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Abstract: The mutation L159R apoA-I or apoA-IL159R (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL−/−, apoA-I−/−) (double knockout or DKO) were crossed>9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr−/−, ApoA-I−/− (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α3-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-IL159R contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945–2010). [Copyright &y& Elsevier]

Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a severe subtype of chronic rhinosinusitis that can affect patients despite medical and surgical interventions. The purpose of this study was to utilize the techniques of proteomics to investigate differences in protein abundance within the sinonasal mucosa of patients with CRSwNP compared to healthy controls. Methods: In a case-control study at a tertiary-care academic medical center, sinonasal mucosa was harvested from 3 patients with CRSwNP and 3 control patients undergoing transsphenoidal excision of pituitary tumors. Two-dimensional gel electrophoresis was used to identify proteins with elevated or reduced abundance in CRSwNP patients compared to controls. The proteins showing the greatest abundance differences were characterized by mass spectrometry. Results: More than 300 differentially abundant proteins (p ≤ 0.05) were identified. Many of these protein species were involved in the host inflammatory response. Proteins up-regulated in CRSwNP patients included eosinophil lysophospholipase by a ratio (R) of 18.13, RHO-GDP dissociation inhibitor 2 (R = 2.80), and apolipoprotein A-l (R = 1.73). Down-regulated proteins in CRSwNP patients included catalase (R = -5.87), annexin Al (R = -6.27), and keratin II-8 (R = -6.73). A detailed analysis of additional protein species is outlined. Conclusions: The proteomic approach allows detection of significant differences in protein abundance in CRSwNP and provides unique insight into the pathophysiology of this common disease. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The study aimed to investigate the predictive value of the combination of high-sensitivity C-reactive protein (hs-CRP) and apolipoprotein B (apoB)/apoA-1 ratio for the outcomes of coronary angiography (CAG), echocardiography and oral glucose tolerance tests (OGTTs). Design and methods: Hs-CRP, apoB, apoA-1, and the profiles of CAG, echocardiography and OGTTs as well as traditional risk factors were measured in 1757 cardiology patients. Results: Hs-CRP or apoB/apoA-1 ratio was significantly correlated with the presence and severity of angiographic profiles, the levels of left ventricular (LV) ejection fraction, LV mass and LV mass index, and the presence of abnormal glucose metabolism. The combination of hs-CRP and apoB/apoA-1 ratio had greater correlation with abnormal glucose metabolism than its individual components in patients with normal fasting glucose, and was an independent predictor for coronary artery disease. Conclusions: The combination of hs-CRP and apoB/apoA-1 ratio may be a strong predictor for coronary artery disease and abnormal glucose metabolism. [Copyright &y& Elsevier]

Background: Hepatitis B virus initiates a complicated cascade process leading to chronic hepatitis B, cirrhosis, and hepatocellular carcinoma. In inflammatory situations, myeloperoxidase is released in plasma and binds to apolipoprotein A-1 in high-density lipoproteins. This study aims to evaluate the level of plasma myeloperoxidase as well as the pattern of plasma proteins in patients with chronic hepatitis B. Methods: Included in this study were 30 male subjects: 19 chronic hepatitis B patients, 6 HBV-related cirrhotic patients, and 5 healthy controls. Plasma myeloperoxidase was measured using enzyme-linked immunosorbent assay. Proteomic analysis of plasma proteins was performed by two-dimensional gel electrophoresis (2-DE) and mass spectrometry. One way ANOVA was used for data analysis. Results: Mean plasma myeloperoxidase levels were higher in patients with liver cirrhosis (65.5±12.5; P=0.007) and chronic hepatitis B (53.7±10.6; P=0.18) when compared with healthy subjects (45±7.6). Moreover, a positive correlation was found between plasma myeloperoxidase levels and hepatic fibrosis stage (r=0.53, P=0.002; r=0.63, P=0.000). Proteomic analysis showed an altered plasma protein pattern in progressive hepatitis B and down-regulation of the major apolipoprotein A-1 along with the appearance of a variety of spots noted to be apolipoprotein A-1 isoforms with different molecular masses. Conclusion: In this study, progressive liver injury due to HBV infection correlated with higher plasma myeloperoxidase and an altered plasma apolipoprotein A-1 pattern. [ABSTRACT FROM AUTHOR]

Purpose: To determine the correlations among apoA-1, apoB, and apoB/A-1, the ratio of the first two and their relation to the severity of diabetic retinopathy (DR). Methods: A total of 116 patients with type 2 diabetes, 34 with nonproliferative diabetic retinopathy (NPDR) and 82 with proliferative diabetic retinopathy (PDR), were included. The serum levels of apoA-1, apoB, and the apoB/A-1 ratio were compared. We performed multiple regression analyses to determine whether age, diabetes duration, glycohemoglobin level, estimated glomerular filtration rate, body mass index, or hypertension contribute to PDR. Results: The apoB levels were lower in the NPDR group than in the PDR group (90.8 ± 21.4 versus 102.5 ± 25.3 mg/dl) ( P = 0.02). The apoA-1 levels did not differ between the groups. The apoA-1 was lower in the PDR group than in the NPDR group (136.9 ± 24.9 versus 145.6 ± 21.2 mg/dl) mg/dl ( P = 0.08). The apoB/A-1 ratio differed significantly between groups (NPDR versus PDR, 0.64 ± 0.20 versus 0.77 ± 0.24) ( P = 0.004). Age, apoB/A-1, and diabetes duration were independent risk factors for PDR ( R = −3.49, 3.06, and 2.44; standard regression coefficient, −0.33, 0.28, and 0.23; P = 0.0007, P = 0.003, and P = 0.02, respectively). The PDR group had significantly higher serum levels of apoB and apoB/A-1 than the NPDR group. Conclusions: The apoB/A-1 ratio may contribute to PDR progression in patients with DR. High apoB and apoB/A-1 values may be related to PDR development. [ABSTRACT FROM AUTHOR]

Atherosclerosis regression has been demonstrated clearly in animal experimental models and, to a lesser extent, in human clinical studies. Imaging techniques for study of the arterial wall are playing a key role in promoting our appreciation of regression. LDL lowering remains the mainstay of current lipid treatment, but given the multiple antiatherosclerotic functions of HDL, including reverse cholesterol transport, agents that target HDL may represent the next generation of treatment for atherosclerotic disease. Currently available agents, including nicotinic acid, have documented antiatherosclerotic effects and trials examining clinical outcomes in the context of contemporary LDL treatment are now underway. Future approaches to HDL treatment may include cholesteryl ester transfer protein inhibitors and apolipoprotein A-I mimetics. INSET: Key issues. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the protein patterns in the sera of myocardial infarction (MI) patients in order to find a relation between proteins and MI in the local population for the prediction and management of MI. Blood samples from patients diagnosed with MI but were not on cholesterol lowering drugs were collected immediately upon their admission to the Punjab Institute of Cardiolog, Lahore, Pakistan. It indicates that the technique of electrophoresis, especially the two-dimensional gel electrophoresis is suitable for the detection of protein variation which can be used for the prediction of MI.

The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers in neuropathologically confirmed Alzheimer’s disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial two-dimensional gel electrophoresis studies or by literature review. Markers selected by the former method included apolipoprotein A-1 (ApoA1), haemopexin (HPX), transthyretin (TTR) and pigment epithelium-derived factor (PEDF), while markers identified from the literature included Aβ1-40, Aβ1-42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). Ventricular CSF concentrations of the markers were measured by enzyme-linked immunosorbent assay (ELISA). The concentrations of Aβ1-42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. Logistic regression analysis for the diagnostic discrimination of AD from ND found that Aβ1-42, ApoA1 and HPX each had significant and independent associations with diagnosis. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1-42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1-42 was significantly related to diagnosis, with a sensitivity of 58%, specificity of 86% and 86% correctly classified. The results indicate that for the discrimination of AD from ND control subjects, measurement of a set of markers including Aβ1-42, ApoA1 and HPX improved diagnostic performance over that obtained by measurement of Aβ1-42 alone. For the discrimination of AD from NADD subjects, measurement of Aβ1-42 alone was superior. [ABSTRACT FROM AUTHOR]

Aims: Few studies have analysed the influence of lipoprotein components (LC) on the development of congestive heart failure (HF) in large healthy populations. We examined LC together with glucose, haptoglobin (Hp), and uric acid (UA) as risk factors for HF in the Apolipoprotein MOrtality RISk (AMORIS) study. We also explored the possible interaction between these factors and the apolipoprotein B to apolipoprotein A-1 ratio (apoB/apoA-1) in HF. [ABSTRACT FROM PUBLISHER]

Abstract: Apolipoprotein A-1 (apoA-I) forms a discoidal membrane structure with phospholipids during the formation of high density lipoprotein and plays a role in the reverse cholesterol transport pathway. The discoidal membrane nanostructure, Nanodisc, can be easily assembled in vitro using apoA-I protein and phospholipids. In this study, the possibility of exploiting this unique membrane structure for the immobilization of membrane proteins on solid surfaces while the proteins are embedded in the membrane was investigated. By using His6-tagged full-length apoA-I, a surface-attachable, membrane-protein-anchored membrane (SAMPAM) structure, in which membrane proteins of interest are embedded into the membrane, was reconstituted. When the SAMPAM was immobilized on a Ni-NTA surface, the structure maintained its size and shape, indicating that the new proposed architecture may be useful for the display of membrane proteins on a solid surface in a membrane-associated form. [Copyright &y& Elsevier]

Abstract: The ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein A1 (ApoA-1) are both involved in the regulation of cholesterol efflux from cells. The overexpression of ABCA1 and ApoA-1 genes are associated with increased high-density lipoprotein (HDL) levels. Previous studies have shown that niacin and chromium reduce plasma cholesterol while increasing HDL levels. The aim of the present study was to determine the effects of niacin and chromium on HDL formation by investigating the changes in ABCA1 and ApoA-1 transcription in the human hepatoblastoma cell line (HepG2 cells). Cells were treated with either niacin or chromium, or the combination of both. The expression of ABCA1 and ApoA-1 mRNA was measured by a relative quantitative real-time reverse transcriptase-polymerase chain reaction method. Results showed that niacin at concentrations of 1 and 5 mM significantly increased ABCA1 (1.3–1.7-fold), without affecting ApoA-1 (0.8–1.2-fold), whereas chromium at 3 mM significantly increased both ABCA1 (1.7±0.01-fold) and ApoA-1 (1.5±0.1-fold) transcription when compared to untreated cells. Niacin and chromium cotreatment significantly induced the expression of peroxisome proliferator-activated receptor-α (PPARα) mRNA by approximately 1.3–1.8-fold. It was likely that the increases observed for the ABCA1 transcript may be regulated by the increases in PPARα transcription. A combination of niacin and chromium chloride did not significantly increase (3+1 mM) but instead reduced (1+3 mM) ABCA1 gene expression. In the case of ApoA gene, the combination of niacin and chromium chloride at concentrations of 1+3 mM significantly elevated expression; however, this effect was not observed at concentrations of 3+1 mM. When cells were treated with the combination at both concentrations, only slight increases in PPARα mRNA was observed. Niacin, but not chromium, significantly reduced intracellular cholesterol. We hypothesize that the stimulation of ABCA1 gene expression causes an enhanced cholesterol efflux, perhaps mediated by PPARα pathway(s). [Copyright &y& Elsevier]

Objectives. To compare lipoprotein components associated with ischaemic and haemorrhagic stroke by age and gender in the Apolipoprotein MOrtality RISk (AMORIS) Study ( n = 148 600). Design. Prospective follow-up study (11.8, range 7–17 years) of fatal and nonfatal ischaemic and haemorrhagic stroke through linkage with Swedish hospital discharge and mortality registers. Setting. Measurements of lipoprotein components from health check-ups in the larger Stockholm area. Results. Ischaemic stroke was more common than haemorrhagic stroke (5 :1), but case fatality was higher in haemorrhagic stroke. An elevated apoB/apoA-1 ratio and triglycerides, non-HDL cholesterol, low HDL cholesterol, and the total cholesterol to high-density cholesterol (TC/HDL-C) ratio were associated with increased incidence of nonfatal and fatal ischaemic stroke as well as all cerebrovascular events ( n = 7480) in both genders. The associations were somewhat stronger for nonfatal than fatal events. In ischaemic stroke the apoB/apoA-1 ratio was a stronger predictor than the TC/HDL-C ratio in all subjects, in those below 65 years of age and in those with LDL-C below 3 mmol L−1. Haemorrhagic stroke was not associated with elevated atherogenic lipoproteins except for increased risk of fatal haemorrhagic stroke in women with a high apoB/apoA-I ratio. Conclusions. Dyslipidaemia is associated with an increased risk of ischaemic stroke but few relations were seen in haemorrhagic stroke. Use of the apoB/apoA-I ratio as a marker of dyslipidaemia is at least as efficient as conventional lipids, for the identification of subjects at increased risk of stroke, especially ischaemic stroke. Practical advantages, fasting is not needed, speak in favour of using apoB and apoA-1 in stroke risk prediction. [ABSTRACT FROM AUTHOR]

Objectives. Examine and compare lipoprotein components associated with fatal and nonfatal acute myocardial infarction (AMI) by time period in the Apolipoprotein MOrtality RISk (AMORIS) Study. Design. Prospective follow-up study of nonfatal and fatal myocardial infarction through linkage with Swedish hospital discharge and Swedish mortality registers. Setting. Measurements of lipoprotein components from health check-ups in the larger Stockholm area. Subjects. The AMORIS subjects ( n = 149 121) free of AMI at blood sampling were followed from 1985 to 2002 with respect to n = 6794 first cases of AMI. Results. Hazard ratios of nonfatal and fatal AMI by lipoprotein parameters were highly significant and about equally strong in both genders. Apolipoprotein B (apoB), nonhigh density cholesterol and low density cholesterol predicted nonfatal AMI (NFAMI) better than fatal AMI, but high density cholesterol or apolipoprotein A-1 did not. Atherogenic components were weaker predictors after 1997 than before. In multivariate analyses apoB/apoA-1 was a better predictor than TC/HDL-C. ApoB/apoA-1 added clinically significant information to TC/HDL-C in men as reflected by a net reclassification improvement (NRI) of 9.4% (P < 0.0001). Conclusion. ApoB, apoB/apoA-1 and non-HDL-C were found about equally predictive with LDL-C being slightly less, but multivariate analyses showed apoB/apoA-1 to be the strongest predictor. Attenuation of prediction ability between nonfatal and fatal AMI may be due to modern treatment of CHD after a NFAMI and attenuation of hazard ratios after 1997 may be due to selection of lower risk subjects surviving to 1997. [ABSTRACT FROM AUTHOR]

Abstract: To evaluate the therapeutic potential of an apolipoprotein A-1 (apoA-1) mimetic peptide, D-4F, in combination with pravastatin in collagen-induced arthritis (CIA), syngeneic Louvain rats were immunized with type II collagen and randomized to vehicle control, D-4F monotherapy, pravastatin monotherapy, or D-4F + pravastatin combination therapy. Clinical arthritis activity was evaluated and radiographs, type II collagen antibody titers, cytokine/chemokine levels, and HDL function analysis were obtained. There was significant reduction in clinical severity scores in the high and medium dose D-4F + pravastatin groups compared to controls (p ≤0.0001). Reduction in erosive disease occurred in the medium/high dose combination groups compared to non-combination groups (p ≤0.01). Favorable changes in cytokines/chemokines were noted with treatment, and response to combination D-4F/pravastatin therapy was associated with improvement in HDL''s anti-inflammatory properties. Combination D-4F/pravastatin significantly reduced clinical disease activity in CIA, and may have dual therapeutic potential in other autoimmune diseases with increased cardiovascular morbidity and mortality. [Copyright &y& Elsevier]

Epidemiological studies have indicated that soya consumption may produce a better plasma lipid profile. The effect may be attributed to the phyto-oestrogens in soya. The red clover (Trifolium pratense) isoflavone biochanin A has a chemical structure similar to those phyto-oestrogens found in soya beans, and is marketed as a nutraceutical for alleviating postmenopausal symptoms. In the present study we investigated the effect of biochanin A on the mRNA expression of ApoA-1 in the hepatic cell line HepG2. Real-time PCR revealed that biochanin A increased ApoA-1??mRNA abundance in cells expressing oestrogen receptor (ER) ??. Without ER?? transfection, biochanin A had no effect on mRNA abundance. In order to study the transcriptional control, a fragment of the 5???-flanking region of the ApoA-1 gene was amplified and inserted in a firefly luciferase reporter plasmid. The reporter assay indicated that the transactivation of the ApoA-1 promoter was induced by biochanin A in HepG2 cells transfected with the ER?? expression plasmid. This induction was reduced by the anti-oestrogen ICI 182,780, whereas the inhibitors of protein kinase (PK) C, PKA, or mitogen-activated kinase (ERK) had no suppressive effect. The present study illustrated that biochanin A might up regulate hepatic apoA-1??mRNA expression through an ER-dependent pathway. [ABSTRACT FROM PUBLISHER]

The article examines the function of high-density lipoprotein (HDL) as a target of lipid-modifying therapy. HDL has many features that protect against atherosclerosis. However, HDL may be modified in certain individuals or circumstances to enhance vascular pro-inflammatory. Cell-based and cell-free assays can be used to assess the anti-inflammatory and pro-inflammatory functional properties of HDL.

There is significant debate regarding high-density lipoprotein cholesterol (HDL-C) and high-fiber, low-fat diets. The present study was designed to examine the effects of lifestyle modification on the inflammatory/anti-inflammatory properties of HDL in obese men (n = 22) with metabolic syndrome factors. Subjects were placed on a high-fiber, low-fat diet in a 3-wk residential program where food was provided ad libitum and daily aerobic exercise was performed. Fasting blood was drawn pre- and postintervention for serum lipids, lipid hydroperoxides, and the ability of subject HDL to alter low-density lipoprotein (LDL)-induced monocyte chemotactic activity (MCA) in a human artery wall coculture. Induction of MCA by control LDL in the absence of HDL was normalized to 1.0. Values >1.0 after HDL addition indicated proinflammatory HDL; values <1.0 indicated anti-inflammatory HDL. In addition, proteins involved in regulating HDL function, apolipoprotein A-I (apoA-I), paraoxonase 1 and 3, and platelet-activating factor acetylhydrolase were measured. After 3 wk, decreases in total-cholesterol, LDL-cholesterol, HDL-C, triglycerides, total cholesterol-to- HDL cholesterol ratio, and lipid hydroperoxides (all P < 0.05) were noted. The HDL inflammatory index decreased (P < 0.05) from pro- (1.14 ± 0.11) to anti-inflammatory (0.94 ± 0.09). ApoA-I level and paraoxonase activity did not change; however, platelet-activating factor acetylhydrolase activity increased (P < 0.05). Despite a quantitative reduction in HDL-C, HDL converted from pro- to anti-inflammatory. These data indicate that intensive lifestyle modification improves the function of HDL even in the face of reduced levels, suggesting increased turnover of proinflammatory HDL. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated potential associations between single nucleotide polymorphism (SNP) variants in estrogen receptor (ERα and ERβ) genes, high-density lipoprotein (HDL) cholesterol, and apolipoprotein A-1 (apoA-1) concentrations in women of 4 races/ethnicities. Participants included 1,520 African American, Caucasian, Chinese, and Japanese women from the Study of Women’s Health Across the Nation (SWAN) who were premenopausal or perimenopausal and who were also enrolled in the SWAN Genetics Study, which collected blood for lipid analyses and carried out lymphocyte transformation from which DNA was extracted and genotyped. We evaluated SNPs from ERα and ERβ genes (ESR1 and ESR2, respectively), including ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, ESR1 rs3798577, ESR2 rs1255998, ESR2 rs1256065, and ESR2 rs1256030. The mean HDL cholesterol and apoA-1 values for these women were 1.47 mmol/L and 1.51 g/L, respectively. Japanese women with the ESR1 rs3798577 TC genotype had significantly lower apoA-1 (P =0.02) and HDL cholesterol levels (P =0.03) than did those with the TT genotype. African American women with the ESR1 rs728524 GG genotype had higher HDL cholesterol levels than did women with the AA or AG genotypes (P =0.05). ESR2 rs1256030 and ESR2 rs1256065 genotypes were associated with HDL cholesterol concentrations in Chinese women (P =0.05). Although associations were identified between the ESR1 and ESR2 SNP variants and lipids in these women, these associations were not consistently observed across the 4 racial/ethnic groups, nor were the associations consistently inclusive of both HDL cholesterol and apoA-1. These genetic variants provide limited evidence of associations with lipids that may help explain the cardioprotective effect of premenopausal status in women. [Copyright &y& Elsevier]

Several new drug therapies with beneficial effects on more than one of the cardiometabolic risk factors that contribute to the metabolic syndrome have been developed recently or are under investigation. Emerging risk factors for coronary heart disease (CHD), including low concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1 (apoA-1), high levels of high-sensitivity C-reactive protein, and small dense low-density lipoprotein cholesterol particles, have been identified. We provide a detailed description of the mechanisms of action and findings from clinical trials of the new drug therapies and discuss established drug therapies with beneficial effects on emerging risk factors for CHD. The new and emerging drug therapies include an antiobesity agent that reduces atherogenic dyslipidemia and abnormal glucose metabolism; cholesteryl ester transfer protein inhibitors that increase HDL cholesterol and apoA-1 levels; glitazars that increase HDL cholesterol and decrease triglyceride concentrations, as well as improve abnormal glucose metabolism; and the amylin analog pramlintide and the incretin mimetic exenatide, both of which reduce body weight as well as improve abnormal glucose metabolism. The insulin-sensitizing effects of angiotensin-converting enzyme inhibitors arid angiotensin II receptor blockers (ARBs), which may help prevent new-onset diabetes mellitus, and the beneficial effects of the ARB telmisartan on the glucose and lipid profiles also are presented. [ABSTRACT FROM AUTHOR]

Summary: Background and aim: It has been shown that aspartate and glutamate inhibit mononuclear cell adhesion to the endothelium and formation of foam cells in the intima of thoracic aorta in cholesterol-fed rabbits. The purpose of the present study was to investigate whether a high cholesterol diet supplemented with aspartate and glutamate may alter lipoproteins cholesterol and apolipoproteins A-1 and B levels in rabbits. Methods and results: Serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein A-1 (apoA-1), apolipoprotein B (apoB), atherogenic index (AI) and apoA-1/apoB ratio were determined in 17 male New Zealand white rabbits fed a cholesterol plus corn oil diet (control group) or the same diet supplemented with aspartate and glutamate (Asp+Glu group) for 4 weeks. Both diets were found to increase TC, LDL-C, apoB and AI, while apoA-1/apoB ratio was decreased compared to baseline values. TG did not seem to be affected in the 4 weeks time in both groups. There was a significant increase of HDL-C in Asp+Glu group and a marked decrease of apoA-1 in control group during the study. Conclusions: Oral administration of aspartate and glutamate has been shown to inhibit fatty streak initiation in cholesterol-fed rabbits. The two amino acids did not have any effect on serum TC, LDL-C, TG and apoB concentrations. However, they increased HDL-C and maintained apoA-1 levels. Their antiatherogenic effect probably may be explained by different mechanisms than these related to the atherogenic lipids lowering, and it is possible to involve HDL-C and apoA-1. [Copyright &y& Elsevier]

Abstract: Anti-apolipoprotein A-1 (Apo A-1) autoantibodies were described in autoimmune disorders such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and might be involved in the genesis of arterial and venous thrombotic events. To investigate the presence of these autoantibodies in patients with acute coronary syndrome (ACS) without other features of autoimmunity, we set up an enzyme-linked immunosorbent assay (ELISA) for anti-Apo A-1 antibodies. We used it to investigate their prevalence in ACS as compared to SLE and APS and correlated them to plasma Apo A-1 and serum amyloid A protein (SAA) concentrations. The prevalence of anti-Apo A-1 autoantibodies in the healthy control group was 1% (1/92), but was significantly higher in other groups: 21% (11/53) in ACS group (P=0.001), 13% (12/92) in SLE and/or APS group (P=0.005). Multiple linear regression revealed a significant correlation between plasma Apo A-1 (r=-0.72, P=0.013), plasma SAA concentration (r=0.76, P=0.0066) and anti-Apo A-1 IgG titre in ACS patients. The presence of anti-Apo A-1 autoantibodies in patients with ACS highlights an additional link between autoimmunity, inflammation and atherosclerosis. [Copyright &y& Elsevier]

Apolipoprotein A-I amyloidosis (AApo A-I) is an inherited systemic disease that results from pathologic deposition in tissues of fibrils composed of Apo A-I-related molecules. This disorder has been linked to mutations occurring within the coding region of the Apo A-I gene and heretofore, nine such variants had been described. Recently, a tenth alteration was found in an Italian population where the substitution of proline for leucine at position 75 (Leu75Pro) was associated with amyloid deposits in the liver. We now report our studies on a patient of different ethnicity who has hepatic amyloidosis and a similar mutation in the amyloidogenic precursor protein, as evidenced from analyses of genomic Apo A-I-encoding DNA. Additionally, fibrils extracted from the liver and characterized chemically were found lo be composed almosi exclusively of a ∼96 residue N-terminal Apo A-I fragment that contained the Leu75Pro substitution. RFLP analyses revealed that the patient was heterozygous for this mutation; however. < 10% of the plasma Apo A-I consisted of the aberrant protein while the remainder had the normal (wild-type) sequence. Our findings provide further evidence that the Leu75Pro variant is associated with a predominant hepatic phenotype and can occur in individuals of diverse ethnic backgrounds. [ABSTRACT FROM AUTHOR]

The level of serum cholesterol (Ch), serum-high density lipoprotein cholesterol (HDLc), serum-low density lipoprotein cholesterol (LDLc), serum very low density lipoprotein cholesterol (VLDLc), Triglyceride (Tg), Apolipoprotein A-1, B and ratio of Apolipoprotein A1/B were observed in 151 survivors of myocardial infarction in different age groups. A significant increase was found in the level of triglyceride, LDLc, apolipoprotein-B and a significant decrease in apolipoprotein-A1 and the ratio of apolipoprotein A1/B. No significant alteration was found in serum cholesterol, HDLc except in the age group of 31–40 years and 41–50 years and VLDLc. Thus, serum Apo A-1 and Apo-B may be considerably better markers for coronary artery disease than traditional lipid parameters. [ABSTRACT FROM AUTHOR]

Conventional epidemiological and clinical studies of apolipoprotein A-1 and high-density lipoprotein-cholesterol have demonstrated, when examined jointly, that high-density lipoprotein is a better predictor of coronary heart disease. This strategy does not take into account known lipid metabolic relationships. A statistical approach that takes into account apoliprotein A-1 being a constituent of the high-density lipoprotein particle is more appropriate. Among 1,177 Japanese-American men of the Honolulu Heart Program cohort free of disease at baseline (1980–1982), 182 new coronary heart disease cases developed over a 12-year follow-up period. After removing the linear relationship with high-density lipoprotein-cholesterol, a relative measure of apoliprotein A-1 concentration was derived. Based on joint conditions of ‘low’ and ‘high’ relative apoliprotein A-1 concentration and ≤40 and >40 mg/dl for the high-density lipoprotein-cholesterol distribution, four groupings were created. Among relative joint groupings of high/≤40, low/≤40, high/>40, and low/>40, respectively, the 12-year coronary heart disease incidence varied from 28.6, 18.2, 8.3, to 11.7 cases per 1,000 person-years. A test of statistical interaction was significant ( P=0.028). Additional analyses revealed coronary heart disease cases were more likely among men with triglycerides >190 mg/dl. Observed patterns of relationships among relative apoliprotein A-1 level, high-density lipoprotein cholesterol, and triglycerides with incident coronary heart disease are consistent with patterns noted in clinical, laboratory, and transgenic animal research more capable of elucidating mechanisms of disease causation. This epidemiological study suggests similar mechanisms may be operating at a population level, and may contribute to the public health burden of coronary heart disease. [ABSTRACT FROM AUTHOR]

Moderate alcohol consumption is associated with a decreased risk of coronary artery disease. The mechanism of the putative protective effect of alcohol intake, however, remains elusive. Recent studies suggest that a ratio of apolipoprotein A-I/apolipoprotein B and Lp(a) are better indicators of the risk of atherosclerosis than total cholesterol and high density lipoprotein cholesterol. To assess the effect of alcohol on these analytes, we determined the concentration of Lp(a), apolipoprotein A-I, apolipoprotein B, total cholesterol, and high-density lipoprotein cholesterol, and calculated low-density lipoprotein cholesterol in serum of 12 patients meeting DSM-III-R criteria for alcohol dependence at the time of admission for treatment of alcohol withdrawal (before). The analyses were repeated after 4 weeks of supervised abstinence on a locked research unit (after). With abstinence, there was a significant increase in the concentration of Lp(a), the atherogenic index and the ratio of low-density to high-density lipoprotein cholesterol but a significant decrease in total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, and the apolipoprotein A-I/B ratio. Apolipoprotein B and low-density lipoprotein cholesterol showed no significant changes before and after alcohol abstinence. Thus, decreased Lp(a) and increased high-density lipoprotein cholesterol and apolipoprotein A-I may be factors mediating the putative protective effect of alcohol in coronary artery disease. [ABSTRACT FROM AUTHOR]

Our previous study demonstrated that apolipoprotein A-1 (apo A-1) immunoreactive peptides were located diffusely in the cytoplasm, not only of human normal hepatocytes, but also of intrahepatic bile ducts and peribiliary glands. It is important to determine whether the presence of these immunoreactive peptides in intrahepatic biliary tree is caused by pinocytosis from the bile, or by intracellular protein synthesis. Thus, we investigated whether apo A-1 is synthesized by cells that line the biliary tree. Normal human liver samples obtained at surgery were used, and the expression and distribution of apo A-1 mRNA in normal human liver tissues were examined, using in situ hybridization histochemistry with a 35S-labeled oligonucleotide probe specific for apo A-1. On the autoradiogram, many silver grains were found to be distributed uniformly in hepatocytes. In addition, an appreciable apo A-1 mRNA signal was also observed in both the surface epithelial lining of the bile ducts and the epithelial cells of the peribiliary glands. In conclusion, these findings suggest that the apo A-1 found in bile is secreted both by hepatocytes and by intrahepatic bile duct cells and peribiliary glands. [ABSTRACT FROM AUTHOR]

Atherosis is accepted to underlie the pathogenesis of preeclampsia, therefore we aimed to determine malonyldialdehyde (MDA) levels as a marker of lipid peroxidation, and lipoprotein(a) (Lp(a)), apolipoprotein A-1 (Apo A-1) and apolipoprotein B (Apo B) levels as a marker of atherogenic profile in preeclamptic and normal pregnant women. Twenty preeclamptic and 20 gestational-age matched normal pregnant patients were enrolled in the study, mean gestational ages for the preeclamptic and the control group were 33.9±1.4 and 35.5±0.7 weeks, respectively. Blood was withdrawn from the patients soon after diagnosis, and from the controls at their routine prenatal visits. MDA levels was significantly higher in preeclamptic patients (P=0.0003), but no difference was observed in Apo A-1 and Apo B and Lp(a) levels between the 2 groups. We consider that higher MDA was due to oxidative stress seen in preeclampsia, and similar Apo A-1 and Apo B and Lp(a) levels were due to lack of systemic atherosis. [ABSTRACT FROM AUTHOR]

Objective: apoA1 (apolipoprotein A-1) is the main lipoprotein associated with HDL (high-density lipoprotein) cholesterol. It was recently reported that intravenous infusion of apoA1 could lower insulin resistance in pregnant rats, leading to the suggestion that apoA1 could provide a target for reducing pregnancy-induced insulin resistance and the risk of gestational diabetes mellitus (GDM) in humans. However, the effects of apoA1 on insulin resistance and risk of GDM in human pregnancy are not known. Thus, we sought to systematically evaluate the relationships of apoA1 with glucose homeostasis and metabolic function in pregnant women. Approach and Results: In this study, 870 pregnant women were recruited in late second trimester and underwent metabolic characterization, including an oral glucose tolerance test on which 214 were diagnosed with GDM. Metabolic characterization included assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance), pancreatic β-cell function, lipids (LDL [low-density lipoprotein] cholesterol, HDL cholesterol, triglycerides, apoB [apolipoprotein B], and apoA1), CRP (C-reactive protein), and adiponectin. Serum apoA1 was strongly correlated with HDL (r=0.79, P <0.0001) and weakly so with adiponectin (r=0.12, P =0.0004) but showed no association with measures of insulin sensitivity/resistance, β-cell function, glycemia, or CRP. There were no significant differences across apoA1 tertiles in mean adjusted Matsuda index ( P =0.24), homeostasis model assessment of insulin resistance ( P =0.08), or area under the glucose curve on the oral glucose tolerance test ( P =0.96). Moreover, there were no differences in risk of GDM across tertiles of apoA1, both before ( P =0.67) and after covariate adjustment ( P =0.78)., Conclusions: Serum apoA1 is not associated with insulin resistance or the risk of GDM in human pregnancy.

Background No reliable tests or validated biomarkers exist to ensure parasitological cure following treatment of Chagas disease (CD) patients chronically infected with Trypanosoma cruzi. As seroreversion, the only marker of cure, happens more quickly in children, we investigated the correlation between previously identified biomarkers and seroreversion in children. Methods Thirty CD children (age 1 month to 10 years) diagnosed as T. cruzi positive (time point S0) were treated with benznidazole (BZ) 5–8 mg/kg/d for 60 days. At least 2 serological tests were used to evaluate treatment efficacy from the end of treatment (S1) until seroreversion (S2). Thirty children (age 1 month to 10 years) and 15 adults were used as healthy controls (HCs). Immunoblot and a proteomic-based assay were used to validate previously identified fragments of apolipoprotein A-1 (ApoA1) and fibronectin (FBN) as CD biomarkers. Results Correlation between seroreversion and absence of ApoA1 and FBN fragments by immunoblot was observed in 30/30 (100%) and 29/30 (96.6%) CD children, respectively. ApoA1 and FBN fragments were absent at the end of BZ treatment in 20/30 (66.6%) and 16/30 (53.3%) children, respectively. Absence of fragments in serum profiles was confirmed by mass spectrometry. Using intact protein analysis, a 28 109-Da protein identified as full-length ApoA1 by tandem mass spectrometry was detected in HC serum samples. Conclusions These data confirm that ApoA1 and FBN fragments can discriminate between healthy and T. cruzi –infected samples. Correlation with seroreversion was shown for the first time; results suggest predictive capacity potentially superior to serology, making them potentially useful as surrogate biomarkers. [ABSTRACT FROM AUTHOR]

A comprehensive study of lipidograms of 36 patients with initial signs of calcification of aortic semilunium was performed. It was determined that the content of apolipoprotein A-1 was significantly lower in comparison with the control groups, which requires further studies of the evaluation of the effect on the process of early development of calcification of drugs capable to increasing its content. If the concentration of apolipoprotein A-1 is less than 1,1 mg/dl and/or the apoB/apoA ratio is increased by more than 1, it is advisable to recommend dispensary follow-up with regular (no less than 1 time in 5 years) echocardiographic study with a detailed study of the functional state of the aortic valve.