Altered Lipoprotein Metabolism Research Articles

Dyslipidemia in Chronic Kidney Disease

Globally chronic kidney (CKD) disease is one of the major health problems. Global prevalence of CKD is 8−16%. Prevalence of chronic kidney disease in Bangladesh is 26%. Patients with chronic kidney disease (CKD) exhibit significant alterations in lipoprotein metabolism. In this review different lipid parameters are shown from different studies and the pathogenesis of CKD induced dyslipidemia is discussed.
 Bangladesh J Med Biochem 2019; 12(2): 31-38

Measurement of atherosclerosis markers in individuals with periodontitis.

The inflammatory response due to inflammatory cytokines, bacterial pathogens, and the altered lipoprotein metabolism in patients with periodontitis indicates that infection with periodontal anaerobic bacteria may influence atherogenesis in vitro and in vivo. We aimed to explore the effect of periodontitis concerning clinical and ultrasound markers of early atherosclerosis. In this case-control study, a total of 30 systemically healthy adults (15 with periodontitis and 15 without periodontitis) over 40 years of age were studied. Periodontitis was determined by measuring the clinical attachment level (CAL) and radiographic bone loss (RBL). Conventional cardiovascular risk factors, including body mass index, serum levels of total cholesterol (TCH), triglycerides (TG), and high-density and low-density lipoprotein (HDL and LDL, respectively) cholesterol were evaluated. Carotid artery intima-media thickness (IMT) was measured using ultrasonography. The mean values of the CAL and carotid IMT were 5.02±0.9 mm and 0.084±0.01 cm vs. 1.6±0.61 mm and 0.072±0.02 cm in the periodontitis and healthy groups, respectively, reflecting statistically significant differences (P=0.001 and P=0.037, respectively). There were statistically significant differences in the serum levels of TCH, TG, and LDL between the 2 groups (P=0.017). The CAL and RBL were positively associated with carotid IMT and serum cholesterol levels, except for HDL, whereas tooth loss was not associated with any markers (P<0.05). Compared to the healthy group, participants with periodontitis exhibited 2.09 times higher odds (95% confidence interval, 1.22-3.59) of having subclinical atherosclerosis. The presence of periodontitis increased the risk of atherosclerosis.

Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease.

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.

Effect of diet and genotype on the miRNome of mice with altered lipoprotein metabolism

The molecular mechanism by which lipid/lipoprotein biosynthesis is regulated in mammals involves a very large number of genes that are subject to multiple levels of regulation. miRNAs are recognized contributors to lipid homeostasis at the post-transcriptional level, although the elucidation of their role is made difficult by the multiplicity of their targets and the ability of more miRNAs to affect the same mRNAs. In this study, an evaluation of how miRNA expression varies in organs playing a key role in lipid/lipoprotein metabolism was conducted in control mice and in two mouse models carrying genetic ablations which differently affect low-density lipoprotein metabolism. Mice were fed a lipid-poor standard diet and a diet enriched in cholesterol and saturated fat. The results obtained showed that there are no miRNAs whose expression constantly vary with dietary or genetic changes. Furthermore, it appears that diet, more than genotype, impacts on organ-specific miRNA expression profiles.

Association between Heavy Metals, Metalloids and Metabolic Syndrome: New Insights and Approaches.

Metabolic syndrome (MetS) is an important public health issue that affects millions of people around the world and is growing to pandemic-like proportions. This syndrome is defined by the World Health Organization (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Moreover, the etiology of MetS is multifactorial, involving many environmental factors, including toxicant exposures. Several studies have associated MetS with heavy metals exposure, which is the focus of this review. Environmental and/or occupational exposure to heavy metals are a major risk, contributing to the development of chronic diseases. Of particular note, toxic metals such as mercury, lead, and cadmium may contribute to the development of MetS by altering oxidative stress, IL-6 signaling, apoptosis, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, and other mechanisms. In this review, we discuss the known and potential roles of heavy metals in MetS etiology as well as potential targeted pathways that are associated with MetS. Furthermore, we describe how new approaches involving proteomic and transcriptome analysis, as well as bioinformatic tools, may help bring about an understanding of the involvement of heavy metals and metalloids in MetS.

Trans-fatty acid blood levels of industrial but not natural origin are associated with cardiovascular risk factors in patients with HFpEF: a secondary analysis of the Aldo-DHF trial

BackgroundIndustrially processed trans-fatty acids (IP-TFA) have been linked to altered lipoprotein metabolism, inflammation and increased NT-proBNP. In patients with heart failure with preserved ejection fraction (HFpEF), associations of TFA blood levels with patient characteristics are unknown.MethodsThis is a secondary analysis of the Aldo-DHF-RCT. From 422 patients, individual blood TFA were analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were: 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E/e′ 7.1 ± 1.5; NT-proBNP 158 ng/L (IQR 82–298). A principal component analysis was conducted but not used for further analysis as cumulative variance for the first two PCs was low. Spearman’s correlation coefficients as well as linear regression analyses, using sex and age as covariates, were used to describe associations of whole blood TFA with metabolic phenotype, functional capacity, echocardiographic markers for LVDF and neurohumoral activation at baseline and after 12 months.ResultsBlood levels of the naturally occurring TFA C16:1n-7t were inversely associated with dyslipidemia, body mass index/truncal adiposity, surrogate markers for non-alcoholic fatty liver disease and inflammation at baseline/12 months. Conversely, IP-TFA C18:1n9t, C18:2n6tt and C18:2n6tc were positively associated with dyslipidemia and isomer C18:2n6ct with dysglycemia. C18:2n6tt and C18:2n6ct were inversely associated with submaximal aerobic capacity at baseline/12 months. No significant association was found between TFA and cardiac function.ConclusionsIn HFpEF patients, higher blood levels of IP-TFA, but not naturally occurring TFA, were associated with dyslipidemia, dysglycemia and lower functional capacity. Blood TFAs, in particular C16:1n-7t, warrant further investigation as prognostic markers in HFpEF.Graphical abstractHigher blood levels of industrially processed TFA, but not of the naturally occurring TFA C16:1n-7t, are associated with a higher risk cardiometabolic phenotype and prognostic of lower aerobic capacity in patients with HFpEF.

Altered Liver Function Test in Type 2 Diabetes Mellitus Subjects and its Association with Dyslipidaemia and Fasting Blood Sugar: A Cross-sectional Study

Introduction: Multiple organ systems are affected due to the metabolic dysregulation associated with Diabetes Mellitus (DM). Altered lipoprotein metabolism and liver enzymes have been identified as independent risk factors for the development of Cardiovascular Disease (CVD). Routine screening of liver function and ultrasound imaging of the liver should be done at the time of diagnosis of type 2 DM and thereafter at regular intervals. Aim: To determine the association between liver function parameters and glycemic status in type 2 diabetics. Additionally, the study aimed to correlate liver enzymes and lipid profiles in Type 2 DM patients. Materials and Methods: A cross-sectional study was conducted from August 23rd, 2021 to October 23rd, 2021 on 100 Type 2 diabetic patients attending the diabetic Outpatient Department of Biochemistry, at Annapoorana Medical College and Hospital, Salem, Tamil Nadu, India. Fasting glucose, total cholesterol, triglyceride, and High-Density Lipoprotein Cholesterol (HDL) were measured using the direct enzymatic method, while LowDensity Lipoprotein Cholesterol (LDL) was calculated using Friedewald’s formula. Total bilirubin, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), total protein, and albumin were analysed using the ERBA EM-200 auto analyser based-on the wet chemistry principle. Pearson’s correlation analysis was performed to examine the relationship between variables. Results: Among the total of 100 type 2 diabetic patients who participated in present study, 59 were males and 41 were females. The mean±SD age of diabetic patients was 51.23±10.810 years, ranging between 35 and 76 years. The frequency of altered liver enzymes in the study sample was found to be 33, with 25 being males and 8 being females. The mean fasting blood sugar levels with normal liver function and abnormal liver function were observed to be 128.37±13.16 mg/ dL and 133.79±15.68 mg/dL, respectively, but the difference was not statistically significant. The mean values of total cholesterol, triglyceride, and low-density lipoprotein with normal liver function were observed to be 137.18±34.44 mg/ dL, 175.12±65.19 mg/dL, and 75.55±9.78 mg/dL, respectively, while with abnormal liver function, they were observed to be 196.05±52.67 mg/dL, 143.28±47.63 mg/dL, and 138.83±38.11 mg/dL, respectively, showing statistical significance. Conclusion: The present study found a strong association between deranged liver enzymes with fasting blood sugar and dyslipidaemia.

Circulating Metabolites and Cardiovascular Disease in Asians with Chronic Kidney Disease

Introduction: Chronic kidney disease (CKD) is a growing public health problem, with significant burden of cardiovascular disease and mortality. The risk of cardiovascular disease in CKD is elevated beyond that predicted by traditional cardiovascular risk factors, suggesting that other factors may account for this increased risk. Through metabolic profiling, this study aimed to investigate the associations between serum metabolites and prevalent cardiovascular disease in Asian patients with CKD to provide insights into the complex interactions between metabolism, cardiovascular disease and CKD. Methods: This was a single-center cross-sectional study of 1,122 individuals from three ethnic cohorts in the population-based Singapore Epidemiology of Eye Disease (SEED) study (153 Chinese, 262 Indians, and 707 Malays) aged 40–80 years with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). Nuclear magnetic resonance spectroscopy was used to quantify 228 metabolites from the participants’ serum or plasma. Prevalent cardiovascular disease was defined as self-reported myocardial infarction, angina, or stroke. Multivariate logistic regression identified metabolites independently associated with cardiovascular disease in each ethnic cohort. Metabolites with the same direction of association with cardiovascular disease in all three cohorts were selected and subjected to meta-analysis. Results: Cardiovascular disease was present in 275 (24.5%). Participants with cardiovascular disease tend to be male; of older age; with hypertension, hyperlipidemia, and diabetes; with lower systolic and diastolic blood pressure (BP); lower high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol than those without cardiovascular disease. After adjusting for age, sex, systolic BP, diabetes, total cholesterol, and HDL cholesterol, 10 lipoprotein subclass ratios and 6 other metabolites were significantly associated with prevalent cardiovascular disease in at least one cohort. Meta-analysis with Bonferroni correction for multiple comparisons found that lower tyrosine, leucine, and valine concentrations and lower cholesteryl esters to total lipid ratio in intermediate-density lipoprotein (IDL) were associated with cardiovascular disease. Conclusion: In Chinese, Indian, and Malay participants with CKD, prevalent cardiovascular disease was associated with tyrosine, leucine, valine, and cholesteryl esters to total lipid ratios in IDL. Increased cardiovascular risk in CKD patients may be contributed by altered amino acid and lipoprotein metabolism. The presence of CKD and ethnic differences may affect interactions between metabolites in health and disease, hence greater understanding will allow us to better risk stratify patients, and also individualize care with consideration of ethnic disparities.

Obesity-Associated Dyslipidemia Is Moderated by Habitual Intake of Marine-Derived n-3 Polyunsaturated Fatty Acids in Yup’ik Alaska Native People: A Cross-Sectional Mediation-Moderation Analysis

BackgroundObesity leads to insulin resistance, altered lipoprotein metabolism, dyslipidemia, and cardiovascular disease. The relationship between long-term intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) and prevention of cardiometabolic disease remains unresolved. ObjectivesThe aim of this study was to explore direct and indirect pathways between adiposity and dyslipidemia, and the degree to which n-3 PUFAs moderate adiposity-induced dyslipidemia in a population with highly variable n-3 PUFA intake from marine foods. MethodsIn total, 571 Yup’ik Alaska Native adults (18–87 y) were enrolled in this cross-sectional study. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated objective measure of n-3 PUFA intake. EPA and DHA were measured in RBCs. Insulin sensitivity and resistance were estimated by the HOMA2 method. Mediation analysis was conducted to evaluate the contribution of the indirect causal path between adiposity and dyslipidemia mediated through insulin resistance. Moderation analysis was used to assess the influence of dietary n-3 PUFAs on the direct and indirect paths between adiposity and dyslipidemia. Outcomes of primary interest included plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), non-HDL-C, and triglycerides (TG). ResultsIn this Yup’ik study population, we found that up to 21.6% of the total effects of adiposity on plasma TG, HDL-C, and non-HDL-C are mediated through measures of insulin resistance or sensitivity. Moreover, RBC DHA and EPA moderated the positive association between waist circumference (WC) and TC or non-HDL-C, whereas only DHA moderated the positive association between WC and TG. However, the indirect path between WC and plasma lipids was not significantly moderated by dietary n-3 PUFAs. ConclusionsIntake of n-3 PUFAs may independently reduce dyslipidemia through the direct path resulting from excess adiposity in Yup’ik adults. NIR moderation effects suggest that additional nutrients contained in n-3 PUFA-rich foods may also reduce dyslipidemia.

Metabolomic profiling for dyslipidemia in pediatric patients with sickle cell disease, on behalf of the IHCC consortium

BackgroundPrevious study has shown that dyslipidemia is common in patients with Sickle cell disease (SCD) and is associated with more serious SCD complications.MethodsThis study investigated systematically dyslipidemia in SCD using a state-of-art nuclear magnetic resonance (NMR) metabolomics platform, including 147 pediatric cases with SCD and 1234 controls without SCD. We examined 249 metabolomic biomarkers, including 98 biomarkers for lipoprotein subclasses, 70 biomarkers for relative lipoprotein lipid concentrations, plus biomarkers for fatty acids and phospholipids.ResultsSpecific patterns of hypolipoproteinemia and hypocholesterolemia in pediatric SCD were observed in lipoprotein subclasses other than larger VLDL subclasses. Triglycerides are not significantly changed in SCD, except increased relative concentrations in lipoprotein subclasses. Decreased plasma FFAs (including total-FA, SFA, PUFA, Omega-6, and linoleic acid) and decreased plasma phospholipids were observed in SCD.ConclusionThis study scrutinized, for the first time, lipoprotein subclasses in pediatric patients with SCD, and identified SCD-specific dyslipidemia from altered lipoprotein metabolism. The findings of this study depict a broad panorama of lipid metabolism and nutrition in SCD, suggesting the potential of specific dietary supplementation of the deficient nutrients for the management of SCD.

The relationship between uric acid and dyslipidemia in type 2 diabetic patients with urolithiasis

Background and objective: Diabetes mellitus (DM) is characterized by insulin resistance which canincrease the risk of kidney stone formation. This study aimed to find out the association between serum levels of uric acid and lipid profile in DM patients with urolithiasis in comparison to those without. Methods: This cross-sectional study was conducted at P K Das institute of medical sciences,Vaniamkulam, Palakkad, Kerala, India with the approval of the institutional ethical review committee for human studies. A total of 60 patients were included in the study.Group A patients with DM and urolithiasis, and group B patients with DM but without urolithiasis. Biochemical parameters studied were glucose, urea, creatinine, uric acid, creatinine, serum uric acid to creatinine ratio, lipid profile, HbA1c, and triglyceride glucose index. Statistical analysis was done using SPSS version 21. Results: We found a significant increase in uric acid, urea, serum uric acid to creatinine ratio, and triglyceride glucose index levels in diabetic urolithiasis cases as compared to diabetes mellitus cases without urolithiasis. We also found that total cholesterol, triglycerides, LDL-C, and VLDL-C levels were significantly increased, and HDL-cholesterol was significantly decreased in diabetic urolithiasis cases. Serum uric acid was positively correlated with total cholesterol, triglycerides, LDL-C, and VLDL-C and negatively correlated with HDL-C in diabetic urolithiasis cases. Conclusions: From this study, it is demonstrated that patients with diabetic urolithiasis are having high insulin resistance, altered lipoprotein metabolism, and increased level of serum uric acid. The dyslipidemia components are strongly associated with increased uric acid.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease.

Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one’s predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.

Trans fatty acid blood levels and HFpEF phenotype: from the Aldo-DHF RCT

Abstract Background Prognosis in HFpEF is determined by risk factor control and treatment of comorbidities. Industrially processed TFA (IP-TFA) from partially hydrogenated oils have been linked to altered lipoprotein metabolism, endothelial dysfunction, increased biomarkers of inflammation and increased NTproBNP. In patients with heart failure with preserved ejection fraction (HFpEF), associations of TFA blood levels with patient characteristics are unknown. Purpose To evaluate associations of blood TFA with cardiovascular risk factors, aerobic capacity and cardiac function in patients with HFpEF. Methods This is a secondary analysis from the Aldo-DHF-RCT. From 422 patients, individual blood TFA were analyzed at baseline in n=404 using the HS-Omega-3-Index® methodology. Patient characteristics were; 67±8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥50%, E/e' 7.1±1.5; median NT-proBNP 158 ng/L (IQR 82–298). Multiple linear regression analyses, using sex and age as covariates, were used to describe associations of TFA with metabolic phenotype, functional capacity, echocardiographic markers for left ventricular diastolic function (LVDF), and neurohumoral activation at baseline and after 12-months-follow-up (12mFU). To account for randomization group, all analyses were repeated as sensitivity analysis with group as covariate. A significance level of α=5% was used for all tests. As all tests were hypothesis generating without confirmatory interpretation, no correction was applied to counteract the problem of multiple comparisons. Results Higher blood levels of the naturally occurring TFA C16:1n-7t were broadly associated with a more favorable lipid profile, lower body weight/central adiposity, lower white blood cell count and lower biochemical markers of non-alcoholic fatty liver disease at baseline/12mFU. Conversely, blood levels of the IP-TFA C18:1n9t were directly associated with lipid risk markers [triglycerides (β=19.7, p&amp;lt;0,001), non-HDL-C (β=7.9, p=0,001), and LDL-C (β=5.4, p=0,011)]. The two IP-TFA C18:2n6 isomers C18:2n6tt and C18:2n6ct were positively associated with HbA1c [(β=14.6, p=0,003) and (β=4.2, p=0,014) respectively]. The IP-TFA C18:2n6tt/-ct isomers were associated with lower submaximal aerobic capacity (distance covered in the 6MWT) at baseline/12mFU. No significant association was found between TFA blood levels and left ventricular filling pressures, left ventricular relaxation or neurohumoral activation. Significant effects of group allocation (spironolactone +/−) were found for the 12mFU outcomes systolic/diastolic blood pressure (all p&amp;lt;0.001), heart rate, E/e$'$ and HbA1c. Conclusions In HFpEF patients, higher blood levels of industrially processed TFA, but not of the TFA C16:1n-7t in full fat dairy and meat, were associated with a higher risk phenotype and lower aerobic capacity. Our findings support efforts to remove IP-TFA from the food supply for improving risk factor control in HFpEF patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Foundation of Heart Research

Genetic tuning of β-carotene oxygenase-1 activity rescues cone photoreceptor function in STRA6-deficient mice.

Rod and cone photoreceptors in the retina mediate dim light and daylight vision, respectively. Despite their distinctive functions, rod and cone visual pigments utilize the same vitamin A-derived chromophore. To sustain vision, vitamin A precursors must be acquired in the gut, metabolized, and distributed to the eyes. Deficiencies in this pathway in inherited ocular disease states deplete cone photoreceptors from chromophore and eventually lead to cell death, whereas the more abundant rod photoreceptors are less affected. However, pathways that support cone function and survival under such conditions are largely unknown. Using biochemical, histological, and physiological approaches, we herein show that intervention with β-carotene in STRA6-deficient mice improved chromophore supply to cone photoreceptors. Relieving the inherent negative feedback regulation of β-carotene oxygenase-1 activity in the intestine by genetic means further bolstered cone photoreceptor functioning in the STRA6-deficient eyes. A vitamin A-rich diet, however, did not improve cone photoreceptor function in STRA6-deficiency. We provide evidence that the beneficial effect of β-carotene on cones results from favorable serum kinetics of retinyl esters in lipoproteins. The respective alterations in lipoprotein metabolism maintained a steady supply of retinoids to the STRA6-deficient eyes, which ameliorated the competition for chromophore between rod and cone photoreceptors. Together, our study elucidates a cone photoreceptor-survival pathway and unravels an unexpected metabolic connection between the gut and the retina.

The Effects of a Mixture of Cadmium, Lead, and Mercury on Metabolic Syndrome and Its Components, as well as Cognitive Impairment: Genes, MicroRNAs, Transcription Factors, and Sponge Relationships : The Effects of a Mixture of Cadmium, Lead, and Mercury on Metabolic Syndrome and Its Components, as well as Cognitive Impairment: Genes, MicroRNAs, Transcription Factors, and Sponge Relationships.

Converging evidence indicates heavy metal-induced genes, transcription factors (TFs), and microRNAs (miRNAs) are critical pathological components of metabolic syndrome (MetS) and cognitive impairment. Thus, our goals are to identify the interaction of mixed heavy metals (cadmium + lead + mercury) with genes, TFs, and miRNAs involved in MetS and its components, as well as cognitive impairment development. The most commonly retrieved genes for each disease were different, but essential biological pathways such as oxidative stress, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, apoptosis, the IL-6 signaling pathway, and Alzheimer's disease were highlighted. The genes CASP3, BAX, BCL2, IL6, TNF, APOE, HMOX1, and IGF were found to be mutually affected by the heavy metal mixture studied, suggesting the importance of apoptosis, inflammation, lipid, heme, and glucose metabolism in MetS and cognitive impairment, as well as the potentiality of targeting these genes in prospective therapeutic intervention for these diseases. EGR2, ATF3, and NFE2L2 were noted as the most key TFs implicated in the etiology of MetS and its components, as well as cognitive impairment. We also found six miRNAs induced by studied heavy metals were the mutual miRNAs linked to MetS, its components, and cognitive impairment. In particular, we used miRNAsong to construct and verify a miRNA sponge sequence for these miRNAs. These sponges are promising molecules for the treatment of MetS and its components, as well as cognitive impairment.

Apolipoprotein A1 Enhances Endothelial Cell Survival in an In Vitro Model of ALS.

Altered lipoprotein metabolism is considered a pathogenic component of amyotrophic lateral sclerosis (ALS). Apolipoprotein A1 (ApoA1), a major high-density lipoprotein (HDL) protein, is associated with prevention of vascular damage. However, ApoA1’s effects on damaged endothelium in ALS are unknown. This study aimed to determine therapeutic potential of ApoA1 for endothelial cell (EC) repair under a pathologic condition reminiscent of ALS. We performed in vitro studies using mouse brain ECs (mBECs) exposed to plasma from symptomatic G93A SOD1 mice. Dosage effects of ApoA1, including inhibition of the phosphoinoside 3-kinase (PI3K)/Akt signaling pathway and integration of ApoA1 into mBECs were examined. Also, human bone marrow-derived endothelial progenitor cells (hBM-EPCs) and mBECs were co-cultured without cell contact to establish therapeutic mechanism of hBM-EPC transplantation. Results showed that ApoA1 significantly reduced mBEC death via the PI3K/Akt downstream signaling pathway. Also, ApoA1 was incorporated into mBECs as confirmed by blocked ApoA1 cellular integration. Co-culture system provided evidence that ApoA1 was secreted by hBM-EPCs and incorporated into injured mBECs. Thus, our study findings provide important evidence for ApoA1 as a potential novel therapeutic for endothelium protection in ALS. This in vitro study lays the groundwork for further in vivo research to fully determine therapeutic effects of ApoA1 in ALS.

The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease.

Both type 1 and type 2 diabetes are associated with an increased risk of atherosclerotic cardiovascular disease (CVD). Research based on human-first or bedside-to-bench approaches has provided new insights into likely mechanisms behind this increased risk. Although both forms of diabetes are associated with hyperglycemia, it is becoming increasingly clear that altered lipoprotein metabolism also plays a critical role in predicting CVD risk in people with diabetes. This review examines recent findings indicating that increased levels of circulating remnant lipoproteins could be a missing link between diabetes and CVD. Although CVD risk associated with diabetes is clearly multifactorial in nature, these findings suggest that we should increase efforts in evaluating whether remnant lipoproteins or the proteins that govern their metabolism are biomarkers of incident CVD in people living with diabetes and whether reducing remnant lipoproteins will prevent the increased CVD risk associated with diabetes.

Effect of glycated HDL on oxidative stress and cholesterol homeostasis in a human bladder cancer cell line, J82

Epidemiological studies suggest associations between diabetes mellitus (DM) andbladder cancer. Several potential mechanisms may explain the increased bladdercancer burden in DM patients. Hyperglycaemia is associated with dysregulation of cellintracellular metabolism and alterations of lipoprotein metabolism and oxidative stress.Dysfunctional HDL including glycated and oxidized HDL are described in DM. Weevaluated the effect of normal HDL (N-HDL) and glycated HDL (G-HDL) on cellproliferation and oxidative stress of J82 bladder cancer cells. We also studied the effectof HDL on cholesterol influx and efflux. In addition, the levels of proteins involvedin cholesterol transport (ABCA1, SRB1, ABCG1) by western blot analysis were studied.Our results demonstrate that N-HDL and G-HDL promote cell proliferation and increase intracellular reactive oxygen species (ROS) levels triggered by incubation of tert-butylhydroperoxide. The increase of intracellular ROS in cells preincubated with G-HDL was associated to higher levels of TBARS in cells compared to N-HDL. Cholesterol efflux wasincreased, on the contrary cholesterol influx was significantly decreased in cellsincubated with G-HDL with respect to cells incubated with N-HDL. Levels of SR-B1 and ABCG1 was increased in cells incubated with G-HDL, suggestingthat dysfunctional HDL could affect cholesterol homeostasis in J82 cells. These resultssuggest that HDL-based treatments should be considered for treatment of urinary bladder cancer.

Anorexia Nervosa Is Associated with a Shift to Pro-Atherogenic Low-Density Lipoprotein Subclasses.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.

Increased Cholesteryl Ester Transfer Protein and Lipoprotein-Associated Phospholipase A2 Activities in Children and Adolescents Presenting High Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio.

To explore the association between Triglyceride/High-density lipoprotein cholesterol (TG/HDL-C) index and these enzymes and proteins in a pediatric population. Children and adolescents (7-14 y old) were recruited (n = 150) and anthropometric data were registered. Glucose, TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C plus cholesteryl ester transfer protein (CETP), lipoprotein-associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1) activities were determined. Twenty-five individuals presented TG/HDL-C ratio ≥ 3.0. These individuals exhibited higher TG [164 (126-186) vs. 65 (48-72) mg/dL; p < 0.01] CETP [250 (232-263) vs. 223 (193-237)% mL/min; p < 0.01] and Lp-PLA2 (4.5 ± 1.9 vs. 3.5 ± 1.3; p < 0.05) plus lower HDL-C [41 (37-49) vs. 52 (48-62) mg/dL; p < 0.01] compared to an age-matched group with TG/HDL-C < 3.0. TG/HDL-C ratio was associated to CETP (p < 0.01) and Lp-PLA2 (p < 0.05). Multiple lineal regression analyses showed TG/HDL-C index as an independent predictor of CETP (r2 = 0.29; beta = 0.49; p < 0.01) and Lp-PLA2 (r2 = 0.21; beta = 0.32; p < 0.05) activities. Children and adolescents with TG/HDL-C ≥ 3.0 presented a more atherogenic lipid profile and higher CETP and Lp-PLA2 activities, which would indicate alterations in lipoprotein metabolism and quality.