Low HDL-C/ApoA-I index is associated with cardiometabolic risk factors and coronary artery calcium: a sub-analysis of the genetics of atherosclerotic disease (GEA) study.

BACKGROUND: The high-density lipoprotein cholesterol to apolipoprotein A-I index (HDL-C/ApoA-I) may be practical and useful in clinical practice as a marker of atherosclerosis. This study aimed to investigate the association between the HDL-C/ApoA-I index with cardiometabolic risk factors and subclinical atherosclerosis. METHODS: In this cross-sectional sub-analysis of the GEA study, 1,363 individuals, women (51.3%) and men (48.7%) between 20 and 75 years old, without coronary heart disease or diabetes mellitus were included. We defined an adverse cardiometabolic profile as excess adipose tissue metrics, non-alcoholic liver fat measured by non-contrasted tomography, metabolic syndrome, dyslipidemias, and insulin resistance. The population was stratified by quartiles of the HDL-C/Apo-AI index, and its dose-relationship associations were analysed using Tobit regression, binomial, and multinomial logistic regression analysis. RESULTS: Body mass index, visceral and pericardial fat, metabolic syndrome, fatty liver, high blood pressure, and CAC were inversely associated with the HDL-C/ApoA-I index. The CAC > 0 prevalence was higher in quartile 1 (29.2%) than in the last quartile (22%) of HDL-C/ApoA-I index (p = 0.035). The probability of having CAC > 0 was higher when the HDL-C/ApoA-I index was less than 0.28 (p < 0.001). This association was independent of classical coronary risk factors, visceral and pericardial fat measurements. CONCLUSION: The HDL-C/ApoA-I index is inversely associated with an adverse cardiometabolic profile and CAC score, making it a potentially useful and practical biomarker of coronary atherosclerosis. Overall, these findings suggest that the HDL-C/ApoA-I index could be useful for evaluating the probability of having higher cardiometabolic risk factors and subclinical atherosclerosis in adults without CAD.

Association of hyperuricemia with apolipoprotein AI and atherogenic index of plasma in healthy Chinese people: a cross-sectional study.

BACKGROUND: The atherogenic index of plasma (AIP) is a predictor for cardiovascular diseases (CVD), while hyperuricemia is an independent risk factor for a variety of CVD. Apolipoprotein AI has been found to be a protective factor for CVD. However, the role of APO AI in the association between plasma uric acid and AIP among healthy Chinese people needs to be further explored. AIMS: To evaluate the relationship between blood uric acid and AIP level in healthy Chinese people. To evaluate the relationship between blood uric acid and Apolipoprotein AI in healthy Chinese people. METHOD: A total of 3501 normal and healthy subjects who had physical examinations were divided into the hyperuricemia (HUA) group and the normouricemia (NUA) group. RESULT: The AIP of HUA group was significantly higher than that of NUA group [0.17±0.30 vs. -0.08±0.29]. Apo AI (1.33 ± 0.21 vs. 1.47 ± 0.26 g/l) and HDL-c (1.12 ± 0.27 vs. 1.36 ± 0.33 mmol/l) were significantly lower in the HUA group than in the NUA group. LDL-C (2.81 ± 0.77 vs. 2.69 ± 0.73 mmol/l), Apo B (0.96 ± 0.20 vs. 0.89 ± 0.20 g/l), FBG (5.48 ± 0.48 vs. 5.36 ± 0.48 mmol/l) and HOMA-IR [2.75 (1.92-3.91) vs. 2.18 (1.50-3.12)] was significantly higher in HAU group than the NUA group. Increases in plasma UA were associated with increases in AIP (ß = 0.307, p < 0.01) and decreases in Apo AI (ß = - 0.236, p < 0.01). CONCLUSION: Hyperuricemia is an independent risk factor for high AIP level. Inhibition of Apolipoprotein AI may be one of the mechanisms of UA which is involved in the progression of cardiovascular disease.

Serum apolipoprotein B/apolipoprotein A1 ratio in relation to intervertebral disk herniation: a cross-sectional frequency-matched case-control study.

STUDY DESIGN: This was a cross-sectional frequency-matched case-control study. BACKGROUND AND AIM: The serum lipid profile of lipoprotein(a) [Lp(a)] level and apolipoprotein B/apolipoprotein A1 ratio (Apo B/Apo A1) ratio were found to be more representative for serum lipid level and were recognized as the independent risk factors for various diseases. Although the blood levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were found to be associated with symptomatic intervertebral disk herniation (IDH), no studies to date have evaluated the association of Apo AI, Apo B, Lp(a), and Apo B/Apo AI levels with symptomatic IDH. This study aimed to assess the link between blood lipid levels and symptomatic IDH. METHOD: The study included 1839 Chinese patients. Of these, 918 patients were diagnosed with IDH and enrolled in the experimental group. A control group of 921 patients underwent a physical examination during the same period. The serum lipid levels of TC, TG, LDL-C, HDL-C, Lp(a), Apo B, and Apo B/Apo AI were examined and analyzed. The control group comprised randomly selected patients who met the baseline levels of the aforementioned lipid molecules. RESULTS: Patients with IDH exhibited significantly higher TC, TG, LDL, Apo B, and Lp(a) levels than controls. The percentage of high TC, high TG, high LDL, high Apo B, and high Lp(a) were obviously higher in the IDH group than in the control group. However, hyperlipidemia had no relationship with the degenerated segment of the IDH (P = 0.201). The odds ratio (OR) for the incidence of IDH with elevated levels of LDL-C, TC, TG, Lp(a), Apo B, and Apo B/Apo AI was 1.583, 1.74, 1.62, 1.58, 1.49, and 1.39, respectively. The correlation analysis revealed the correlation between elevated LDL-C, TC, TG, Apo B, Lp(a), and incidence of IDH was significant (R2LDL = 0.017; R2TC = 0.004; R2TG = 0.015; R2Apo B = 0.004; R2Lp(a) = 0.021) (P < 0.05). CONCLUSION: This study suggested that elevated levels of serum TC, TG, LDL, Apo B, Lp(a), and Apo B/Apo AI were associated with a higher risk of IDH. This study provided useful information to identify a population that might be at risk of developing IDH based on elevated lipid levels.

Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics.

Cholesterol is a foundational molecule of biology. There is a long-standing interest in understanding how cholesterol metabolism is intertwined with cancer biology. In this review, we focus on the known connections between lung cancer and molecules mediating cholesterol efflux. A major take-home lesson is that the roles of many cholesterol efflux factors remain underexplored. It is our hope that this article would motivate others to investigate how cholesterol efflux factors contribute to lung cancer biology.

Importance of lipid ratios for predicting intracranial atherosclerotic stenosis.

BACKGROUND: This study aims to investigate the association of lipid ratios with intracranial atherosclerotic stenosis (ICAS) in a Chinese population. METHODS: This cross-sectional study included 658 consecutive patients with ischemic stroke. Intracranial and extracranial arteries were evaluated for atherosclerotic stenosis using digital subtraction angiography or computed tomography angiography. Lipid ratios [total cholesterol (TC)/high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG)/HDL-C, low-density lipoprotein-cholesterol (LDL-C)/HDL-C, non-high-density lipoprotein-cholesterol (non-HDL-C)/HDL-C, remnant cholesterol (RC)/HDL-C, apolipoprotein B (apo B)/apolipoprotein A-I (apo A-I), and apo B/HDL-C] were calculated. RESULTS: The TC/HDL-C, LDL-C/HDL-C, RC/HDL-C, non-HDL-C/HDL-C, apo B/HDL-C and apo B/apo A-I ratios (all P < 0.05) were significantly associated with ICAS but not with extracranial atherosclerotic stenosis after adjustment for confounding factors. Receiver operating characteristic (ROC) curves analysis revealed that the apo B/apo A-I ratio had the largest area under the ROC curve (AUC) among lipid levels alone and for lipid ratios (AUC = 0.588). Lipid ratios had higher AUC values than those for lipid levels alone for the identification of ICAS. CONCLUSION: The TC/HDL-C, LDL-C/HDL-C, RC/HDL-C, non-HDL-C/HDL-C apo B/HDL-C, and apo B/apo A-I ratios were significantly related to ICAS risk. Compared with the other variables tested, the apo B/apo A-I ratio appeared to be a better discriminator for identifying ICAS risk in stroke patients.

D-4F, an apolipoprotein A-I mimetic, suppresses IL-4 induced macrophage alternative activation and pro-fibrotic TGF-ß1 expression.

Context: We reported that D-4F, an apolipoprotein A-I (Apo A-I) mimetic polypeptide with 18 d-amino acids, suppressed IL-4 induced macrophage alternative activation and TGF-ß1 expression in phorbol 12-myristate 13-acetate (PMA) treated human acute monocytic leukemia cells (THP-1). Objective: Macrophage alternative activation, TGF-ß1 and epithelial-mesenchymal transition (EMT) are intensively involved in pulmonary fibrosis. Recent studies demonstrated that Apo A-I resolved established pulmonary fibrotic nodules, and D-4F inhibited TGF-ß1 induced EMT in alveolar cells. Therefore, this study evaluated the effects of D-4F on IL-4 induced macrophage alternative activation and TGF-ß1 expression. Materials and methods: THP-1 cells were simulated with PMA (100 ng/mL) for 48 h and treated with medium control, IL-4 (20 ng/mL) alone, or IL-4 (20 ng/mL) in the presence of D-4F (1, 5, and 10 µg/mL) for 24 and 48 h. Flow cytometry, RT-PCR and ELISA evaluations were performed to investigate the subsequent effects of D-4F. Results: Compared to stimulation with IL-4 alone, 1, 5, and 10 µg/mL of D-4F reduced alternative activation by 45.38%, 59.98%, and 60.10%, increased TNF-α mRNA levels by 8%, 11%, and 16% and decreased TGF-ß1 mRNA levels by 21%, 37%, and 39%, respectively (all p ≤ 0.05). In addition, TNF-α protein levels increased from 388 pg/mL (IL-4 alone) to 429, 475, and 487 pg/mL (1, 5, and 10 µg/mL D-4F), while TGF-ß1 protein levels dropped from 27.01 pg/mL (IL-4 alone) to 19.15, 12.27, and 10.47 pg/mL (1, 5, and 10 µg/mL D-4F). Conclusion: D-4F suppressed IL-4 induced macrophage alternative activation and pro-fibrotic TGF-ß1 expression.

Role of LCAT and Apo A-I in Newly Diagnosed HIV Patients.

Human immunodeficiency virus (HIV) infection is a growing concern for health workers. The two major components of dyslipidemia in HIV infected patients are hypertriglyceridemia and decreased levels of high density lipoprotein (HDL) which contribute to increased atherosclerotic risk. The study included 150 newly diagnosed HIV patients and 150 healthy controls. In all these cases Lecithin cholesterol acyl transferase (LCAT) activity was assessed by measuring the difference between esterified and free cholesterol by digitonin precipitation method and levels of Apolipoprotein A-I (apo A-I) were measured by immunoturbidimetric method. There was a significantly decreased LCAT activity (p < 0.05) as well as reduced levels of apo A-I (p < 0.05) in newly diagnosed HIV patients (54.98 ± 3.44 IU/L and 131.85 ± 8.49 mg/dl) when compared with healthy controls (88.17 ± 14.36 IU/L and 187.05 ± 35.25 mg/dL). A significant positive correlation (r = 0.7406) was found between LCAT activity and apo A-I levels. In conclusion decreased LCAT activity and decreased levels of apo A-I reduce the reverse cholesterol transport in newly diagnosed HIV patients which may lead to atherosclerosis in the future.

Quantifying protein measurands by peptide measurements: where do errors arise?

Clinically actionable quantification of protein biomarkers by mass spectrometry (MS) requires analytical performance in concordance with quality specifications for diagnostic tests. Laboratory-developed tests should, therefore, be validated in accordance with EN ISO 15189:2012 guidelines for medical laboratories to demonstrate competence and traceability along the entire workflow, including the selected standardization strategy and the phases before, during, and after proteolysis. In this study, bias and imprecision of a previously developed MS method for quantification of serum apolipoproteins A-I (Apo A-I) and B (Apo B) were thoroughly validated according to Clinical and Laboratory Standards Institute (CLSI) guidelines EP15-A2 and EP09-A3, using 100 patient sera and either stable-isotope labeled (SIL) peptides or SIL-Apo A-I as internal standard. The systematic overview of error components assigned sample preparation before the first 4 h of proteolysis as major source (∼85%) of within-sample imprecision without external calibration. No improvement in imprecision was observed with the use of SIL-Apo A-I instead of SIL-peptides. On the contrary, when the use of SIL-Apo A-I was combined with external calibration, imprecision improved significantly (from ∼9% to ∼6%) as a result of the normalization for matrix effects on linearity. A between-sample validation of bias in 100 patient sera further supported the presence of matrix effects on digestion completeness and additionally demonstrated specimen-specific biases associated with modified peptide sequences or alterations in protease activity. In conclusion, the presented overview of bias and imprecision components contributes to a better understanding of the sources of errors in MS-based protein quantification and provides valuable recommendations to assess and control analytical quality in concordance with the requirements for clinical use.

Relationship of high leptin levels with an adverse lipid and insulin profile in 6-8 year-old children in Spain.

BACKGROUND AND AIMS: Leptin, an adipokine elevated in obesity, may be related to an adverse cardiovascular risk profile in childhood. However, evidence for this relationship in pre-pubertal children is scarce. We aimed to analyze the relationship between leptin levels and lipid and insulin profiles in Spanish children. METHODS AND RESULTS: Our population-based sample included 389 males and 369 females aged 6-8 years. Lipid levels were determined by standard methods, insulin by radioimmunoassay and leptin by sandwich ELISA. Leptin levels were higher in girls (8.6 ng/ml) than boys (4.7 ng/ml) (p < 0.001). Leptin increased from ages 6 to 8 in girls, but remained steady in boys. In both sexes, leptin increased significantly (p < 0.001) across weight category from normal weight to obese. Children in the highest tertile of leptin concentration showed significantly (p < 0.01) lower levels of HDL-cholesterol (HDL-C) and apolipoprotein-AI (apo-AI) and significantly higher triglyceride (TG) levels than children in lower tertiles. However, in linear regression analysis, after adjustment for body mass index (BMI), leptin only accounted for 1.5% of the variance of HDL-C in boys, and 2.6% of the variance of apo-AI in girls. Leptin was strongly and positively correlated with insulin and HOMA. Upon regression analysis, leptin contributed to over 20% of the variability in insulin and HOMA, independent of BMI. CONCLUSION: Leptin levels show sex differences in pre-pubertal children. In this age group, leptin levels are strongly related to insulin, and affect lipid profile -namely HDL-C, apo-AI and TG- particularly when leptin levels are high.

A decreased level of high-density lipoprotein is a possible risk factor for type 2 diabetes mellitus: A review.

Introduction: Type 2 diabetes mellitus (T2DM) is characterized primarily by dyslipidemia and hyperglycemia due to insulin resistance. High-density lipoprotein (HDL) play a significant role in preventing the incidence of dyslipidemia and its complications. HDL has different protective functions, such as reducing oxidation, vascular inflammation, and thrombosis; additionally, its anti-diabetic role is one of the most significant recent discoveries about HDL and some of its constituent lipoproteins. Methods: This research reviews ongoing studies and preliminary investigations into the assessment of relation between decreased level of HDL and T2DM. Results: The levels of HDL and its functions contribute to glucose hemostasis and the development of T2DM through four possible mechanisms, including insulin secretion by beta cells, peripheral insulin sensitivity, non-insulin-dependent glucose uptake, and adipose tissue metabolic activity. Additionally, the anti-oxidant properties of HDL protect beta cells from apoptosis caused by oxidative stress and inflammation induced by low-density lipoprotein, which facilitate insulin secretion. Conclusion: Therefore, HDL and its compositions, especially Apo A-I, play an important role in regulating glucose metabolism, and decreased levels of HDL can be considered a risk factor for DM. Different factors, such as hypoalphalipoproteinemia that manifests as a consequence of genetic factors, such as Apo A-I deficiency, as well as secondary causes arising from lifestyle choices and underlying medical conditions that decrease the level of HDL, could be associated with DM. Moreover, intricate connections between HDL and diabetic complications extend beyond glucose metabolism to encompass complications like cardiovascular disease and kidney disease. Therefore, the exact interactions between HDL level and DM should be evaluated in future studies.

Regulating the Size of Simvastatin-loaded Discoidal Reconstituted Highdensity Lipoprotein: Preparation, Characterization, and Investigation of Cellular Cholesterol Efflux.

BACKGROUND: Reverse cholesterol transportation is essential for high-density lipoprotein (HDL) particles to reduce the cholesterol burden of peripheral cells. Studies have shown that particle size plays a crucial role in the cholesterol efflux capacity of HDLs, and the reconstituted HDLs (rHDLs) possess a similar function to natural ones. OBJECTIVE: The study aimed to investigate the effect of particle size on the cholesterol efflux capacity of discoidal rHDLs and whether drug loadings may have an influence on this effect. METHODS: Different-sized simvastatin-loaded discoidal rHDLs (ST-d-rHDLs) resembling nascent HDL were prepared by optimizing key factors related to the sodium cholate of film dispersion-sodium cholate dialysis method with a single controlling factor. Their physicochemical properties, such as particle size, zeta potential, and morphology in vitro, were characterized, and their capacity of cellular cholesterol efflux in foam cells was evaluated. RESULTS: We successfully constructed discoidal ST-d-rHDLs with different sizes (13.4 ± 1.4 nm, 36.6 ± 2.6 nm, and 68.6 ± 3.8 nm) with over 80% of encapsulation efficiency and sustained drug release. Among them, the small-sized ST-d-rHDL showed the strongest cholesterol efflux capacity and inhibitory effect on intracellular lipid deposition in foam cells. In addition, the results showed that the loaded drug did not compromise the cellular cholesterol efflux capacity of different-sized ST-d-rHDL. CONCLUSION: Compared to the larger-sized ST-d-rHDLs, the small-sized ST-d-rHDL possessed enhanced cellular cholesterol efflux capacity similar to drug-free one, and the effect of particle size on cholesterol efflux was not influenced by the drug loading.

Sex-Dependent Mediation of Leptin in the Association of Perilipin Polymorphisms with BMI and Plasma Lipid Levels in Children.

Variations in the perilipin (PLIN) gene have been suggested to be associated with obesity and its related alterations, but a different nutritional status seems to contribute to differences in these associations. In our study, we examined the association of several polymorphisms at the PLIN locus with obesity and lipid profile in children, and then analyzed the mediation of plasma leptin levels on these associations. The single-nucleotide polymorphisms (SNPs) rs894160, rs1052700, and rs2304795 in PLIN1, and rs35568725 in PLIN2, were analyzed by RT-PCR in 1264 children aged 6-8 years. Our results showed a contrasting association of PLIN1 rs1052700 with apolipoprotein (Apo) A-I levels in boys and girls, with genotype TT carriers showing significantly higher Apo A-I levels in boys and significantly lower Apo A-I levels in girls. Significant associations of the SNP PLIN2 rs35568725 with high-density lipoprotein cholesterol (HDL-cholesterol), Apo A-I, and non-esterified fatty acids (NEFA) were observed in boys but not in girls. The associations of the SNPs studied with body mass index (BMI), NEFA, and Apo A-I in boys and girls were different depending on leptin concentration. In conclusion, we describe the mediation of plasma leptin levels in the association of SNPs in PLIN1 and PLIN2 with BMI, Apo A-I, and NEFA. Different leptin levels by sex may contribute to explain the sex-dependent association of the PLIN SNPs with these variables.

The Effects of Calorie Restriction and Time-Restricted Feeding on IGF1 Serum Level and Lipid Profile in Male Wister Rats with Previous Obesity.

BACKGROUND: Calorie restriction (CR) is known as a nutritional gold standard for life extension and different studies have shown that insulin-like growth factor (IGF1) reduction through CR may be involved in CR's anti-aging effects. Besides, time-restricted-feeding (TRF) is also highlighted due to more feasibility and positive health effects. We designed this study to compare the effects of CR and TRF on IGF1 and other metabolic parameters. METHODS: Fifty-two male Wistar rats (3 weeks old) were subjected to either a control (CON, n = 11) diet or high-fat diet (HFD, n = 42) for 17 weeks. In the second phase of the study, the HFD group were divided into four groups (n = 9) 1) 30% CR, 2) Night Intermittent Fasting (NIF, active phase), 3) day intermittent fasting (DIF, rest phase), and 4) Ad-Libitum (AL) with a standard diet for 10 weeks. Blood samples were collected at the end of both phases. RESULTS: HFD increased IGF1 and deteriorated lipid profiles, except for triglycerides (P: 0.018, 0.008.0.012, 0.032) but CR in these obese subjects could not lower the IGF1 level. HDL significantly decreased in DIF compared to CON and CR (P; 0.001). Meanwhile, HOMA-IR increased in DIF and was significant compared to CR (P: 0.002). Serum glucose levels decreased in CR compared to all groups except for CON (P: 0.001). CONCLUSION: Data indicates the role of previous obesity on the effect of CR on the IGF1 level and highlights the effect of inappropriate time of food intake on HDL and APOA1.

The Prognostic Impact of Preoperative Serum Apolipoprotein A-I in Patients with Esophageal Basaloid Squamous Cell Carcinoma.

BACKGROUND: Esophageal basaloid squamous cell carcinoma (EBSCC) is a rare malignancy. Serum apolipoprotein A-I (APO A-I) has proved to be a potentially useful prognostic indicator in various cancers. However, no studies have analyzed the prognostic significance of serum APO A-I in patients with EBSCC. The aim of this study was to investigate the prognostic impact of preoperative serum APO A-I in patients with EBSCC. METHODS: Between 2007 and 2018, a retrospective study of 4050 patients with resectable esophageal squamous cell carcinoma (ESCC) including the levels of preoperative serum lipids was conducted and evaluated. The best cut-off values of the preoperative serum lipids were evaluated by receiver operating characteristic (ROC) curves. Kaplan-Meier analyses and Cox regression analyses were analyzed the overall survival (OS) and recurrence-free survival (RFS). A prediction model of nomogram was developed to predict individual OS and RFS in EBSCC. RESULTS: There were 53 patients enrolled in the study, which accounted for 1.31% (53/4050) of all primary ESCC. The best cut-off point was 1.305 g/L for serum APO A-I according to the ROC curve. Patients with lower levels of serum preoperative APO A-I were associated with worse RFS (16.1% vs 54.5%, P = 0.006) and OS (29.0% vs 63.6%, P = 0.010). The results indicated that serum APO A-I serves as an independent predictor in patients with EBSCC regarding OS [hazard ratio (HR): 0.352; 95% confidence interval (CI): 0.154-0.808; P = 0.014] and RFS (HR: 0.397; 95% CI: 0.185-0.850; P = 0.017). CONCLUSION: Preoperative serum APO A-I is an independent predictor regarding OS and RFS in EBSCC. As far as we know, this is the first study in EBSCC to explore the serum APO A-I in patients with EBSCC.

The Proteins Interacting with Prmt5 in Medaka (Oryzias latipes) Identified by Yeast Two-Hybridization.

BACKGROUND: Prmt5 plays major role in regulation of gene expression, RNA processing, cell growth and differentiation, signal transduction, germ cell development, etc., in mammals. Prmt5 is also related to cancer. Knowing the proteins interacting with Prmt5 is important to understand Prmt5's function in cells. Although there have been reports on proteins binding with Prmt5 in mammals, the partner proteins of Prmt5 in fish are still unclear. OBJECTIVES: The objective was to obtain proteins that bind with Prmt5 in medaka, a model fish. METHODS: Yeast two hybridization was adopted to achieve the objective. Medaka Prmt5 was used as a bait to fish the prey, binding proteins in a cDNA library of medaka. Co-immunoprecipitation and in silicon analysis were performed to study the interaction of medaka Mep50 and Prmt5. RESULTS: Eight proteins were identified to bind with Prmt5 from 69 preliminary positive colonies. The binding proteins are methylosome protein 50 (Mep50), apolipoprotein A-I-like (Apo-AI), PR domain containing protein 1a with zinc fingers (Prdm1a), Prdm1b, T-cell immunoglobulin mucin family member 3 (Tim-3), phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (Paics), NADH dehydrogenase subunit 4 (ND4) and sciellin (Scl). Co-immunoprecipitation confirmed the interaction of medaka Prmt5 and Mep50. Predicted structures of medaka Prtm5 and Mep50 are similar to that of human PRMT5 and MEP50. CONCLUSION: Medaka Mep50, Prdm1a, Prdm1b, Apo-AI, Tim-3, Paics, ND4, and Scl bind with Prmt5.

Solid-state NMR structural investigations of peptide-based nanodiscs and of transmembrane helices in bicellar arrangements.

The membrane topology of the peptide 18A, a derivative of apolipoprotein A-I, is investigated in structural detail. Apolipoprotein A-I is the dominant protein component of high density lipoproteins with important functions in cholesterol metabolism. 18A (Ac-DWLKA FYDKV AEKLK EAF- NH2) was designed to mimic the structure of tandem domains of class A amphipathic helices and has served as a lead peptide for biomedical applications. At low peptide-to-lipid ratios 18A partitions into phosphatidylcholine membranes with helix topologies parallel to the membrane surface, an alignment that is maintained when disc-like bicelles form at higher peptide-to-lipid ratios. Notably, the bicelles interact cooperatively with the magnetic field of the NMR spectrometer, thus the bilayer normal is oriented perpendicular to the magnetic field direction. A set of peptides that totals four 15N or 2H labelled positions of 18A allowed the accurate analysis of tilt and azimuthal angles relative to the membrane surface under different conditions. The topology agrees with a double belt arrangement forming a rim that covers the hydrophobic fatty acyl chains of the bicelles. In another set of experiments, it was shown that POPC nanodiscs prepared in the presence of diisobutylene/maleic acid (DIBMA) polymers can also be made to align in the magnetic field. Finally, the transmembrane domains of the DQ alpha-1 and DQ beta-1 subunits of the major histocomptability complex (MHC) class II have been prepared and reconstituted into magnetically oriented bicelles for NMR structural analysis.

Association of Glycated Haemoglobin and Serum Apolipoproteins with Diabetic Retinopathy: An Indian Overview.

INTRODUCTION: India is presently facing an epidemic of diabetes mellitus and the risks of chronic complications from the disease are associated with the duration of the disease as well as the degree of hyperglycaemia. Diabetic retinopathy is a known microvascular complication of diabetes mellitus and is the most common cause of blindness in the western countries.Apolipoproteins are the protein component of lipoproteins. Apart from acting as structural proteins, they also act as cofactors to various enzymes. AIM: To measure the levels of serum apolipoproteins and glycated haemoglobin in cases of diabetic retinopathy and to assess their association with the stages of diabetic retinopathy. MATERIAL AND METHODS: The 135 diabetic cases [with (110) and without (125) retinopathy] attending the Ophthalmology OPD of this tertiary care hospital were included in the present study. Following retinoscopy, the patients were classified as Non-Proliferative Diabetic Retinopathy (NPDR) (n=75) and Proliferative Diabetic Retinopathy (PDR) (n=35). The controls (n=100) were age and sex matched patients who did not have diabetes. The cases and controls were assessed for HbA1c, total cholesterol, triglycerides, HDL cholesterol, Apo A-I and Apo B-100. RESULTS: The HbA1c was found to be higher in diabetics without retinopathy (7.02%) as compared to controls (5.58%) (p<0.05) and the highest value was seen in the mild NPDR group (8.82%). The mean value of Apo A-I was found to be lowest in the diabetics without retinopathy at 88 mg/dl and the highest in severe NPDR at 167 mg/dL. The mean value of Apo B-100 was found to be highest in severe NPDR at 114 mg/dL. The mean value of HDL cholesterol was lowest in moderate NPDR at 36.6 mg/dl. Total cholesterol was highest in severe NPDR at 280.88mg/dl while triglyceride was highest in severe NPDR at 286.4mg/dl. CONCLUSION: In our study, the level of HbA1c was found to range from 5.58% in non-diabetic to 8.82% in mild NPDR. There was a clear association between Apo B-100 and total cholesterol, triglycerides with the highest value of each parameter seen in the severe NPDR group. There was a discordance noted in the levels of HDL and Apo A-I in various groups. Apo B-100 values may be of value in prognosis of diabetic retinopathy as higher values may result in progression of the disease. Further studies involving Lp(a) and homocysteine may be required in cases of diabetic retinopathy.

Association of serum lipids and coronary artery disease with polymorphisms in the apolipoprotein AI-CIII-AIV gene cluster.

Genetic variants are considered as one of the main determinants of the concentration of serum lipids and coronary artery disease (CAD). Polymorphisms in the Apolipoprotein (Apo) AI-CIII-AIV gene cluster has been known to affect the concentrations of various lipid sub-fractions and the risk of CAD. The present study assessed associations between polymorphisms of the Apo AI-CIII-AIV gene cluster, [ApoA-I,-75G > A, (rs1799837); ApoC-III 3238C > G, (SstI), (rs5128) and ApoA-IV, Thr347Ser(347A > T), (rs675)] with serum lipids and their contributions to CAD in North Indian population. We recruited age, sex matched, 200 CAD patients and 200 healthy controls and tested them for fasting levels of serum lipids. We genotyped selected polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. There were no statistically significant association of selected polymorphisms (or their combinations) with CAD even after employing additive, dominant and recessive models. However there was significant association of selected polymorphisms with various lipid traits amongst the control cohort (p < 0.05). Mean levels of high density lipoprotein cholesterol and triglycerides were found to be significantly higher among controls carrying at least one mutant allele at ApoA1-75G > A (p = 0.019) and ApoCIII SstI (p < 0.001) polymorphism respectively. Our study observed that the selected polymorphisms in the ApoAI-CIII-AIV gene cluster although significantly affect various lipid traits but this affect does not seem to translate into association with CAD, at least among North Indian population.

Atorvastatin and fenofibrate combination induces the predominance of the large HDL subclasses and increased apo AI fractional catabolic rates in New Zealand white rabbits with exogenous hypercholesterolemia.

The anti-atherogenic properties of high-density lipoproteins (HDLs) may be related to their structure and metabolism. The HDL physicochemical characteristics that determine their plasma clearance during treatment with statins and fibrates are not well understood. In this study, we analyzed HDL-apo AI fractional catabolic rates (FCRs), size distributions, and the lipid composition of the HDL subclasses in New Zealand white rabbits with exogenous dyslipidemia that received low doses of atorvastatin and fenofibrate. Hypercholesterolemia decreased only partially with the combination of both drugs. HDL size distribution shifted toward larger particles among the groups of rabbits that received atorvastatin, fenofibrate, or their combination, compared with both the control group and the dyslipidemic group. The HDL subclasses were significantly rich in cholesterol in each of the groups compared with controls. The structural changes noted in the HDL subclasses were not associated with impaired plasma paraoxonase-1 (PON1) activity. The groups receiving monotherapy and the drug combination group were all associated with a higher apo AI FCR value compared with both the dyslipidemic rabbits and the control group. In conclusion, the combination of atorvastatin and fenofibrate induced a more favorable HDL subclass profile than did the individual use of these drugs. Similarly, the apo AI FCR values were augmented in every group receiving drug treatment (either monotherapy or combination therapy) in the setting of hypercholesterolemia. The anti-atherogenic properties of HDLs, excluding their capacity to bind PON1, may be enhanced by the structural and metabolic modifications induced by the combination of atorvastatin and fenofibrate.

Screening and identification of apolipoprotein A-I as a potential hepatoblastoma biomarker in children, excluding inflammatory factors.

The aim of the present study was to identify a child hepatoblastoma serum biomarker that is unaffected by inflammatory factors, with the ultimate aim of finding an effective method for the early diagnosis of hepatoblastoma. The magnetic bead-based weak cation exchange chromatography technique was used to process serum harvested from 30 children with hepatoblastoma, 20 children with systemic inflammatory response syndrome (SIRS) and 20 healthy children. Proteins differentially expressed in SIRS were excluded from consideration as biomarkers for hepatoblastoma. Proteins differentially expressed in hepatoblastoma and healthy controls were screened using surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS). Target proteins were purified by SDS-PAGE, and matrix-assisted laser desorption/ionization (MALDI)-TOF-MS was used to determine their amino acid sequences. Protein matches were searched in the SwissProt database. Quantitative polymerase chain reaction (qPCR) and ELISA were employed to confirm the expression of target proteins. Following screening to exclude inflammatory factors, SELDI-TOF-MS revealed a protein with a mass-to-charge ratio of 9,348 Da that was expressed at significantly lower levels in the serum of children with hepatoblastoma compared with healthy controls (P<0.01). Sequence analysis identified this protein as apolipoprotein A-1 (Apo A-I). qPCR and ELISA confirmed that the expression of Apo A-I mRNA and protein were significantly lower in children with hepatoblastoma compared with healthy controls (P<0.05). These results indicate that Apo A-I is a non-inflammatory protein marker for hepatoblastoma with the potential for use in early diagnosis of hepatoblastoma. In addition, the present study demonstrates the feasibility of proteomic screening for the identification of proteins that can serve as markers for a specific tumor.