High-density Apolipoprotein Research Articles

Relationship between Triglyceride and Bone Mineral Density in Healthy Korean Men

Background: As the elderly population increasing, the interest in osteoporosis, hyperlipidemia, and cardiovascular diseases has increased in recent years. In accordance with such trend, many studies regarding correlations between bone density and hyperlipidemia have been conducted. However, the study outcomes have been inconsistent so far, and most of the studies focused on females. Therefore, this study aimed to investigate the correlation between serum lipid levels and bone density in healthy Korean male adults. Methods: This study surveyed 851 male adults, who visited an examination center at a university hospital, on smoking, drinking, hypertension, and diabetes history. A laboratory examination measured total cholesterol, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apolipoprotein A-1, and apolipoprotein B. For bone density, lumbar, femoral neck, and femur were measured using dual energy X-ray absorptiometry. Results: Body mass index (BMI) and bone density T-value showed a positive correlation. Triglyceride exhibited a positive correlation with bone density T-value, and they still revealed a significant positive correlation after correcting for age and BMI. While high density lipoprotein cholesterol showed a negative correlation with bone density, they were not correlated significantly after correcting for age and BMI. There was no correlation found between low density lipoprotein cholesterol and bone density. Conclusions: This study confirmed that bone densities of all areas measured were significantly increased in Korean male adults as triglyceride increased. Total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol did not show a significant correlation with bone density. Korean J Health Promot 2015;15(3):115-120

Apolipoprotein A-I enhances proliferation of human endothelial progenitor cells and promotes angiogenesis through the cell surface ATP synthase

BackgroundHuman endothelial progenitor cells (hEPC) correspond to a subtype of stem cells which, in the presence of angiogenic stimuli, can be mobilized from bone marrow to circulation and then recruited to the damaged endothelium, where they differentiate into mature endothelial cells. High-density lipoproteins (HDL) increase the level and functionality (proliferation, migration, differentiation, angiogenesis capacity) of circulating hEPC; however, the contribution of receptors for HDL and/or apolipoprotein A-I (apoA-I), the main HDL apolipoprotein, in these effects is still unclear. On mature endothelial cells, the cell surface F1-ATP synthase has been previously characterized as a high affinity receptor of apoA-I, whereas the scavenger receptor SR-BI mainly binds with fully lipidated HDL and displays a poor affinity for lipid-free apoA-I. Furthermore, it was shown that apoA-I binding to surface ATP synthase on mature endothelial cells promotes cell proliferation, whereas inhibits apoptosis. In this work, we aimed to determine the effect of apoA-I in the proliferation and the angiogenic capacity of early hEPC, and the contribution of the cell surface ATP synthase in these events. ResultsWe first evidenced that early hEPC express the ATP synthase at the surface of nonpermeabilized cells, where it is not colocalized with MitoTracker, a mitochondria marker. ApoA-I (50μg/mL) increases hEPC proliferation (+14.5%, p<0.001) and potentiates the effect of hEPC on a cellular model of angiogenesis, with an increase of +31% (p<0.01) in branch point counting and in tubule length. These effects of apoA-I were totally reversed in the presence of ATP synthase inhibitors, such as IF1 or oligomycin, whereas the inhibition of the HDL receptor, SR-BI, partially inhibits these events. ConclusionsThese results provide the first evidence that surface ATP synthase is expressed on early hEPC, where it mediates apoA-I effects in hEPC proliferation and in angiogenesis. This knowledge could be helpful for future investigations focused on the regulation of the number and functionality of these cells and in the development of new therapies for the treatment of diseases, such as cardiovascular disease.

ABCA1 and nascent HDL biogenesis.

ABCA1 mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein (HDL). Thus, ABCA1 is a key molecule in cholesterol homeostasis. Functional studies of certain Tangier disease mutations demonstrate that ABCA1 has multiple activities, including plasma membrane remodeling and apoAI binding to cell surface, which participate in nascent HDL biogenesis. Recent advances in our understanding of ABCA1 have demonstrated that ABCA1also mediates unfolding the N terminus of apoAI on the cell surface, followed by lipidation of apoAI and release of nascent HDL. Although ABCA1-mediated cholesterol efflux to apoAI can occur on the plasma membrane, the role of apoAI retroendocytosis during cholesterol efflux may play a role in macrophage foam cells that store cholesterol esters in cytoplasmic lipid droplets.

Factors Affecting Serum Paraoxonase 1 Activity in Migrant and Resident Gujarati South Asians

Paraoxonase 1 (PON1) protects against the development of atherosclerosis by hydrolysing damaging lipid peroxides formed in low-density lipoprotein (LDL) and cell membranes. The effect of migration on PON1 activity is unknown. We have investigated the effect of migration on serum PON1 activity by comparing an Indian Gujarati community who had migrated to Sandwell (West Midlands, UK) with people still living in their villages of origin around the town of Navsari (Gujarat, North-West India) and determined biochemical and nutritional parameters which may correlate with PON1 activity. PON1 activity was almost double in men and women living in Sandwell compared to those in Navsari. In the Spearman’s Rank correlation analysis, PON1 activity was significantly negatively correlated with fasting glucose and C-reactive protein, and positively with fasting non-esterified fatty acids, homeostasis model assessment (HOMA)-insulin sensitivity, and high-density lipoprotein (HDL) in rural Indian men, positively with HDL and apolipoprotein A1 (apo A1) in migrant Indian men, negatively with HOMA-β-cell activity and apo A1. It was positively correlated with HDL cholesterol, mean LDL particle diameter, and oxidised-LDL (ox-LDL) in rural Indian women and positively with HDL cholesterol, apo A1, and ox-LDL in migrant Indian women. Multivariate analysis with PON1 as the dependent variable indicated significant relationships with migrant status and HDL cholesterol only (both p&lt;0.001). In conclusion, in the South Asian populations studied here, PON1 activity significantly correlated with measures of insulin sensitivity and the metabolic syndrome; however, by far the strongest determinant of PON1 activity was migration, or at least environmental and dietary changes which accompany migration. We also found an as yet unexplained lack of gender difference in HDL cholesterol, which requires further investigation.

Reduced glutathione increases quercetin stimulatory effects on HDL- or apoA1-mediated cholesterol efflux from J774A.1 macrophages

In our in vitro study, we analyzed the effects of incubation of J774A.1 macrophages with reduced glutathione (GSH) and quercetin on the extent of cellular cholesterol efflux by high-density lipoprotein (HDL) or apolipoprotein A1 (apoA1). This combination was the most potent one among other exogenous and endogenous antioxidant combinations, since it significantly increased the extent of HDL-mediated cholesterol efflux from macrophages by 47% versus control cells, whereas quercetin (20 μM) or GSH (200 μM) alone increased it by only 37% or 17%, respectively. Similarly, apoA1-mediated cholesterol efflux was increased by 11% or 22% in quercetin or quercetin + GSH-treated cells, respectively, versus control cells. These stimulatory effects were noted only after 20 h of cell incubation. The combination of quercetin + GSH demonstrated high scavenging capacity of free radicals versus quercetin or GSH alone. In addition, quercetin + GSH significantly decreased macrophage oxidative stress as measured by the scavenging capacity of free radicals in the cells, the formation of reactive oxygen species, and the levels of cellular glutathione and lipid peroxides. There was no significant effect of quercetin + GSH on cellular HDL binding, on ATP-binding cassette A1 (ABCA1) activity, or on ABCG1 messenger RNA (mRNA) levels.In contrast, mRNA levels for ABCA1 and peroxisome proliferator-activated receptor alpha (PPARα) were both significantly increased by 89% and 93%, respectively, in quercetin + GSH-treated cells versus control cells. Quercetin alone increased the mRNA levels for ABCA1 or PPARα by 42% or 77%, respectively, whereas GSH alone increased it by 22% or 28%, respectively. Mass spectra analysis revealed that oxidized quercetin reacts with GSH to form a new adduct product. We thus conclude that the stimulatory effects of quercetin + GSH on apoA1- or HDL-mediated macrophage cholesterol efflux are related to the ability of GSH to preserve quercetin in its reduced form.

Apolipoprotein A-I increases insulin secretion and production from pancreatic β-cells via a G-protein-cAMP-PKA-FoxO1-dependent mechanism.

Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal β-cell lines. This study identifies the signaling pathways that mediate these effects. Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2'5' dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Gαs subunit of a heterotrimeric G-protein and a Gαs subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A-specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I-treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels. ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1-dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and β-cell survival genes.

Interrelationships between the kinetics of VLDL subspecies and HDL catabolism in abdominal obesity: a multicenter tracer kinetic study.

Low plasma high-density lipoprotein (HDL) cholesterol is a major abnormality in abdominal obesity. This relates due to accelerated HDL catabolism, but the underlying mechanism requires further elucidation. The relationships between HDL catabolism and other variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, liver fat, or visceral adiposity, remain to be investigated. Our aim was to study the associations between HDL apolipoprotein (apo)-A-I fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and estimates of liver and visceral and sc fat. We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity. In a multivariate analysis, among the morphological and biological parameters that may predict apoA-I FCR, liver fat (β = .400, P = .003), and VLDL1-apoB (β = .307, P = .020) were independently associated with apoA-I FCR. In a multivariate analysis, among the kinetic parameters, VLDL1-triglycerides (TGs) indirect FCR (β = -.357, P = .001), VLDL1-TG production rate (β = 0.213, P = .048), and apoA-II FCR (β = .667, P < .0001) were independently associated with apoA-I FCR. After adjustment for VLDL1-TG production rate, liver fat was no more correlated with apoA-I FCR. No association between apoA-I FCR and visceral fat was observed. We show that VLDL1 is an important independent determinant of apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and the production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.

Anti-Inflammatory Effects of High-Density Lipoprotein Through Activating Transcription Factor 3

High-density lipoprotein (HDL) cholesterol levels are inversely proportional to the risk of atherosclerosis. However, the evidence that raising HDL per se will reduce atherosclerosis and thereby cardiovascular events remains controversial, and mechanisms of putative HDL-mediated atheroprotection remain unclear. In addition to canonical role of HDL in mobilizing excess cholesterol from arterial wall macrophages (the first step in reverse cholesterol transport), there is compelling evidence to support the anti-inflammatory effects of HDL, both dependent and independent of its cholesterol transport capacities.1 Macrophages serve as important orchestrators of inflammation at the intersection of immunity, metabolism, and cardiovascular diseases. Yet anti-inflammatory effects of HDL in macrophages are less well understood. In a recent issue of Nature Immunology , De Nardo et al2 report that anti-inflammatory effects of HDL in macrophages are mediated through the induction of activating transcription factor 3 (ATF3), an ancient transcriptional modulator that provides negative feedback on toll-like receptor (TLR) innate immune signaling. The authors first describe that pretreatment with both native HDL and reconstituted HDL (apoA-I and phospholipids) inhibited cytokine production by multiple distinct TLR ligands in murine bone marrow–derived macrophages (BMDM), human peripheral blood mononuclear cells, and TLR ligand–treated mice, an in vivo model of acute inflammation and liver injury. Although HDL is known to interact and neutralize the TLR4 ligand lipopolysaccharide directly, the authors showed that HDL did not interact with TLR1/2 ligands (Pam3CSK4) and the TLR9 ligand (CpG DNA) and did not directly modulate TLR1/2/9 activation, signaling transduction (eg, …

Palm oil and blood lipid–related markers of cardiovascular disease: a systematic review and meta-analysis of dietary intervention trials

Palm oil (PO) may be an unhealthy fat because of its high saturated fatty acid content. The objective was to assess the effect of substituting PO for other primary dietary fats on blood lipid-related markers of coronary heart disease (CHD) and cardiovascular disease (CVD). We performed a systematic review and meta-analysis of dietary intervention trials. Studies were eligible if they included original data comparing PO-rich diets with other fat-rich diets and analyzed at least one of the following CHD/CVD biomarkers: total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, TC/HDL cholesterol, LDL cholesterol/HDL cholesterol, triacylglycerols, apolipoprotein A-I and B, very-low-density lipoprotein cholesterol, and lipoprotein(a). Fifty-one studies were included. Intervention times ranged from 2 to 16 wk, and different fat substitutions ranged from 4% to 43%. Comparison of PO diets with diets rich in stearic acid, monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) showed significantly higher TC, LDL cholesterol, apolipoprotein B, HDL cholesterol, and apolipoprotein A-I, whereas most of the same biomarkers were significantly lower when compared with diets rich in myristic/lauric acid. Comparison of PO-rich diets with diets rich in trans fatty acids showed significantly higher concentrations of HDL cholesterol and apolipoprotein A-I and significantly lower apolipoprotein B, triacylglycerols, and TC/HDL cholesterol. Stratified and meta-regression analyses showed that the higher concentrations of TC and LDL cholesterol, when PO was substituted for MUFAs and PUFAs, were not significant in young people and in subjects with diets with a lower percentage of energy from fat. Both favorable and unfavorable changes in CHD/CVD risk markers occurred when PO was substituted for the primary dietary fats, whereas only favorable changes occurred when PO was substituted for trans fatty acids. Additional studies are needed to provide guidance for policymaking.

Native protein mapping and visualization of protein interactions in the area of human plasma high‐density lipoprotein by combining nondenaturing micro 2DE and quantitative LC‐MS/MS

A human plasma sample was subjected to nondenaturing micro 2DE and a gel area (5 mm × 18 mm) that includes high-density lipoprotein (HDL) was cut into 1 mm × 1 mm squares, then the proteins in the 90 gel pieces were analyzed by quantitative LC-MS/MS. Grid-cutting of the gel was employed to; (i) ensure the total analysis of the proteins in the area, (ii) standardize the conditions of analysis by LC-MS/MS, (iii) reconstruct the protein distribution patterns from the quantity data. Totally 154 proteins were assigned in the 90 gel pieces and the quantity distribution of each was reconstructed as a color density pattern (a native protein map). The map of apolipoprotein (Apo) A-I showed a wide apparent mass distribution characteristic to HDL and was compared with the maps of the other 153 proteins. Eleven proteins showed maps of wide distribution that overlapped with the map of Apo A-I, and all have been reported to be the components of HDL. Further, seven minor proteins associated with HDL were detected at the gel positions of high Apo A-I quantity. These results for the first time visualized the localization of HDL apolipoproteins on a nondenaturing 2DE gel and strongly suggested their interactions.

Abstract 628: Hepatic Insulin Signaling Regulates ApoA-I Gene Expression Through the Type I Deiodinase.

People with low levels of high density lipoprotein cholesterol (HDLC) and apolipoprotein A-I (ApoA-I) have a higher risk of cardiovascular disease. Low levels of HDLC are common in individuals who are insulin resistant (IR), e.g., with metabolic syndrome and type 2 diabetes mellitus (T2DM). Despite the high prevalence of these two disorders, very little work has been reported regarding the molecular pathways linking insulin signaling or action and the levels of either HDLC or ApoA-1. We reported previously that liver specific insulin receptor (InsR) knockout mice (LIRKO) have markedly reduced plasma HDLC levels that increase after restoration of hepatic Akt signaling. In the present study, we created acute LIRKO mice by injecting an albumin-Cre adenovirus (Ad) into InsR floxed mice and observed marked reductions in HDLC, the expression of ApoA-I, and the expression of the gene coding Type1 iodothyronine deiodinase1, a selenoenzyme expressed highly in the liver that converts thyroxine to 3,5,3’-triiodothyronine (T3) or reverse T3. Deiodinase 1 knockout mice also had significantly reduced hepatic ApoA-I mRNA levels. Overexpression of Dio1 in LIRKO restored HDLC and significantly increased the expression of ApoA-I mRNA. In vitro studies showed that the expression of ApoA-I was significantly reduced after knockdown of either InsR or Dio1 expression in HepG2 cells. Moreover, overexpression of Dio1 restored ApoA-I promoter activity that had been decreased by knockdown of InsR. Deletion analysis of ApoAI promoter regions showed that insulin signaling regulated ApoA-I expression by acting on a region which does not contain any thyroid response elements. Pulse-chase experiments in HepG2 cells showed that deficiency of insulin signaling resulted in decreased synthesis and secretion of ApoAI. Our results indicates that defective hepatic insulin signaling results in reduced expression of Dio1 which, in turn, leads to reduced expression of ApoA-I and decreased synthesis and secretion of ApoA-I from hepatocytes. We believe our studies have defined a novel pathway from insulin signaling to ApoA-I synthesis that may lead to new approaches for increasing HDL levels in people with defective insulin signaling.

Abstract 671: Beyond Cholesterol Efflux: Defining HDL Function in Atherosclerosis and the Requirement for Procollagen C-Endopeptidase Enhancer Protein 2

Recent studies suggest that assessment of high density lipoprotein (HDL) function provides a more reliable metric of athero-protection than plasma concentration alone. One important function attributed to apolipoprotein A-I (apoA-I), the major protein constituent of HDL, is its ability to accept newly effluxed cholesterol from ATP-binding cassette A-I (ABCA1) to form nascent HDL (nHDL). New studies suggest that the protein, procollagen c-endopeptidase enhancer protein 2 (PCOLCE2; PCPE2), is involved in mediating nHDL particle formation. PCPE2 is a 52 kDa glycoprotein sharing 43% amino acid identity with PCOLCE (PCPE1). Both are secreted into the extracellular matrix where they enhance the catalytic cleavage of the C-terminal propeptides of procollagen catalyzed by bone morphogenetic protein 1 (BMP1). The connection between PCPE2 and HDL was discovered after significant correlations were found between single-nucleotide polymorphisms and plasma HDL-cholesterol concentrations in population studies. Consistent with these findings a recent genome-wide siRNA screening study indicated that PCPE2 was a significant modulator of HDL apoA-I secretion from cells, while other studies in mice lacking PCPE2 showed defective ABCA1-mediated cholesterol efflux, despite elevated plasma HDL. Thus, we began the current studies to determine if the increased plasma HDL, in light of defective cholesterol efflux, would be atheroprotective or atherogenic. PCPE2 null mice were crossed with LDL receptor null mice to obtain double knockout, LDLr -/- , PCPE2 -/- mice. Both LDLr -/- and LDLr -/- , PCPE2 -/- mice were fed an atherogenic diet for 12 wks after which the lipid deposition in the aortic root was evaluated. As expected, LDLr -/- , PCPE2 -/- mice showed elevated levels of enlarged HDL compared to control mice, while LDL levels were similar between the two genotypes. Despite elevations in plasma HDL, LDLr -/- , PCPE2 -/- mice showed significantly more atherosclerosis compared to LDLr -/- mice, similar in extent to that found in mice that lack HDL due to an absence of plasma apoA-I (LDLr -/- , apoA-I -/- ). This outcome suggests that PCPE2 is atheroprotective and likely participates at various levels of HDL metabolism, including HDL production, remodeling and catabolism.

Abstract 293: ApoB-Containing Lipoproteins Contribute to Augmentation of AngII-Induced Abdominal Aortic Aneurysms

Background and objective: Presence of abdominal aortic aneurysms (AAA) is associated with dyslipidemia in humans. Hypercholesterolemic mice having a predominance of ApoB-containing lipoproteins are more susceptible to Angiotensin (Ang)II-induced AAA formation. A recent publication demonstrated that exogenously delivered high-density lipoprotein (HDL) prevented AngII-induced AAAs. ApoAI is the major apolipoprotein of HDL. The purpose of this study was to determine whether manipulations of ApoAI or ApoB-containing lipoproteins influence the development of AngII-induced AAA. Methods and Results: Eight week old male ApoAI +/+ or -/- mice with either wild type or LDL receptor -/- background were fed normal diet and infused with AngII (1 mg/kg/min) for 28 days. Plasma lipoprotein distributions were resolved by size exclusion gel chromatography. Deficiency of ApoAI led to profound reductions of plasma HDL-C concentrations in both strains. However, ApoAI deficiency did not exacerbate AngII-induced AAA as determined by maximal outer widths of suprarenal aortas (ApoAI +/+ versus -/-:1.52 ± 0.25 versus 1.22 ± 0.18 mm, P= 0.2 for C57BL/6 strain;1.21 ± 0.18 versus 1.11 ± 0.17 mm, P= 0.2 for LDLR -/- strain). Ezetimibe, an intestinal cholesterol absorption inhibitor, was administered to eight week old male ApoE -/- mice fed normal diet. Ezetimibe decreased plasma cholesterol concentrations from 451 ± 8 to 204 ± 18 mg/dl (P&lt;0.001). This reduction was due to reductions in ApoB-containing lipoproteins. Administration of ezetimibe decreased AngII-induced AAA (control versus ezetimibe: 2.25 ± 0.28 mm versus 1.37 ± 0.1 mm, P=0.009). The same dose of ezetimibe was also administered to ApoE -/- mice fed western diet. Plasma cholesterol concentrations were reduced (from 980 ± 86 to 546 ± 11 mg/dl, P&lt;0.001) attributed to reductions of apoB-containing lipoproteins. Administration of ezetimibe led to a profound reduction of atherosclerosis in western diet fed apoE -/- mice, but did not attenuate AngII-induced AAAs. Conclusion: ApoB-containing lipoproteins, rather than HDL, contribute to the augmentation of AngII-induced AAAs. However, substantial reductions in apoB-containing lipoproteins were required to attenuate AngII-induced AAA.

Serum paraoxonase-1 activity is more closely related to HDL particle concentration and large HDL particles than to HDL cholesterol in Type 2 diabetic and non-diabetic subjects

ObjectivesWe determined relationships of the anti-oxidative enzyme, paraoxonase-1 (PON-1), with high density lipoprotein (HDL) subfractions, and tested whether these relationships are stronger than those with HDL cholesterol and apolipoprotein A-I (apoA-I) in subjects with and without type 2 diabetes mellitus (T2DM). Design and methodsSerum PON-1 (arylesterase activity) and HDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 67 T2DM patients and in 56 non-diabetic subjects. ResultsPON-1 activity, HDL cholesterol and apoA-I were decreased in T2DM (all p<0.05). The HDL particle concentration was unaltered, but large HDL particles, medium HDL particles and HDL particle size were decreased, whereas small HDL particles were increased in T2DM (all p<0.05). PON-1 was more closely related to HDL cholesterol than to apoA-I (p=0.001). In turn, the positive relationship of PON-1 with the HDL particle concentration and with large HDL particles was stronger than that with HDL cholesterol (both p<0.01). The inverse relationship of PON-1 with T2DM was only modestly attenuated by HDL cholesterol or HDL particle characteristics. ConclusionsPON-1 activity is more closely related to the HDL particle concentration or large HDL particles than to HDL cholesterol. Impaired PON-1 activity in T2DM is not to a considerable extent explained by altered HDL subfraction levels.

Rosuvastatin Improves Plaque Morphology in Cerebral Embolism Patients with Normal Low-Density Lipoprotein and Severe Aortic Arch Plaque

The effect of rosuvastatin was investigated on complicated aortic arch plaque (CAP) morphology and lipid profiles in acute cerebral embolism (CE) patients with normal low-density lipoprotein-cholesterol (LDL-c) levels. Transesophageal echocardiography (TEE) studies were performed in 56 consecutive CE patients with LDL-c less than 140 mg/dL who were not taking lipid-lowering agents at baseline. CAP observed by TEE was defined as the presence of greater than 4-mm diameter, ulcerated, or mobile aortic plaque. Patients were divided into those with CAP versus without CAP (group A, n=24, age 69±8 years) and without CAP (group B, n=32, age 62±10 years). Of the 24 group A patients, 18 received 5 mg/d of rosuvastatin for 6 months and had follow-up TEE studies. In Group A, the baseline values of high-density lipoprotein-cholesterol (HDL-c) and apolipoprotein A-1 (ApoA-1) were significantly lower than in Group B (44±15 versus 55±15 mg/dL, P=.0059; 103±19 versus 137±25 mg/dL, P=.0006, respectively) and age and serum high-sensitivity C-reactive protein concentration were significantly higher (69±8 vs. 62±10 years, P=.0080; 2.34±3.05 vs. 0.67±1.00 mg/dL, P=.0054, respectively). By multivariate logistic regression analysis, ApoA-1 was shown to be an independent predictor of CAP (odds ratio=.894, 95% confidence intervals .800-.996, P=.0483). In the 18 group A patients receiving rosuvastatin for 6 months, aortic arch plaque diameter and serum LDL-c were significantly decreased (5.8±2.2 to 5.1±2.1 mm, P=.0377; 110±23 to 81±23 mg/dL, P=.0008, respectively), whereas serum HDL-c and ApoA-1 concentrations were significantly increased (42±8 to 52±9 mg/dL, P=.0002; 109±22 to 135±15 mg/dL, P=.0002, respectively). Plaques were morphologically improved in 11 patients, unchanged in 6, and worsened in 1. These data suggest that rosuvastatin improves plaque morphology concomitant with improving lipid profiles in CE patients with normal LDL-c levels.

Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

In the acute phase of the inflammatory response, secretory phospholipase A2 (sPLA2) reaches its maximum levels in plasma, where it is mostly associated with high density lipoproteins (HDL). Overexpression of human sPLA2 in transgenic mice reduces both HDL cholesterol and apolipoprotein A-I (apoA-I) plasma levels through increased HDL catabolism by an unknown mechanism. To identify unknown PLA2-mediated activities on the molecular components of HDL, we characterized the protein and lipid products of the PLA2 reaction with HDL. Consistent with previous studies, hydrolysis of HDL phospholipids by PLA2 reduced the particle size without changing its protein composition. However, when HDL was destabilized in the presence of PLA2 by the action of cholesteryl ester transfer protein or by guanidine hydrochloride treatment, a fraction of apoA-I, but no other proteins, dissociated from the particle and was rapidly cleaved. Incubation of PLA2 with lipid-free apoA-I produced similar protein fragments in the range of 6-15 kDa, suggesting specific and direct reaction of PLA2 with apoA-I. Mass spectrometry analysis of isolated proteolytic fragments indicated at least two major cleavage sites at the C-terminal and the central domain of apoA-I. ApoA-I proteolysis by PLA2 was Ca(2+)-independent, implicating a different mechanism from the Ca(2+)-dependent PLA2-mediated phospholipid hydrolysis. Inhibition of proteolysis by benzamidine suggests that the proteolytic and lipolytic activities of PLA2 proceed through different mechanisms. Our study identifies a previously unknown proteolytic activity of PLA2 that is specific to apoA-I and may contribute to the enhanced catabolism of apoA-I in inflammation and atherosclerosis.

Abstract P271: Relationship among Dietary Patterns, Apolipoproteins, C Reactive Protein and Other Lipids in Adult Populations in Four Cities of the Southern Cone of Latin America

Background: In the last decades, the nutrition transition in Latin America turned to diets with higher total caloric intake and lower consumption of vegetables, cereals and fruits. An unhealthy dietary pattern affects plasma levels of apolipoprotein (Apo) AI, Apo B and C-reactive protein (CRP) which are independently associated with the incidence of coronary heart disease and stroke). There is no data regarding these biomarkers in relation to dietary patterns from the Southern Cone of Latin America. Therefore the objective of this study is to analyze these biomarkers in relation to our traditional dietary patterns. Methods: CESCAS I study is an observational prospective cohort study with a multistage probabilistic sample of 7,600 participants from general population of 4 sites in Argentina, Chile and Uruguay. We conducted a cross-sectional analysis in a randomly selected subsample of 988 subjects. Subjects with previous cardiovascular event or under lipid lowering agents were excluded. Diet was assessed using a previously validated 126-item food frequency questionnaire. We used a factor analysis to derive the major dietary patterns by gender. Linear regression model were used to examine the independent associations among Apo AI, B, CRP, other lipids by tertiles of dietary pattern scores. Results: The population sample included 418 men and 570 women. Higher scores of “Prudent pattern”, characterized by intake of fruits, vegetables, low fat dairy products, fish, seafood and whole cereal was independently and significantly associated in men with the reduction of Apo B (β -4,4), low density lipoprotein (LDL) (β -7,2), Apo B/A ratio (β -0,03) and a non-significant reduction of CRP (β -0,6). In women, we observed a significant reduction in Apo B (β -1,3), LDL (β -2,1), total cholesterol (TC) /high density lipoprotein (HDL) ratio (β -0,1) and a non-significant reduction of triglycerides (β -4 mg/dl). The “Western like pattern” (WLP) was characterized by meat, processed foods, pizza, empanadas, sweets and desserts, refined grains, vegetables oils and other fats. Higher scores of WLP showed in men a non-significant increment of Apo B (β 0,7), TC/HDL ratio (β 0,1), CRP (β 0,1), LDL (β 3), triglycerides (β 1,3) and a non-significant reduction of Apo AI (β -1,7) and HDL (β -0,7). In women, we observed a significant increment of TC/HDL ratio (β 0,2) and triglycerides (β 12). We also found a non-significant increment of Apo B and LDL and to reduce HDL and CRP. Conclusion: Our findings confirm that diet has an important role on health. Prudent diet pattern was associated with a healthier lipid profile especially in men. The WLP showed a trend to adversely affect the lipids profile and CRP.

Chromium picolinate inhibits cholesterol-induced stimulation of platelet aggregation in hypercholesterolemic rats

Hypercholesterolemia indirectly increases the risk of myocardial infarction by enhancing platelet aggregation. Chromium has been shown to lower plasma lipids. This study was designed to investigate whether chromium inhibits platelet aggregation under hypercholesterolemic conditions. Albino rats were divided into four groups: control rats fed with a normolipemic diet (NLD group), chromium-supplemented rats fed with NLD (NLD + Cr group), rats fed with a high-fat diet (HF group), and chromium-supplemented rats fed with HF (HF + Cr group). After 10 weeks, blood was collected to determine adenosine diphosphate and collagen-induced platelet aggregation and plasma levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein A1, apolipoprotein B, and thromboxane B2. Low-density lipoprotein cholesterol was calculated by Friedewald formula. High-fat diet animals displayed significant elevation of plasma lipids and platelet aggregation which was normalized to control levels by chromium supplementation. Chromium supplementation in normolipemic (NLD + Cr) rats did not produce significant changes in either plasma lipids or platelet activity. Chromium supplementation to hypercholesterolemic rats improves the lipid profile and returns platelet hyperaggregability to control levels. This normalization is mostly due to a reduction in plasma cholesterol level.

The Effect of Nutritional Supplements on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I

One of the factors contributing to the increased risk of developing premature atherosclerosis is low plasma concentrations of high-density lipoprotein (HDL) cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein A-I (apo A-I). Diet has an important role in modulating HDL cholesterol level. The widespread use of nutritional supplements may also alter the biology of HDL. In this review, we discuss the effect of select nutritional supplements on serum HDL cholesterol and apo A-I levels. Some nutritional supplements, such as phytosterols, soy proteins, and black seed extracts, may increase HDL cholesterol levels, while others such as cholic acid and high doses of commonly used antioxidant vitamins may downregulate HDL cholesterol levels and reduce its cardioprotection. Multiple mechanisms are involved in the regulation of HDL levels, so changes in production and clearance of HDL may have different clinical implications. The clinical relevance of the changes in HDL and apo A-I caused by nutrient supplementation needs to be tested in controlled clinical trials.

The HDL anti-inflammatory function is impaired in myocardial infarction and may predict new cardiac events independent of HDL cholesterol

BackgroundIntrinsic functional properties of high density lipoproteins (HDL) are considered to be physiologically important for atheroprotection. We compared the HDL anti-inflammatory capacity between patients with acute myocardial infarction (MI) and patients with non-cardiac chest pain, and prospectively determined the association of new major adverse cardiovascular events (MACE) with this metric of HDL function. MethodsA prospective study was carried out in 93 patients referred for acute chest pain (65 patients with acute MI). The HDL anti-inflammatory capacity was determined as the ability to suppress tumor necrosis factor-α-induced vascular cell adhesion molecule-1 mRNA expression in endothelial cells in vitro. ResultsAcute MI at admission was associated with impaired HDL anti-inflammatory capacity (p=0.001), even after adjustment for HDL cholesterol and apolipoprotein A-I (p=0.003). Twenty nine MACE were ascertained during a median follow-up of 1210 (910–1679) days. New MACE was associated with impaired HDL anti-inflammatory capacity (hazard ratio: 1.80 (1.17–2.77) per SD change, p=0.007) in age, sex, HDL cholesterol and apolipoprotein-AI adjusted analysis. ConclusionsThe ability of HDL to attenuate endothelial inflammation is impaired in acute MI, and this metric of HDL function may serve as a predictor of new MACE, even independent of HDL cholesterol and apolipoprotein A-I.