Neuron-Astrocyte Metabolic Coupling Protects against Activity-Induced Fatty Acid Toxicity.

Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial ß-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.

Dengue virus NS1 protein conveys pro-inflammatory signals by docking onto high-density lipoproteins.

The dengue virus nonstructural protein 1 (NS1) is a secreted virulence factor that modulates complement, activates immune cells and alters endothelial barriers. The molecular basis of these events remains incompletely understood. Here we describe a functional high affinity complex formed between NS1 and human high-density lipoproteins (HDL). Collapse of the soluble NS1 hexamer upon binding to the lipoprotein particle leads to the anchoring of amphipathic NS1 dimeric subunits into the HDL outer layer. The stable complex can be visualized by electron microscopy as a spherical HDL with rod-shaped NS1 dimers protruding from the surface. We further show that the assembly of NS1-HDL complexes triggers the production of pro-inflammatory cytokines in human primary macrophages while NS1 or HDL alone do not. Finally, we detect NS1 in complex with HDL and low-density lipoprotein (LDL) particles in the plasma of hospitalized dengue patients and observe NS1-apolipoprotein E-positive complexes accumulating overtime. The functional reprogramming of endogenous lipoprotein particles by NS1 as a means to exacerbate systemic inflammation during viral infection provides a new paradigm in dengue pathogenesis.

Associations of diet quality and food consumption with serum biomarkers for lipid and amino acid metabolism in Finnish children: the PANIC study.

PURPOSE: To investigate the associations of overall diet quality and dietary factors with serum biomarkers for lipid and amino acid metabolism in a general population of children. METHODS: We studied 194 girls and 209 boys aged 6-8 years participating in the Physical Activity and Nutrition in Children study. Food consumption was assessed by 4-day food records and diet quality was quantified by the Finnish Children Healthy Eating Index (FCHEI). Fasting serum fatty acids, amino acids, apolipoproteins, as well as lipoprotein particle sizes were analyzed with high-throughput nuclear magnetic resonance spectroscopy. Data were analyzed using linear regression adjusted for age, sex, and body fat percentage. RESULTS: FCHEI was directly associated with the ratio of polyunsaturated (PUFA) to saturated fatty acids (SFA) (PUFA/SFA), the ratio of PUFA to monounsaturated fatty acids (MUFA) (PUFA/MUFA), the ratio of PUFA to total fatty acids (FA) (PUFA%), the ratio of omega-3-fatty acids to total FA (omega-3 FA%), and inversely associated with the ratio of MUFA to total FA (MUFA%), alanine, glycine, histidine and very-low density lipoprotein (VLDL) particle size. Consumption of vegetable oils and vegetable-oil-based margarine (≥ 60% fat) was directly associated with PUFA/SFA, PUFA/MUFA, PUFA%, the ratio of omega-6 FA to total FA (omega-6 FA%), and inversely associated with SFA, MUFA, SFA to total FA (SFA%), MUFA%, alanine and VLDL particle size. Consumption of high-fiber grain products directly associated with PUFA/SFA, PUFA/MUFA, omega-3 FA%, omega-6 FA%, PUFA% and inversely associated with SFA and SFA%. Fish consumption directly related to omega-3 FA and omega-3 FA%. Consumption of sugary products was directly associated with histidine and VLDL particle size. Vegetable, fruit, and berry consumption had direct associations with VLDL particle size and the ratio of apolipoprotein B to apolipoprotein A1. Consumption of low fat (< 1%) milk was directly associated with phenylalanine. A higher consumption of high-fat (≥ 1%) milk was associated with lower serum MUFA/SFA and higher SFA%. Sausage consumption was directly related to SFA% and histidine. Red meat consumption was inversely associated with glycine. CONCLUSIONS: Better diet quality, higher in intake of dietary sources of unsaturated fat and fiber, and lower in sugary product intake were associated with more favorable levels of serum biomarkers for lipid and amino acid metabolism independent of adiposity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01803776, registered March 3, 2013.

Different clinical phenotypes of a pair of siblings with familial hypercholesterolemia: a case report and literature review.

BACKGROUND: Familial hypercholesterolemia (FH) leads to high plasma low-density lipoprotein cholesterol (LDL-C) levels and early cardiovascular morbidity and mortality. We treated a pair of siblings with FH. The cardiovascular manifestations in the proband were more severe than those in his elder sister, although they had almost similar LDL-C levels, ages, and lifestyles. Herein, we report the cases of this family to explore the possible causes of clinical phenotypic differences within the same genetic background. CASE PRESENTATION: We treated a 27-year-old male patient and his 30-year-old sister, both with FH. The coronary angiogram in the male patient revealed 80, 70, and 100% stenosis of the initial, distal right coronary artery branch, and left anterior descending branch, respectively, whereas his sister had almost no coronary stenosis. We treated them accordingly and performed family screening. We found that the LDL-C/particle discordance of the proband is much greater than that of his elder sister. In addition, the average size of LDL-C particle in the proband was smaller than that in his sister. CONCLUSIONS: Patients with FH have a much higher risk of premature atherosclerotic cardiovascular disease, but the clinical manifestations are heterogeneous. The smaller LDL particle size may be the underlying cause for different clinical outcomes in this pair of FH cases and be a potential novel indicator for predicting the prognosis of FH.

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

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

Caregiving stress and burden associated with cardiometabolic risk in family caregivers of individuals with cancer.

Chronic stress is a well-established risk factor for cardiometabolic disease. Caregiving for individuals with cancer is perceived as a chronic stressor yet research on the risk for cardiometabolic disease in this population, opposed to the elderly and those with Alzheimer's disease, is limited. Additionally, few studies have explored the early physiological changes that occur in family caregivers suggesting an elevated risk for illness. This cross-sectional study was designed to examine levels of cardiometabolic risk biomarkers and their correlates in caregivers of patients with colorectal cancer. Caregivers completed questionnaires that measure exposures to stress and vulnerability factors, psychological distress, and health habits as potential correlates. Traditional lipid and nontraditional lipoprotein particle biomarkers (e.g. concentration and size for all lipoprotein classes) were assayed from blood serum. Caregivers (N = 83, mean age = 49.8, 73% female) displayed levels of cardiometabolic biomarkers that suggest an elevated risk for cardiometabolic disease. Caregivers who were Hispanic, married, highly educated, employed, reported more hours spent caregiving daily, experienced higher caregiver burden associated with the lack of family support and impact on schedule, and psychological distress, demonstrated an elevated risk for cardiometabolic disease; primarily determined by nontraditional lipid biomarkers - large TRL-P, LDL-P, small HDL-P, large HDL-P, TRL-Z, LDL-Z and HDL-Z. These findings suggest that traditional lipid biomarkers may not be robust enough to detect early physiological changes associated with cardiometabolic disease risk in family caregivers. Moreover, findings reiterate the importance of assessing caregiver burden and providing evidence-based interventions to manage caregiving stress with the potential to improve caregivers' cardiometabolic health.

Characterization of serum protein expression profiles in the early sarcopenia older adults with low grip strength: a cross-sectional study.

BACKGROUND: Sarcopenia refers to the progressive loss of skeletal muscle mass and muscle function, which seriously threatens the quality of life of the older adults. Therefore, early diagnosis is urgently needed. This study aimed to explore the changes of serum protein profiles in sarcopenia patients through a cross-sectional study, and to provide the reference for clinical diagnosis. METHODS: This study was a cross-sectional study carried out in the Tianjin institute of physical education teaching experiment training center from December 2019 to December 2020. Ten older adults were recruited, including 5 sarcopenia and 5 healthy older adults. After a detailed diagnostic evaluation, blood samples were collected to prepare serum for proteomic analysis using the HPLC System Easy nLC method. The differentially expressed proteins (DEPs) were screened by the limma package of R software (version 4.1.0). RESULTS: A total of 114 DEPs were identified between the patients and healthy older adults, including 48 up-regulated proteins and 66 down-regulated proteins. The functional enrichment analysis showed that the 114 DEPs were significantly enriched in 153 GO terms, which mainly involved in low-density lipoprotein particle remodeling, and negative regulation of immune response,etc. The PPI network further suggested that the cholesteryl ester transfer protein and Apolipoprotein A2 could serve as biomarkers to facilitate diagnosis of sarcopenia. CONCLUSIONS: This study provided a serum proteomic profile of sarcopenia patients, and identified two proteins with diagnostic value, which might help to improve the diagnostic accuracy of sarcopenia.

Effect of PCSK9 inhibitor on lipoprotein particles in patients with acute coronary syndromes.

BACKGROUND: To assess the effects of proprotein convertase subtilisin/kexin type 9 inhibitor (evolocumab) on lipoprotein particles subfractions with Nuclear Magnetic Resonance spectroscopy in patients with acute coronary syndromes. METHODS: A total of 99 consecutive patients with ACS were enrolled and assigned to either the experimental group (n = 54) or the control group (n = 45). The combination therapy of PCSK9 inhibitor (Repatha®, 140 mg, q2w) and moderate statin (Rosuvastatin, 10 mg, qn) was administered in the experimental group, with statin monotherapy (Rosuvastatin, 10 mg, qn) in the control group. The therapeutic effects on lipoprotein particle subfractions were assessed with NMR spectroscopy after 8 weeks treatment, and the achievement of LDL-C therapeutic target in both groups were analyzed. RESULTS: In the experimental group, after 8 weeks of evolocumab combination treatment, the concentrations of blood lipids (TC, LDL-C and its subfractions [LDL-1 to 6], VLDL-C and its subfractions [VLDL-1 to 5], IDL-C, and HDL-C), lipoprotein particles, and their subfractions [VLDL-P, IDL-P, LDL-P, and its subfractions [LDL-P1 to 6], apoB, and LP(a)] demonstrated therapeutic benefits with statistical significance (P < 0.05). The decrease in total LDL-P concentrations was mainly due to a decreased concentration of small-sized LDL particles (LDL-P 5 + 6), which was significantly more prominent than the decrease in medium-sized LDL-P (LDL-P3 + 4) and large-sized LDL-P (LDL-P1 + 2) (P < 0.001). According to lipid control target recommended by the latest China Cholesterol Education Program Expert Consensus in 2019, after 8 weeks treatment, 96.3% patients in the experimental group and 13.3% in the control group had achieved the LDL-C therapeutic target (P < 0.01). CONCLUSIONS: Evolocumab combination treatment for 8 weeks significantly improves the plasma lipid profiles in ACS patients, and significantly decrease the concentration of lipoprotein particles which might contribute to the pathonesis of atherosclerosis.

Prognostic utility of triglyceride-rich lipoprotein-related markers in patients with coronary artery disease.

TG-rich lipoprotein (TRL)-related biomarkers, including TRL-cholesterol (TRL-C), remnant-like lipoprotein particle-cholesterol (RLP-C), and apoC-III have been associated with atherosclerosis. However, their prognostic values have not been fully determined, especially in patients with previous CAD. This study aimed to examine the associations of TRL-C, RLP-C, and apoC-III with incident cardiovascular events (CVEs) in the setting of secondary prevention of CAD. Plasma TRL-C, RLP-C, and total apoC-III were directly measured. A total of 4,355 participants with angiographically confirmed CAD were followed up for the occurrence of CVEs. During a median follow-up period of 5.1 years (interquartile range: 3.9-6.4 years), 543 (12.5%) events occurred. Patients with incident CVEs had significantly higher levels of TRL-C, RLP-C, and apoC-III than those without events. Multivariable Cox analysis indicated that a log unit increase in TRL-C, RLP-C, and apoC-III increased the risk of CVEs by 49% (95% CI: 1.16-1.93), 21% (95% CI: 1.09-1.35), and 40% (95% CI: 1.11-1.77), respectively. High TRL-C, RLP-C, and apoC-III were also independent predictors of CVEs in individuals with LDL-C levels ≤1.8 mmol/l (n = 1,068). The addition of RLP-C level to a prediction model resulted in a significant increase in discrimination, and all three TRL biomarkers improved risk reclassification. Thus, TRL-C, RLP-C, and apoC-III levels were independently associated with incident CVEs in Chinese CAD patients undergoing statin therapy.

Associations of High-Density Lipoprotein Particle and High-Density Lipoprotein Cholesterol With Alcohol Intake, Smoking, and Body Mass Index　- The INTERLIPID Study.

BACKGROUND: Recently, high-density lipoprotein particles (HDL-P) have been found to be more strongly inversely associated with coronary artery disease (CAD) risk than their counterpart, HDL cholesterol (HDL-C). Given that lifestyle is among the first targets in CAD prevention, we compared the associations of HDL-P and HDL-C with selected lifestyle factors. Methods and Results: We examined 789 Japanese participants of the INTERLIPID Study: men (n=386) and women (n=403) aged 40-59 years in 1996-1998. Participants treated for dyslipidemias were excluded. Lifestyle factors included alcohol intake, smoking amount, and body mass index (BMI). Multivariable linear regression was used for cross-sectional analyses of these factors with HDL-P, HDL-C, HDL-P size subclasses (small, medium and large) and mean HDL-P size. In men, higher alcohol intake was associated with higher HDL-P and higher HDL-C. The associations of alcohol, however, were strongest with HDL-P. A higher smoking amount tended to be associated with lower HDL-P and HDL-C. In contrast, BMI was not associated with HDL-P, but was strongly inversely associated with HDL-C. While alcohol intake favored larger mean HDL-P size, smoking and BMI favored a lipid profile with smaller HDL-P subclasses and overall smaller mean HDL-P size. Similar, but generally weaker results were observed in women. CONCLUSIONS: Although both HDL-P and HDL-C are parameters of HDL, they have different associations with alcohol, smoking and BMI.

The small dense LDL particle/large buoyant LDL particle ratio is associated with glucose metabolic status in pregnancy.

BACKGROUND: The lipoprotein subfraction particle profile can be used to improve clinical assessments of cardiovascular disease risk and contribute to early detection of atherogenic dyslipidemia. Lipid alterations in gestational diabetes have been extensively studied, but the results have been inconsistent. Here, we investigated serum lipoprotein subfraction particle levels and their association with glucose metabolic status in pregnancy. METHODS: Twenty-eight pregnant women with gestational diabetes and 56 pregnant women with normal glucose tolerance matched for body mass index were enrolled in this study. We assessed fasting serum lipid concentrations and lipoprotein subfraction particle levels in participants between 24 and 28 weeks of gestation. RESULTS: The level of low-density lipoprotein (LDL) cholesterol was significantly lower in women with gestational diabetes than in those with normal glucose tolerance, but the triglyceride and high-density lipoprotein (HDL) cholesterol levels of the two groups were similar. Lipoprotein particle analysis showed that very-low-density lipoprotein (VLDL) particle number and the small dense LDL particle/large buoyant LDL particle (sdLDL-P/lbLDL-P) ratio were significantly higher in women with gestational diabetes than in those with normal glucose tolerance (P = 0.013 and P = 0.015, respectively). In multivariate analysis, fasting glucose was independently and positively associated with sdLDL-P/lbLDL-P ratio even after adjustment for maternal age, gestational weight gain, BMI and LDL cholesterol (standardized Beta = 0.214, P = 0.029). CONCLUSIONS: The sdLDL-P/lbLDL-P ratio is higher in GDM compared with non-diabetic pregnant women, and positively and independently associated with fasting glucose in pregnant women.

Differences in GlycA and lipoprotein particle parameters may help distinguish acute kawasaki disease from other febrile illnesses in children.

BACKGROUND: Glycosylation patterns of serum proteins, such as α1-acid glycoprotein, are modified during an acute phase reaction. The response of acute Kawasaki disease (KD) patients to IVIG treatment has been linked to sialic acid levels on native IgG, suggesting that protein glycosylation patterns vary during the immune response in acute KD. Additionally, the distribution and function of lipoprotein particles are altered during inflammation. Therefore, the aim of this study was to explore the potential for GlycA, a marker of protein glycosylation, and the lipoprotein particle profile to distinguish pediatric patients with acute KD from those with other febrile illnesses. METHODS: Nuclear magnetic resonance was used to quantify GlycA and lipoprotein particle classes and subclasses in pediatric subjects with acute KD (n = 75), post-treatment subacute (n = 36) and convalescent (n = 63) KD, as well as febrile controls (n = 48), and age-similar healthy controls (n = 48). RESULTS: GlycA was elevated in acute KD subjects compared to febrile controls with bacterial or viral infections, IVIG-treated subacute and convalescent KD subjects, and healthy children (P <0.0001). Acute KD subjects had increased total and small low density lipoprotein particle numbers (LDL-P) (P <0.0001) and decreased total high density lipoprotein particle number (HDL-P) (P <0.0001) compared to febrile controls. Consequently, the ratio of LDL-P to HDL-P was higher in acute KD subjects than all groups tested (P <0.0001). While GlycA, CRP, erythrocyte sedimentation rate, LDL-P and LDL-P/HDL-P ratio were able to distinguish patients with KD from those with other febrile illnesses (AUC = 0.789-0.884), the combinations of GlycA and LDL-P (AUC = 0.909) or GlycA and the LDL-P/HDL-P ratio (AUC = 0.910) were best at discerning KD in patients 6-10 days after illness onset. CONCLUSIONS: High levels of GlycA confirm enhanced protein glycosylation as part of the acute phase response in KD patients. When combined with common laboratory tests and clinical characteristics, GlycA and NMR-measured lipoprotein particle parameters may be useful for distinguishing acute KD from bacterial or viral illnesses in pediatric patients.

Liposcale: a novel advanced lipoprotein test based on 2D diffusion-ordered 1H NMR spectroscopy.

Determination of lipoprotein particle size and number using advanced lipoprotein tests (ALTs) is of particular importance to improve cardiovascular risk prediction. Here we present the Liposcale test, a novel ALT based on 2D diffusion-ordered (1)H NMR spectroscopy. Our method uses diffusion coefficients to provide a direct measure of the mean particle sizes and numbers. Using 177 plasma samples from healthy individuals and the concentration of ApoB and ApoA from isolated lipoprotein fractions, our test showed a stronger correlation between the NMR-derived lipoprotein particle numbers and apolipoprotein concentrations than the LipoProfile(®) test commercialized by Liposcience. We also converted LDL particle numbers to ApoB equivalents (milligrams per deciliter) and our test yielded similar values of LDL-ApoB to the LipoProfile(®) test (absolute mean bias of 8.5 and 7.4 mg/dl, respectively). In addition, our HDL particle number values were more concordant with the calibrated values determined recently using ion mobility. Finally, principal component analysis distinguished type 2 diabetic patients with and without atherogenic dyslipidemia (AD) on a second cohort of 307 subjects characterized using the Liposcale test (area under the curve = 0.88) and showed concordant relationships between variables explaining AD. Altogether, our method provides reproducible and reliable characterization of lipoprotein particles and it is applicable to pathological states such as AD.

Metabolic dysfunction in obese Hispanic women with polycystic ovary syndrome.

STUDY QUESTION: Are certain ethnic groups with polycystic ovary syndrome (PCOS) at increased risk of metabolic disorders? SUMMARY ANSWER: Obese Hispanic women with PCOS are at increased risk of metabolic disorders compared with age- and BMI-matched obese non-Hispanic white women with PCOS in the USA. WHAT IS KNOWN ALREADY: Ethnic differences in body composition and metabolic risk are well established. PCOS is a common disorder in women of reproductive age and is associated with high rates of insulin resistance, glucose intolerance and dyslipidemia. STUDY DESIGN, SIZE, DURATION: A cross-sectional observational study was performed at an Academic Medical Center on 60 women of reproductive age with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood was obtained after fasting from 17 Hispanic, 22 non-Hispanic black and 21 non-Hispanic white women with PCOS who were similar in age and BMI. Anthropometric parameters, insulin, lipid and lipoprotein levels (measured by nuclear magnetic resonance) were compared between the three groups. MAIN RESULTS AND THE ROLE OF CHANCE: Age and BMI did not differ between the groups. Hispanic women with PCOS had higher waist-to-hip ratio (WHR) (P = 0.02), homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.03) and a more atherogenic lipid and lipoprotein profile consisting of lower high-density lipoprotein (HDL) (P = 0.02), higher low-density lipoprotein (LDL) particle number (P = 0.02), higher very low-density lipoprotein particle (VLDL) size (P = 0.03) and lower LDL (P = 0.03) and HDL particle size (P = 0.005) compared with non-Hispanic white women. The differences in HDL, HOMA-IR, VLDL and LDL size did not persist after adjustment for WHR while differences in LDL particle number (P = 0.04) and HDL size (P = 0.01) persisted. LIMITATIONS, REASON FOR CAUTION: The sample size for the three groups was small but the findings were still significant. The women were mostly obese so the ethnic differences in metabolic disorders may not apply to non-obese women with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: Independent of BMI, obese, reproductive age, Hispanic women with PCOS in the USA had a greater degree of abdominal obesity, insulin resistance and dyslipidemia. Hispanic women with PCOS may benefit from more focused management of metabolic parameters. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the following National Institutes of Health grants: K23 DK080988-01A1 to S.S. and UL1RR029879 to CTSA at University of Illinois. None of the authors report any conflict of interests.

Associations of small dense low-density lipoprotein and adiponectin with complications of type 2 diabetes.

BACKGROUND: Small dense low-density lipoprotein (sd-LDL) has been demonstrated to be associated with cardiovascular diseases (CVD). The proposed atherogenic properties of hypoadiponectinemia might be mediated through increased sd-LDL. In this study, the associations of sd-LDL with cardiovascular and other complications of diabetes, and also with plasma levels of adiponectin, were investigated in diabetic patients. METHODS: 173 patients, with documented type 2 diabetes mellitus, were enrolled in this cross-sectional study. Laboratory, anthropometric, and clinical characteristics were all determined. The presence of CVD, hypertention, and microalbuminuria were also evaluated. Homeostasis model assessment of insulin resistance was calculated. RESULTS: Sd-LDL concentrations were significantly lower in patients with CVD than those without CVD (p = 0.020); and also lower in hypertensive patients relative to non-hypertensive ones (p = 0.008). Serum levels of adiponectin were significantly lower in patients with CVD (p < 0.001), and hypertension (p = 0.002), compared with those without each of these complications. Sd-LDL and adiponectin concentrations were positively correlated (r = 0.36, p < 0.001). Sd-LDL was also significantly associated with HbA1c (r = 0.24, p = 0.002). CONCLUSION: Our data suggest that decreased levels of adiponectin might be associated with developing complications of diabetes. This study did not provide any supportive results for the association of increased sd-LDL concentrations with CVD; neither for its association with other complications of diabetes.

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles.

Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4(+) T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10(-7) in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10(-12) in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.

Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis.

BACKGROUND & AIMS: Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting. METHODS: We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease. RESULTS: Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high-normal range (19-40 IU/L in women and 31-40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high-normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 µU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all). CONCLUSIONS: In an analysis of asymptomatic individuals, increased serum levels of ALT (even high-normal levels) are associated with markers of cardiovascular disease.

Impact of short-term low-dose atorvastatin on low-density lipoprotein and high-density lipoprotein subfraction phenotype.

Statins can significantly reduce low-density lipoprotein-cholesterol (LDL-C) and modestly raise or not alter high-density lipoprotein-cholesterol (HDL-C). However, their impact on high-density lipoprotein (HDL) and low-density lipoprotein (LDL) subfractions has been less examined. The aim of the present study was to investigate the short-term impact of low-dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty-seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day (n = 17) or 20 mg/day (n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL-C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL-C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size.

High LDL Particle and APOB Concentrations in Patients With Adrenal Cortical Adenomas: A Cross Sectional Study.

CONTEXT: Patients with nonfunctioning adenomas (NFA), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk. OBJECTIVE: To determine the extent of lipoprotein abnormalities in NFA, MACS, and CS. METHODS: We conducted a single-center cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142) and referent subjects (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low density lipoprotein particles (LDLP), high density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes and lipid lowering drug therapy. RESULTS: In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP and greater TRL size (odds ratio (OR) ranging from 1.22 to 2.08) and total LDLP (OR ranging from 1.22 to 1.75) and decreased LDL and HDL size compared to referent subjects. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (odds ratios ranging from 1.31 to 1.84). Total cholesterol, LDL cholesterol, triglycerides and apolipoprotein B were also higher in all patient categories in age- and sex-adjusted analysis with apoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and apoB elevations were observed in all patient categories after excluding subjects on lipid lowering therapy. CONCLUSION: Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and apoB concentrations, which conceivably contribute to high cardiometabolic risk.

Low-density lipoprotein particle profiles compared with standard lipids measurements in the association with asymptomatic intracranial artery stenosis.

The Shiga Epidemiological Study of Subclinical Atherosclerosis was conducted in Kusatsu City, Shiga, Japan, from 2006 to 2008. Participants were measured for LDL-p through nuclear magnetic resonance technology. 740 men participated in follow-up and underwent 1.5 T brain magnetic resonance angiography from 2012 to 2015. Participants were categorized as no-ICAS, and ICAS consisted of mild-ICAS (1 to < 50%) and severe-ICAS (≥ 50%) in any of the arteries examined. After exclusion criteria, 711 men left for analysis, we used multiple logistic regression to examine the association between lipid profiles and ICAS prevalence. Among the study participants, 205 individuals (28.8%) had ICAS, while 144 individuals (20.3%) demonstrated discordance between LDL-c and LDL-p levels. The discordance "low LDL-c-high LDL-p" group had the highest ICAS risk with an adjusted OR (95% CI) of 2.78 (1.55-5.00) in the reference of the concordance "low LDL-c-low LDL-p" group. This was followed by the concordance "high LDL-c-high LDL-p" group of 2.56 (1.69-3.85) and the discordance "high LDL-c-low LDL-p" group of 2.40 (1.29-4.46). These findings suggest that evaluating LDL-p levels alongside LDL-c may aid in identifying adults at a higher risk for ICAS.