease. We aimed to identify a dyslipidemic profile associated with both dysglycemia and subclinical coronary atherosclerosis. MethodsStudy participants (n = 5050) were classified in three groups: normoglycemia, pre-diabetes, and diabetes. A coronary artery calcium score (CACS) > 0 defined subclinical coronary atherosclerosis. Two independent methods were used to identify, among 225 lipid biomarkers, those that were associated with pre-diabetes and diabetes and were further tested for association by zero inflated Poisson regression with CACS and with CACS burden in study participants with CACS>0. Estimates were adjusted for cardiovascular risk factors with an interaction term for dispensed lipid lowering drugs. ResultsThirty-two biomarkers associated with prediabetes and diabetes were further investigated for association with CACS. HDL diameter [multi-adjusted OR of 0.85 and 95 %CI (0.78–0.92)] as well as free cholesterol, phospholipids and total lipids in extra large HDL were inversely associated with CACS. There was a borderline significant interaction between small HDL and dispensed lipid lowering drugs on the presence of CACS, with and multi-adjusted OR of 0.53 and 95 %CI (0.36–0.77). None of the 32 glycemic profile-related lipid biomarkers associated with the relative increase of CACS in those with CACS>0. No consistent association was observed between non-HDL lipoproteins and CACS. ConclusionsChanges in composition and relative concentration of HDL associated with both dysglycemia and subclinical coronary atherosclerosis. Treatment with lipid lowering drugs may contribute to reduce the risk associated with high circulating levels of small HDL.

Comparison of low-density lipoprotein cholesterol (LDL-c) estimates by in-lab and point-of-care devices in the context of emerging LDL-c equations

Abstract Low-density lipoprotein cholesterol (LDL-c) and lipid measurements are used for hyperlipidemia diagnosis, cardiovascular disease risk classification, and medication management. Millions of lipid panels are performed annually. Given the widespread need for lipid testing, there are two CLIA-waived point-of-care (POC) lipid testing devices. These devices were FDA-approved using the Friedewald equation to estimate LDL-c based on measurements of (triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and total cholesterol (TC). By contrast, for laboratory-based LDL-c estimation, the Friedewald equation is being replaced by newer, more accurate equations such as the NIH-Sampson equation. These equations use the same lipid panel results to estimate LDL-c and only differ in the arithmetic of the estimation. This study evaluates how differences between the in-clinic POC machines and in-laboratory lipid measurements affect the estimated LDL-c results and are compounded by differences in the equations used for LDL-c estimation. This retrospective observational study collected deidentified lipid results (TG, HDL-c, TC, LDL-c) and demographic data (age, gender) for all samples that had lipid panel results from in-lab and POC within twenty-four hours of each other in a single hospital system between 2014 and 2023. Three hundred twenty samples were identified; samples with non-numerical values or results outside of the reportable range for TG, HDL-c, or TC were not included in subsequent LDL-c calculations using the Friedewald and NIH-Sampson equations (69 results). Patients under the age of 18 were excluded (2 results). Two hundred and forty-nine samples met inclusion criteria; this cohort showed non-significant differences in lipid, age, and gender distributions relative to all POC results tested in the same time frame. Consistent with prior reports, we observed discordance between POC and the in-lab lipid measurements, particularly for TG (Bland-Altman: bias:-23.04 mg/dL, standard deviation:61.3 mg/dL). These analytical differences may not change clinical management if the cardiovascular risk classification using estimated LDL-c is unchanged. However, the risk classification based on the in-lab versus in-clinic testing differed for 20% of patients. The most pronounced difference in LDL-c estimation occurred when the POC machine used Friedewald and in-lab testing used NIH-Sampson, and resulted in 5% more patients differentially classified. Regardless of testing platform, more patients are categorized as higher risk on an individual and population-based level with the NIH-Sampson equation. This study highlights the need for transparency in lipid panel reports regarding which LDL-c equation is used in both POC and in-lab testing formats, and the need for readily available tools for conversion between different LDL-c estimation equations.

A-213 Comparison of low-density lipoprotein cholesterol (LDL-c) estimates by in-lab and point-of-care devices in the context of emerging LDL-c equations

Abstract Background Low-density lipoprotein cholesterol (LDL-c) and lipid measurements are used for hyperlipidemia diagnosis, cardiovascular disease risk classification, and medication management. Millions of lipid panels are performed annually. Given the widespread need for lipid testing, there are two CLIA-waived point-of-care (POC) lipid testing devices. These devices were FDA-approved using the Friedewald equation to estimate LDL-c based on measurements of (triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), and total cholesterol (TC). However, in laboratory-based testing, the Friedewald equation is being replaced by newer, more accurate equations such as the NIH-Sampson equation. These equations use the same lipid panel results to estimate LDL-c and only differ in the arithmetic of the estimation. The study objective is to evaluate how differences between the in-clinic POC machines and in-laboratory lipid measurements affect the estimated LDL-c results and are compounded by differences in the equations used for LDL-c estimation. Methods This retrospective observational study collected deidentified lipid results (TG, HDL-c, TC, LDL-c) and demographic data (age, gender) for all samples that had lipid panel results from in-lab and POC within twenty-four hours of each other in a single hospital system between 2014 and 2023. Three hundred twenty samples were identified; samples with non-numerical values or results outside of the reportable range for TG, HDL-c, or TC were not included in subsequent LDL-c calculations using the Friedewald and NIH-Sampson equations (69 results). Patients under the age of 18 were excluded (2 results). Two hundred and forty-nine samples met inclusion criteria; this cohort showed non-significant differences in lipid, age, and gender distributions relative to all POC results tested in the same time frame. Results Consistent with prior reports, we observed discordance between POC and the in-lab lipid measurements, particularly for TG (Bland-Altman: bias:-23.04 mg/dL, standard deviation:61.3 mg/dL). Regardless of the testing platform, LDL-c results are higher on an individual and population-based level with the NIH-Sampson equation. These analytical differences may not change clinical management if the cardiovascular risk classification using estimated LDL-c is unchanged. However, the risk classification based on the in-lab versus in-clinic testing differed for 20-30% of patients. The most pronounced difference in LDL-c estimation occurred when the POC machine used Friedewald and in-lab testing used NIH-Sampson, and resulted in 5% more patients differentially classified. Conclusions This study highlights the need for transparency in lipid panel reports regarding which LDL-c equation is used in both POC and in-lab testing formats, and the need for readily available tools for conversion between different LDL-c estimation equations.

Nutritional Composition and Effect of Loquat Fruit (Eriobotrya japonica L. var. Navela) on Lipid Metabolism and Liver Steatosis in High-Fat High-Sucrose Diet-Fed Mice.

Loquat (Eriobotrya japonica L.) is a popular fruit known for its sweet and slightly tangy flavor, which is widely consumed both fresh and in various processed forms. This study aimed to analyze the biochemical composition of loquat juice and investigate its metabolic benefits in mice fed a high-fat/high-sucrose diet (HFSD). Mice were fed either a standard diet or an HFSD and received or not the loquat juice at 4 or 8 mL/kg body weight for 8 weeks. Body weight, food efficiency ratio, plasma lipoprotein profile, plasma glucose, and lipid indices were monitored throughout the experiment. At the end of the experiment, additional assessments were performed, including lipid content measurements in liver, adipose tissue, bile, and feces; hepatic antioxidant enzyme activities (superoxide dismutase and catalase); hepatic malondialdehyde content; plasma biomarkers of liver injury; liver histology; and organ relative weight. Feeding mice with the HFSD resulted in a significant perturbation in lipid and glucose metabolism, obesity, liver steatosis, and oxidative stress-related enzymes. However, the concomitant administration of loquat juice significantly corrected this imbalance. Fresh loquat juice is low in fat and protein, moderately sugary, and energetically light; however, it is rich in minerals, vitamin C, and various phytochemicals compounds, such as phenolic acids, flavonoids, and carotenoids. The loquat juice could be considered a functional food and could be valorized through the extraction of active substances and their use as food supplements to prevent lipid metabolism disorders and the resulting health complications.

Selective regulation of macrophage lipid metabolism via nanomaterials’ surface chemistry

Understanding the interface between nanomaterials and lipoproteins is crucial for gaining insights into their impact on lipoprotein structure and lipid metabolism. Here, we use graphene oxide (GOs) nanosheets as a controlled carbon nanomaterial model to study how surface properties influence lipoprotein corona formation and show that GOs have strong binding affinity with low-density lipoprotein (LDL). We use advanced techniques including X-ray reflectivity, circular dichroism, and molecular simulations to explore the interfacial interactions between GOs and LDL. Specifically, hydrophobic GOs preferentially associate with LDL’s lipid components, whereas hydrophilic GOs tend to bind with apolipoproteins. Furthermore, these GOs distinctly modulate a variety of lipid metabolism pathways, including LDL recognition, uptake, hydrolysis, efflux, and lipid droplet formation. This study underscores the importance of structure analysis at the nano-biomolecule interface, emphasizing how nanomaterials’ surface properties critically influence cellular lipid metabolism. These insights will inspire the design and application of future biocompatible nanomaterials and nanomedicines.

The impact of air temperature and humidity on Children’s blood pressure mediated by Lipids: A prospective cohort study

ObjectivesFew studies illustrate the mechanism between air temperature and blood pressure (BP) in childhood. This study aims to investigate the associations between air temperature, humidity exposure, and BP trajectories in children and adolescents, and explore the potential mediating roles of lipid profiles in these relationships. MethodsThis prospective cohort study included 5,971 children with 10,800 person-times measurements at baseline from the Chongqing Health Cohort, with evaluations conducted in 2014–2015 (baseline) and follow-ups in 2016 (urban areas) and 2019 (urban and rural areas). Multilevel mixed-effects models were used to analyse the impacts of air temperature and humidity on BP levels and the incidence of elevated BP, while accounting for potential confounders. Mediation analyses were performed to evaluate the mediating effects of lipid profiles, including low-density lipoprotein (LDL), total cholesterol (TC), and specific lipid species. ResultsAfter adjusting for covariates, higher air temperature quartiles were associated with both decreased BP levels and elevated BP risk (RR: 0.83; 95 % CIs: 0.78, 0.89; P = 0.028). Conversely, higher humidity quartiles exhibited a U-shaped relationship with BP levels. Greater variability in air temperature was linked to increase BP levels. The cumulative effects of air temperature exposure on BP were significant from pregnancy to age 10, with females exhibiting larger effects (β:-3.291, 95 % CIs: −4.242,-2.340, P < 0.001). LDL and TC partially mediated the associations between air temperature and BP levels, particularly in males. Specific lipid species, including SM (d21:1), LPC (17:0), and PC (O-36:3), also exhibited significant mediating effects. ConclusionsThis study provides novel insights into the intricate interplay between air temperature, humidity, lipid metabolism, and blood pressure regulation in children. Lower average temperatures and extreme humidity levels were associated with increased risks of elevated BP, potentially mediated by lipid profiles. Early interventions targeting air temperature exposure and lipid metabolism could mitigate hypertension risk, promoting improved cardiovascular outcomes in children.

DNA Methylation Age Mediates Effect of Metabolic Profile on Cardiovascular and General Aging.

Alterations in lipid metabolism and DNA methylation are 2 hallmarks of aging. Connecting metabolomic, epigenomic, and aging outcomes help unravel the complex mechanisms underlying aging. We aimed to assess whether DNA methylation clocks mediate the association of circulating metabolites with incident atherosclerotic cardiovascular disease (ASCVD) and frailty. The China Kadoorie Biobank is a prospective cohort study with a baseline survey from 2004 to 2008 and a follow-up period until December 31, 2018. We used the Infinium Methylation EPIC BeadChip to measure the methylation levels of 988 participants' baseline blood leukocyte DNA. Metabolite profiles, including lipoprotein particles, lipid constituents, and various circulating metabolites, were measured using quantitative nuclear magnetic resonance. The pace of DNA methylation age acceleration (AA) was calculated using 5 widely used epigenetic clocks (the first generation: Horvath, Hannum, and Li; the second generation: Grim and Pheno). Incident ASCVD was ascertained through linkage with local death and disease registries and national health insurance databases, supplemented by active follow-up. The frailty index was constructed using medical conditions, symptoms, signs, and physical measurements collected at baseline. A total of 508 incident cases of ASCVD were documented during a median follow-up of 9.5 years. The first generation of epigenetic clocks was associated with the risk of ASCVD (P<0.05). For each SD increment in LiAA, HorvathAA, and HannumAA, the corresponding hazard ratios for ASCVD risk were 1.16 (1.05-1.28), 1.10 (1.00-1.22), and 1.17 (1.04-1.31), respectively. Only LiAA mediated the association of various metabolites (lipids, fatty acids, histidine, and inflammatory biomarkers) with ASCVD, with the mediating proportion reaching up to 15% for the diameter of low-density lipoprotein (P=1.2×10-2). Regarding general aging, a 1-SD increase in GrimAA was associated with an average increase of 0.10 in the frailty index (P=2.0×10-3), and a 33% and 63% increased risk of prefrailty and frailty at baseline (P=1.5×10-2 and 5.8×10-2), respectively; this association was not observed with other clocks. GrimAA mediated the effect of various lipids, fatty acids, glucose, lactate, and inflammatory biomarkers on the frailty index, with the mediating proportion reaching up to 22% for triglycerides in very small-sized very low-density lipoprotein (P=6.0×10-3). These findings suggest that epigenomic mechanisms may play a role in the associations between circulating metabolites and the aging process. Different mechanisms underlie the first and second generations of DNA methylation age in cardiovascular and general aging.

Liver transcriptome and proteome are modulated by nutrient restriction in early lactation cows challenged with intramammary lipopolysaccharide

The objective was to evaluate the effects of nutrient restriction on liver function 24 h after an intramammary lipopolysaccharide (LPS) challenge in early lactation cows using transcriptomic and proteomic analyses. Multiparous Holstein cows were fed a lactation diet (CONT, n = 8) throughout the study or were switched to a diet diluted with barley straw (48 % DM) for 96 h (REST, n = 8) starting at 24 (18 to 30) days in milk. At 72 h, a healthy rear mammary quarter was infused with 50 μg of LPS in all cows. Blood and liver biopsies were collected at 96 h, corresponding to 24 h after LPS challenge. Liver transcriptome was analyzed with a 44 K bovine microarray and proteome by LC MS/MS. Transcriptomic and proteomic data were analyzed using GeneSpring (moderated t-test with Westfall-Young correction) and the “between subject design”, respectively. Data mining was performed using Panther and Pathway Studio software. By design, the negative energy balance was −68 and −37 MJ/d in REST and CONT, respectively. Plasma non-esterified FAs, and β-hydroxybutyrate were significantly greater in REST compared to CONT, which is consistent with 96 h of nutrient restriction in REST and ketosis induction. We detected 77 and 91 differentially expressed genes at mRNA and protein levels, respectively, between CONT and REST. Genes involved in fatty acid synthesis (e.g.: ACAT, FASN, SCD) were downregulated in REST, whereas those involved in fatty acid oxidation, detoxification, cholesterol synthesis, lipoprotein lipid secretion, and gluconeogenesis (e.g.: ACAD, CPT1A, CPT1B, CPT2) were upregulated. Differentially abundant mRNAs and proteins were consistent with negative energy balance and plasma metabolite concentrations, and reflected a state of intense lipomobilization, glucose deficit and ketogenesis in REST cows. Nutrient restriction did not change in deep liver expression of genes directly involved in immune function 24 h after an intramammary LPS challenge.

IMPACT OF DYSLIPIDEMIA ON CORONARY HEART DISEASE IN WOMEN (REVIEW)

Introduction:The increase in the level of lipids in the blood is one of the risk factors for cardiovascular diseases (due to atherosclerosis and thrombosis) increasing premature morbidity, disability, financial cost and mortality, not only in the EU and the USA, but also in countries developing worldwide. It has been proven that lipid disorders promote the development of atherosclerosis and its clinical consequences such as CVD including (coronary heart disease, acute myocardial infarction, peripheral artery disease, heart failure and sudden death). Combinations of lipoprotein levels and lipid fractions play a major risk role in terms of coronary heart diseases. Purpose: Evidence of dyslipidemia as a risk factor for CVD, especially in obese women who suffer from metabolic syndrome or diabetes and have lipid profiles that negatively affect the risk of coronary heart disease. Methodology: International literature review in PubMed, CINAHL, Am J Cardiology, Int J Public Health; in accordance with the purpose and objectives of the study. Result: Coronary heart diseases are the leading cause of death among women and men although they are less common and appear later in women than in men. Each year 345,000 women suffer from an initial or recurrent myocardial infarction, and 261,000 women die from MI. Compared to men, women, and especially women in the postmenopausal period, remain at high risk for coronary disease. In women, calcification occurs 10 to 15 years later. Multiple angiographic studies of coronary arteries have shown a lower rate of epicardial coronary artery disease in women than in age-matched men. Elevated levels of Lp (a) appear to be more associated with the occurrence of coronary heart disease than with the severity of coronary artery disease in both sexes. Outcome data in women using lipid-lowering medications other than statins are extremely limited. Conclusion: The importance of a healthy lifestyle should begin in childhood and continue throughout life. Although the benefits of lipid-lowering therapy in women with cardiovascular disease are clear, more data are needed in those without cardiovascular disease. Clinical trials for lipid-lowering women with cardiovascular disease to date have used a strategy focused on lowering LDL-cholesterol, which may not be optimal for women who have low HDL-cholesterol or triglyceride levels. which are very important factors affecting coronary heart disease. It remains to be determined whether outcomes among women will improve if treatment strategies are directed toward more aggressive and comprehensive modification of lipoprotein profiles.

APOE gene polymorphism in ischemic stroke patients from Huizhou and its correlation with blood lipids and homocysteine

ObjectivesTo investigate the correlation between apolipoprotein E (APOE) gene polymorphisms and ischemic stroke and its relationship with blood lipids and homocysteine (HCY) level in Huizhou City. Materials and methodsIn this analytical cross-sectional study, we selected 2612 patients who underwent APOE genotyping from November 2019 to November 2021 at the Third People's Hospital of Huizhou. Among them, 2014 were ischemic stroke patients and 598 were non-stroke patients. The independent variables were ischemic stroke, different genotypes, and different alleles, while the dependent variables were blood lipid levels and HCY levels. ResultsThe distribution frequency of ε4 allele in stroke group was higher than that in non-stroke group (P < 0.05). Compared with ε4 allele carriers in the stroke group, the levels of lipid total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in ε2 and ε3 allele carriers were significantly lower, while the levels of high-density lipoprotein cholesterol (HDL-C) were significantly higher (P < 0.01). The levels of lipid Lipoprotein a (LPa) and small dense low-density lipoprotein (sdLDL) in ε2 allele carriers in stroke group were significantly lower than those of ε4 allele carriers (P < 0.05). Logistics regression analysis showed that age, TC, HCY level and allele ε4 were positively correlated with the risk of ischemic stroke (P < 0.01), TG level was positively correlated with the risk of ischemic stroke in females (P < 0.01). ConclusionsAPOE gene polymorphism is associated with ischemic stroke, and ε4 allele carriers have a higher risk than ε3 allele carriers.

Lipoprotein Lipidomics as a Frontier in Non-Alcoholic Fatty Liver Disease Biomarker Discovery.

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.

Lipoprotein Metabolism, Dyslipidemia, and Lipid-Lowering Therapy in Women: A Comprehensive Review.

Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk.

Changes in serum lipids following consumption of coconut oil and palm olein oil: A sequential feeding crossover clinical trial

BackgroundHigh incidence of cardiovascular disease (CVD) in South Asia is linked to genetic predisposition and diets high in saturated fatty acids (SFAs). Increased CVD prevalence correlates with rising palm oil consumption in some South Asian countries, where coconut oil and palm olein oil are primary SFA sources. ObjectiveCompare the effects of coconut oil and palm olein oil on serum lipoprotein lipids and biochemical parameters in healthy adults. MethodsA sequential feeding crossover clinical trial with two feeding periods of 8 weeks each was conducted among 40 healthy adults. Participants were provided palm olein oil in the first feeding period followed by coconut oil with a 16-week washout period in between. The outcomes measured were the difference in serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), TC/HDL-C ratio, triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), fasting plasma glucose (FPG), and liver enzymes. ResultsThirty-seven participants completed the study. LDL-C decreased by 13.0 % with palm olein oil (p < 0.001) and increased by 5.6 % with coconut oil (p = 0.044), showing a significant difference (p < 0.001). TC decreased by 9.9 % with palm olein oil (p < 0.001) and increased by 4.0 % with coconut oil (p = 0.044). ConclusionPalm olein oil consumption resulted in more favorable changes in lipid-related CVD risk factors (TC, LDL-C, TC:HDL-C, and FPG) compared to coconut oil.Clinical Trial Registry number and website where it was obtained: (SLCTR/2019/034); https://slctr.lk/trials/slctr-2019-034.

Peculiarities of metabolic and autonomic-endocrine accompaniments of urate-losing/retaining kidneys

Background. This publication initiates the project "Neuro-endocrine regulation of the clearance of nitrogenous metabolites". The first stage of project implementation is the clarification of peculiarities of metabolic and neuro-endocrine accompaniments of urate-losing and urate-retaining kidneys. Materials and Methods. The object of observations were patients with chronic pyelonephritis in the phase of remission (34 males aged 23-70 years and 10 females aged 33-76 years). Testing was performed twice - on admission and after 7-10 days of standard balneotherapy on Truskavets Spa. The battery of tests was created in line with concepts functional-metabolic continuum and NEI network. The content of nitrogenous metabolites and electrolytes was determined in daily urine and blood serum. In addition, indicators of the lipoprotein spectrum and lipids peroxidation, as well as the level of the main adaptation hormones, were determined in the blood. The state of the autonomic nervous system was assessed by the HRV method. Results. In 63.6% of cases, the renal clearance of uric acid was within the classical norm (±2σ), in 12.5% it was moderately reduced, but in the remaining cases it was increased, including drastically in 3 cases. The method of discriminant analysis revealed 20 parameters, according to the totality of which all 4 clusters of uric acid clearance clearly differ from each other (classification accuracy 100%). Conclusion. Constitutionally distinct types of uric acid metabolism (euricosis, urate-losing and urate-retaining kidneys) are characterized by specific constellations of metabolic and autonomic-endocrine parameters.

Discordance Between Very Low-Density Lipoprotein Cholesterol and Low-Density Lipoprotein Cholesterol Increases Cardiovascular Disease Risk in a Geographically Defined Cohort.

Clinical risk scores are used to identify those at high risk of atherosclerotic cardiovascular disease (ASCVD). Despite preventative efforts, residual risk remains for many individuals. Very low-density lipoprotein cholesterol (VLDL-C) and lipid discordance could be contributors to the residual risk of ASCVD. Cardiovascular disease-free residents, aged ≥40 years, living in Olmsted County, Minnesota, were identified through the Rochester Epidemiology Project. Low-density lipoprotein cholesterol (LDL-C) and VLDL-C were estimated from clinically ordered lipid panels using the Sampson equation. Participants were categorized into concordant and discordant lipid pairings based on clinical cut points. Rates of incident ASCVD, including percutaneous coronary intervention, coronary artery bypass grafting, stroke, or myocardial infarction, were calculated during follow-up. The association of LDL-C and VLDL-C with ASCVD was assessed using Cox proportional hazards regression. Interaction between LDL-C and VLDL-C was assessed. The study population (n=39 098) was primarily White race (94%) and female sex (57%), with a mean age of 54 years. VLDL-C (per 10-mg/dL increase) was significantly associated with an increased risk of incident ASCVD (hazard ratio, 1.07 [95% CI, 1.05-1.09]; P<0.001]) after adjustment for traditional risk factors. The interaction between LDL-C and VLDL-C was not statistically significant (P=0.11). Discordant individuals with high VLDL-C and low LDL-C experienced the highest rate of incident ASCVD events, 16.9 per 1000 person-years, during follow-up. VLDL-C and lipid discordance are associated with a greater risk of ASCVD and can be estimated from clinically ordered lipid panels to improve ASCVD risk assessment.

Evaluation of Plasma Biomarkers for Causal Association With Peripheral Artery Disease.

Hundreds of biomarkers for peripheral artery disease (PAD) have been reported in the literature; however, the observational nature of these studies limits causal inference due to the potential of reverse causality and residual confounding. We sought to evaluate the potential causal impact of putative PAD biomarkers identified in human observational studies through genetic causal inference methods. Putative circulating PAD biomarkers were identified from human observational studies through a comprehensive literature search based on terms related to PAD using PubMed, Cochrane, and Embase. Genetic instruments were generated from publicly available genome-wide association studies of circulating biomarkers. Two-sample Mendelian randomization was used to test the association of genetically determined biomarker levels with PAD using summary statistics from a genome-wide association study of 31 307 individuals with and 211 753 individuals without PAD in the Veterans Affairs Million Veteran Program and replicated in data from FinnGen comprised of 11 924 individuals with and 288 638 individuals without PAD. We identified 204 unique circulating biomarkers for PAD from the observational literature, of which 173 were genetically instrumented using genome-wide association study results. After accounting for multiple testing (false discovery rate, <0.05), 10 of 173 (5.8%) biomarkers had significant associations with PAD. These 10 biomarkers represented categories including plasma lipoprotein regulation, lipid homeostasis, and protein-lipid complex remodeling. Observational literature highlighted different pathways including inflammatory response, negative regulation of multicellular organismal processes, and regulation of response to external stimuli. Integrating human observational studies and genetic causal inference highlights several key pathways in PAD pathophysiology. This work demonstrates that a substantial portion of biomarkers identified in observational studies are not well supported by human genetic evidence and emphasizes the importance of triangulating evidence to understand PAD pathophysiology. Although the identified biomarkers offer insights into atherosclerotic development in the lower limb, their specificity to PAD compared with more widespread atherosclerosis requires further study.

Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

The association of circulating lipoprotein lipids and apolipoproteins with risk of endometriosis: a Mendelian randomization study.

Endometriosis is a poorly understood disease that affects up to 196 million women worldwide and imposes high costs in terms of economic burden and quality of life of women. Traits of circulating lipids have been related to the onset and progression of endometriosis in previous observational studies but the results have remained contradictory. We performed univariable and multivariable Mendelian randomization (MR) analyses using instrument variables to genetically predict the associations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides, and apolipoprotein (apo) A-I and B from the UK Biobank with endometriosis (consisting of 8288 cases and 68 969 controls from the FinnGen consortium). The inverse-variance weighted (IVW) method was used as the primary estimate, whereas MR-Egger and weighted median were conducted as complements to the IVW model. Increased levels of triglycerides were associated with higher risk of endometriosis and endometriosis of the pelvic peritoneum in the univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, triglycerides still retained a robust effect. Decreased levels of apoA-I and HDL cholesterol were associated with increased risk of endometriosis and endometriosis of the pelvic peritoneum in univariable MR analyses. After mutual adjustment, HDL cholesterol retained a robust effect whereas the association for apoA-I was attenuated. This is the first MR-based evidence to suggest that triglycerides and HDL cholesterol are the predominant traits that account for the aetiological relationship of lipoprotein lipids with risk of endometriosis, in particular endometriosis of the pelvic peritoneum. Further well-designed randomized controlled trials are needed to address these results.

Zebrafish ApoB-Containing Lipoprotein Metabolism: A Closer Look.

Zebrafish have become a powerful model of mammalian lipoprotein metabolism and lipid cell biology. Most key proteins involved in lipid metabolism, including cholesteryl ester transfer protein, are conserved in zebrafish. Consequently, zebrafish exhibit a human-like lipoprotein profile. Zebrafish with mutations in genes linked to human metabolic diseases often mimic the human phenotype. Zebrafish larvae develop rapidly and externally around the maternally deposited yolk. Recent work revealed that any disturbance of lipoprotein formation leads to the accumulation of cytoplasmic lipid droplets and an opaque yolk, providing a visible phenotype to investigate disturbances of the lipoprotein pathway, already leading to discoveries in MTTP (microsomal triglyceride transfer protein) and ApoB (apolipoprotein B). By 5 days of development, the digestive system is functional, making it possible to study fluorescently labeled lipid uptake in the transparent larvae. These and other approaches enabled the first in vivo description of the STAB (stabilin) receptors, showing lipoprotein uptake in endothelial cells. Various zebrafish models have been developed to mimic human diseases by mutating genes known to influence lipoproteins (eg, ldlra, apoC2). This review aims to discuss the most recent research in the zebrafish ApoB-containing lipoprotein and lipid metabolism field. We also summarize new insights into lipid processing within the yolk cell and how changes in lipid flux alter yolk opacity. This curious new finding, coupled with the development of several techniques, can be deployed to identify new players in lipoprotein research directly relevant to human disease.

Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial

BackgroundDistinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. ObjectivesWe investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. MethodsThis study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 mo after the weight-loss diet intervention. The ASCVD risk estimates were calculated using the validated equations. ResultsAt baseline, higher concentrations of specific BA subtypes were related to higher concentrations of atherogenic very low-density lipoprotein lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions in triglycerides and total cholesterol [every 1 standard deviation (SD) decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to β (standard error) –3.3 (1.3), –3.4 (1.3), or –3.8 (1.3) mg/dL, respectively; PFDR < 0.05 for all]. Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 mo; there was β –4.0 (1.1) mg/dL per 1-SD decrease of glycoursodeoxycholate (PFDR =0.003) for changes in low-density lipoprotein cholesterol. We found significant interactions (P-interaction < 0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet, but not after consuming a low-fat diet. ConclusionsDecreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk.This trial was registered at clinicaltrials.gov as NCT00072995