Science.gov

Sample records for alta densidade hdl

  1. Antioxidant properties of HDL

    PubMed Central

    Soran, Handrean; Schofield, Jonathan D.; Durrington, Paul N.

    2015-01-01

    High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL. PMID:26528181

  2. 77 FR 29633 - Alta Wind VII, LLC, Alta Wind IX, LLC, Alta Wind X, LLC, Alta Wind XI, LLC, Alta Wind XII, LLC...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-18

    ... Energy Regulatory Commission Alta Wind VII, LLC, Alta Wind IX, LLC, Alta Wind X, LLC, Alta Wind XI, LLC, Alta Wind XII, LLC, Alta Wind XIII, LLC, Alta Wind XIV, LLC, Alta Wind XV, LLC, Alta Windpower... Practice and Procedure, 18 CFR 385.207, Alta Wind VII, LLC, Alta Wind IX, LLC, Alta Wind X, LLC, Alta...

  3. Genetic determinants of HDL metabolism.

    PubMed

    Ossoli, A; Gomaraschi, M; Franceschini, G; Calabresi, L

    2014-01-01

    Plasma high density lipoproteins (HDL) comprise a highly heterogeneous family of lipoprotein particles, with subclasses that can be separated and identified according to density, size, surface charge as well as shape and protein composition. There is evidence that these subclasses may differ in their functional properties. The individual plasma HDL cholesterol (HDL-C) level is generally taken as a snapshot of the steady-state concentration of all circulating HDL subclasses together, but this is insufficient to capture the structural and functional variation in HDL particles. HDL are continuously remodeled and metabolized in plasma and interstitial fluids, through the interaction with a large number of factors, including structural proteins, membrane transporters, enzymes, transfer proteins and receptors. Genetic variation in these factors can lead to essential changes in plasma HDL levels, and to remarkable changes in HDL particle density, size, surface charge, shape, and composition in lipids and apolipoproteins. This review discusses the impact of rare mutations and common variants in genes encoding factors involved in HDL remodeling and metabolism on plasma HDL-C levels and particle distribution. The study of the effects of human genetic variation in major players in HDL metabolism provides important clues on how individual factors modulate the formation, maturation, remodeling and catabolism of HDL. PMID:24606513

  4. Glycoxidized HDL, HDL enriched with oxidized phospholipids and HDL from diabetic patients inhibit platelet function

    PubMed Central

    Lê, Quang Huy; El Alaoui, Meddy; Véricel, Evelyne; Ségrestin, Bérénice; Soulère, Laurent; Guichardant, Michel; Lagarde, Michel; Moulin, Philippe; Calzada, Catherine

    2015-01-01

    Context High-density lipoproteins (HDL) possess atheroprotective properties including anti-thrombotic and antioxidant effects. Very few studies relate to the functional effects of oxidized HDL on platelets in type 2 diabetes (T2D). Objective The objective of our study was to investigate the effects of in vitro glycoxidized HDL, and HDL from T2D patients on platelet aggregation and arachidonic acid signaling cascade. At the same time, the contents of hydroxylated fatty acids were assessed in HDL. Results Compared to control HDL, in vitro glycoxidized HDL had decreased proportions of linoleic (LA) and arachidonic (AA) acids in phospholipids and cholesteryl esters, and increased concentrations of hydroxy-octadecadienoic acids (9-HODE and 13-HODE) and 15-hydroxy-eicosatetraenoic acid (15-HETE), derived from LA and AA respectively, especially hydroxy derivatives esterified in phospholipids. Glycoxidized HDL dose-dependently decreased collagen-induced platelet aggregation by binding to SR-BI. Glycoxidized HDL prevented collagen-induced increased phosphorylation of platelet p38 MAPK and cytosolic phospholipase A2, as well as intracellular calcium mobilization. HDL enriched with oxidized phospholipids, namely PC(16:0/13-HODE) dose-dependently inhibited platelet aggregation. Increased concentrations of 9-HODE, 13-HODE and 15-HETE in phospholipids (2.1, 2.1 and 2.4-fold increase respectively) were found in HDL from patients with T2D, and these HDL also inhibited platelet aggregation via SR-BI. Conclusions Altogether, our results indicate that in vitro glycoxidized HDL as well as HDL from T2D patients inhibit platelet aggregation, and suggest that oxidized LA-containing phospholipids may contribute to the anti-aggregatory effects of glycoxidized HDL and HDL from T2D patients. PMID:25794249

  5. 75 FR 23263 - Alta Wind I, LLC; Alta Wind II, LLC; Alta Wind III, LLC; Alta Wind IV, LLC; Alta Wind V, LLC...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-03

    ... Energy Regulatory Commission Alta Wind I, LLC; Alta Wind II, LLC; Alta Wind III, LLC; Alta Wind IV, LLC; Alta Wind V, LLC; Alta Wind VI, LLC; Alta Wind VII, LLC; Alta Wind VIII, LLC; Alta Windpower... Federal Energy Regulatory Commission (Commission), 18 CFR 285.207 (2009), Alta Wind I, LLC, Alta Wind...

  6. HDL, Atherosclerosis, and Emerging Therapies

    PubMed Central

    Genest, Jacques

    2013-01-01

    This review aims to provide an overview on the properties of high-density lipoproteins (HDLs) and their cardioprotective effects. Emergent HDL therapies will be presented in the context of the current understanding of HDL function, metabolism, and protective antiatherosclerotic properties. The epidemiological association between levels of HDL-C or its major apolipoprotein (apoA-I) is strong, graded, and coherent across populations. HDL particles mediate cellular cholesterol efflux, have antioxidant properties, and modulate vascular inflammation and vasomotor function and thrombosis. A link of causality has been cast into doubt with Mendelian randomization data suggesting that genes causing HDL-C deficiency are not associated with increased cardiovascular risk, nor are genes associated with increased HDL-C, with a protective effect. Despite encouraging data from small studies, drugs that increase HDL-C levels have not shown an effect on major cardiovascular end-points in large-scale clinical trials. It is likely that the cholesterol mass within HDL particles is a poor biomarker of therapeutic efficacy. In the present review, we will focus on novel therapeutic avenues and potential biomarkers of HDL function. A better understanding of HDL antiatherogenic functions including reverse cholesterol transport, vascular protective and antioxidation effects will allow novel insight on novel, emergent therapies for cardiovascular prevention. PMID:23781332

  7. HDL biogenesis, remodeling, and catabolism.

    PubMed

    Zannis, Vassilis I; Fotakis, Panagiotis; Koukos, Georgios; Kardassis, Dimitris; Ehnholm, Christian; Jauhiainen, Matti; Chroni, Angeliki

    2015-01-01

    In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research. PMID:25522986

  8. Paraoxonase 1 and HDL maturation.

    PubMed

    Gugliucci, Alejandro; Menini, Teresita

    2015-01-15

    Understanding the kinetics and function of paraoxonase 1 (PON1) is becoming an important issue in atherosclerosis. Low PON1 activity has been consistently linked with an increased risk of major cardiovascular events in the setting of secondary prevention of coronary artery disease. Recent studies have shown that there is a specific interaction of myeloperoxidase (MPO)-apoAI-PON1 on HDL surface that seems to be germane to atherogenesis. MPO specifically inhibits PON1 and PON1 mitigates MPO effects. Surprisingly, very little is known about the routes by which PON1 gets integrated into HDL or its fate during HDL remodeling in the intravascular space. We have developed a method that assesses PON1 activity in the individual HDL subclasses with the aid of which we have shown that PON1 is present across the HDL particle range and preferentially in HDL3, confirming data from ultracentrifugation (UC) studies. Upon HDL maturation ex vivo PON1 is activated and it shows a flux to both smaller and larger HDL particles as well as to VLDL and sdLDL. At the same time apoE, AI and AII are shifted across particle sizes. PON1 activation and flux across HDL particles are blocked by CETP and LCAT inhibitors. In a group of particles with such a complex biology as HDL, knowledge of the interaction between apo-lipoproteins, lipids and enzymes is key for an increased understanding of the yet multiple unknown features of its function. Solving the HDL paradox will necessitate the development of techniques to explore HDL function that are practical and well adapted to clinical studies and eventually become useful in patient monitoring. The confluence of proteomic, functional studies, HDL subclasses, PON1 assays and zymogram will yield data to draw a more elaborate and comprehensive picture of the function of HDL. It must be noted that all these studies are static and conducted in the fasting state. The crucial phase will be achieved when human kinetic studies (both in the fasting and post

  9. Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112

    PubMed Central

    Didichenko, Svetlana A.; Navdaev, Alexei V.; Cukier, Alexandre M.O.; Gille, Andreas; Schuetz, Patrick; Spycher, Martin O.; Thérond, Patrice; Chapman, M. John; Kontush, Anatol

    2016-01-01

    Rationale: CSL112, human apolipoprotein A-I (apoA-I) reconstituted with phosphatidylcholine, is known to cause a dramatic rise in small high-density lipoprotein (HDL). Objective: To explore the mechanisms by which the formation of small HDL particles is induced by CSL112. Methods and Results: Infusion of CSL112 into humans caused elevation of 2 small diameter HDL fractions and 1 large diameter fraction. Ex vivo studies showed that this remodeling does not depend on lipid transfer proteins or lipases. Rather, interaction of CSL112 with purified HDL spontaneously gave rise to 3 HDL species: a large, spherical species composed of apoA-I from native HDL and CSL112; a small, disc-shaped species composed of apoA-I from CSL112, but smaller because of the loss of phospholipids; and the smallest species, lipid-poor apoA-I composed of apoA-I from HDL and CSL112. Time-course studies suggest that remodeling occurs by an initial fusion of CSL112 with HDL and subsequent fission leading to the smaller forms. Functional studies showed that ATP-binding cassette transporter 1–dependent cholesterol efflux and anti-inflammatory effects in whole blood were carried by the 2 small species with little activity in the large species. In contrast, the ability to inactivate lipid hydroperoxides in oxidized low-density lipoprotein was carried predominantly by the 2 largest species and was low in lipid-poor apoA-I. Conclusions: We have described a mechanism for the formation of small, highly functional HDL species involving spontaneous fusion of discoidal HDL with spherical HDL and subsequent fission. Similar remodeling is likely to occur during the life cycle of apoA-I in vivo. PMID:27436846

  10. Raising HDL cholesterol in women

    PubMed Central

    Eapen, Danny J; Kalra, Girish L; Rifai, Luay; Eapen, Christina A; Merchant, Nadya; Khan, Bobby V

    2010-01-01

    High-density lipoprotein cholesterol (HDL-C) concentration is essential in the determination of coronary heart disease (CHD) risk in women. This is especially true in the postmenopausal state, where lipid profiles and CHD risk mimic that of age-matched men. Thus, interventions designed to reduce CHD risk by raising HDL-C levels may have particular significance during the transition to menopause. This review discusses HDL-C-raising therapies and the role of HDL in the primary prevention of CHD in women. Lifestyle-based interventions such as dietary change, aerobic exercise regimens, and smoking cessation are initial steps that are effective in raising HDL-C, and available data suggest women respond similarly to men with these interventions. When combined with pharmacotherapy, the effects of these lifestyle alterations are further amplified. Though studies demonstrating gender-specific differences in therapy are limited, niacin continues to be the most effective agent in raising HDL-C levels, especially when used in combination with fibrate or statin therapy. Emerging treatments such as HDL mimetic therapy show much promise in further raising HDL-C levels and improving cardiovascular outcomes. PMID:21072287

  11. HDL therapy for cardiovascular diseases: the road to HDL mimetics.

    PubMed

    White, C Roger; Datta, Geeta; Zhang, Zhenghao; Gupta, Himanshu; Garber, David W; Mishra, Vinod K; Palgunachari, Mayakonda N; Handattu, Shaila P; Chaddha, Manjula; Anantharamaiah, G M

    2008-10-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are currently the drug of choice for the clinical management of elevated low-density lipoprotein (LDL) cholesterol. Although statin treatment provides an overall improvement in outcomes, clinical trial data reveal a significant number of cardiac events despite reaching targeted LDL levels. A low serum high-density lipoprotein (HDL) cholesterol level is an independent predictor of cardiovascular risk. Accordingly, there has been interest in determining whether HDL elevation, in addition to LDL lowering, further reduces risk in patients with coronary artery disease. Several commonly prescribed lipid-lowering therapies modestly raise HDL, but their use may be limited by the development of adverse reactions. Emerging data suggest that HDL quality and function may also be significantly reduced by atherosclerosis and other inflammatory diseases. The goal of this review is to discuss the current status of HDL therapeutics, with emphasis on a novel class of agent, the apolipoprotein A-I mimetic peptides, which improve the functional properties of HDL cholesterol. PMID:18706282

  12. HDL cholesterol: physiology, pathophysiology, and management.

    PubMed

    Link, Jeffrey J; Rohatgi, Anand; de Lemos, James A

    2007-05-01

    Numerous epidemiological studies have identified high-density lipoprotein cholesterol (HDL) to be an independent risk factor for coronary heart disease (CHD). HDL is an emerging therapeutic target that could rival the impact of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on LDL and CHD risk reduction. HDL metabolism, HDL kinetics, the concentration of various HDL subclasses, and other genetic factors affecting HDL functionality may all contribute to the anti-atherogenic properties of HDL; thus, standard plasma measurement may not capture the full range of HDL effects. Algorithms have been suggested to treat low HDL levels in subgroups of patients; however, no formal HDL target goals or treatment guidelines have been implemented as there is a lack of strong clinical evidence to support effective pharmacologic therapy for primary risk reduction. Available therapies have a modest impact on serum HDL levels; however, emerging therapies could have a more significant influence. PMID:17481993

  13. Impact of Mifepristone, a Glucocorticoid/Progesterone Antagonist, on HDL Cholesterol, HDL Particle Concentration, and HDL Function

    PubMed Central

    Krauss, Ronald M.; Gross, Coleman; Ishida, Brian; Heinecke, Jay W.; Tang, Chongren; Amory, John K.; Schaefer, Peter M.; Cox, Cheryl J.; Kane, John; Purnell, Jonathan Q.; Weinstein, Richard L.; Vaisar, Tomáš

    2012-01-01

    Context: Mifepristone is a glucocorticoid and progestin antagonist under investigation for the treatment of Cushing's syndrome. Mifepristone decreases high-density lipoprotein (HDL) cholesterol (HDL-C) levels in treated patients, but the clinical significance of this is unclear because recent studies suggest that functional properties of HDL predict cardiovascular disease status better than does HDL-C concentration. Objective: The aim of the study was to characterize the impact of mifepristone administration on HDL particle concentration and function. Design and Setting: We conducted a double-blind, randomized, placebo-controlled trial at a single-site, clinical research center. Participants: Thirty healthy postmenopausal female volunteers participated in the study. Intervention: Individuals were randomized to receive daily oral mifepristone (600 mg) or placebo for 6 wk. Main Outcome Measures: We measured HDL-C, serum HDL particle concentration, and HDL-mediated cholesterol efflux by treatment group. Results: As expected, ACTH, cortisol, estradiol, and testosterone levels increased in the mifepristone group. Mifepristone treatment decreased HDL-C and HDL particle concentration by 26 and 25%, respectively, but did not alter pre-β HDL concentration. In contrast, the serum HDL-mediated cholesterol efflux decreased with mifepristone treatment by only 12%, resulting in an effective increase of the efflux capacity per HDL particle. No changes were observed in cholesterol ester transfer protein or lecithin:cholesterol acyltransferase activity. Conclusions: Treatment with mifepristone reduced HDL-C, HDL particle concentration, and serum HDL cholesterol efflux in postmenopausal women. However, on a per particle basis, the efflux capacity of serum HDL increased. These observations support the concept that a decrease in HDL-C may not represent proportional impairment of HDL function. PMID:22399518

  14. Effect of HDL composition and particle size on the resistance of HDL to the oxidation

    PubMed Central

    2010-01-01

    Objectives To study the resistance of HDL particles to direct oxidation in respect to the distribution of HDL particles. Design and Methods We studied HDL composition, subclass distribution, and the kinetics of CuSO4-induced oxidation of total HDL and HDL3 in vitro in 36 low-HDL-C subjects and in 41 control subjects with normal HDL-C. Results The resistance of HDL3 to oxidation, as assessed from the propagation rate was significantly higher than that of total HDL. The propagation rate and diene formation during HDL oxidation in vitro was attenuated in HDL derived from low-HDL-C subjects. Propagation rate and maximal diene formation during total HDL oxidation correlated significantly with HDL mean particle size. The propagation rate of total HDL oxidation in vitro displayed a significant positive association with HDL2 particle mass and HDL mean particle size by multiple regression analyses. Conclusions These observations highlight that the distribution of HDL subpopulations has important implications for the potential of HDL as an anti-oxidant source. PMID:20863394

  15. Solar Innovator | Alta Devices

    SciTech Connect

    Mattos, Laila; Le, Minh

    2012-01-01

    Selected to participate in the Energy Department's SunShot Initiative, Alta Devices produces solar cells that convert sunlight into electricity at world record-breaking levels of efficiency. Through its innovative solar technology Alta is helping bring down the cost of solar. Learn more about the Energy Department's efforts to advance solar technology at energy.gov/solar .

  16. Solar Innovator | Alta Devices

    ScienceCinema

    Mattos, Laila; Le, Minh

    2013-05-29

    Selected to participate in the Energy Department's SunShot Initiative, Alta Devices produces solar cells that convert sunlight into electricity at world record-breaking levels of efficiency. Through its innovative solar technology Alta is helping bring down the cost of solar. Learn more about the Energy Department's efforts to advance solar technology at energy.gov/solar .

  17. HDL Function, Dysfunction, and Reverse Cholesterol Transport

    PubMed Central

    Fisher, Edward A.; Feig, Jonathan E.; Hewing, Bernd; Hazen, Stanley L.; Smith, Jonathan D.

    2012-01-01

    Although high HDL-cholesterol levels are associated with decreased cardiovascular risk in epidemiological studies, recent genetic and pharmacological findings have raised doubts about the beneficial effects of HDL. Raising HDL levels in animal models by infusion or over expression of apolipoprotein A-I has shown clear vascular improvements, such as delayed atherosclerotic lesion progression and accelerated lesion regression, along with increased reverse cholesterol transport. Inflammation and other factors, such as myeloperoxidase mediated oxidation, can impair HDL production and HDL function, in regard to its reverse cholesterol transport, antioxidant, and anti-inflammatory activities. Thus, tests of HDL function, which have not yet been developed as routine diagnostic assays, may prove useful and be a better predictor of cardiovascular risk than HDL-cholesterol levels. PMID:23152494

  18. Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct?

    PubMed Central

    Mani, Preethi; Rohatgi, Anand

    2016-01-01

    High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested. PMID:26048725

  19. Dialysis Modalities and HDL Composition and Function.

    PubMed

    Holzer, Michael; Schilcher, Gernot; Curcic, Sanja; Trieb, Markus; Ljubojevic, Senka; Stojakovic, Tatjana; Scharnagl, Hubert; Kopecky, Chantal M; Rosenkranz, Alexander R; Heinemann, Akos; Marsche, Gunther

    2015-09-01

    Lipid abnormalities may have an effect on clinical outcomes of patients on dialysis. Recent studies have indicated that HDL dysfunction is a hallmark of ESRD. In this study, we compared HDL composition and metrics of HDL functionality in patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) with those in healthy controls. We detected a marked suppression of several metrics of HDL functionality in patients on HD or PD. Compositional analysis revealed that HDL from both dialysis groups shifted toward a more proinflammatory phenotype with profound alterations in the lipid moiety and protein composition. With regard to function, cholesterol efflux and anti-inflammatory and antiapoptotic functions seemed to be more severely suppressed in patients on HD, whereas HDL-associated paraoxonase activity was lowest in patients on PD. Quantification of enzyme activities involved in HDL metabolism suggested that HDL particle maturation and remodeling are altered in patients on HD or PD. In summary, our study provides mechanistic insights into the formation of dysfunctional HDL in patients with ESRD who are on HD or PD. PMID:25745027

  20. Structural modifications of HDL and functional consequences.

    PubMed

    Ferretti, Gianna; Bacchetti, Tiziana; Nègre-Salvayre, Anne; Salvayre, Robert; Dousset, Nicole; Curatola, Giovanna

    2006-01-01

    High density lipoproteins (HDL) are susceptible to structural modifications mediated by various mechanisms including oxidation, glycation, homocysteinylation or enzymatic degradation. Structural alterations of HDL may affect their functional and atheroprotective properties. Oxidants, such as hypochlorous acid, peroxyl radicals, metal ions, peroxynitrite, lipoxygenases and smoke extracts, can alter both surface and core components of HDL. The formation of lipid peroxidation derivatives, such as thiobarbituric acid reactive substances, conjugated dienes, lipid hydroperoxides and aldehydes, is associated with changes of physical properties (fluidity, molecular order) and of apoprotein conformation. Non-enzymatic glycation, generally associated with lipoxidation, leads to form irreversible complexes called advanced glycation end products. These HDL modifications are accompanied with altered biological activities of HDL and associated enzymes, including paraoxonase, CETP and LCAT. Homocysteine-induced modification of HDL is mediated by homocysteine-thiolactone, and can be prevented by a calcium-dependent thiolactonase/paraoxonase. Tyrosylation of HDL induces the formation of dimers and trimers of apo AI, and alters cholesterol efflux. Phospholipases and proteolytic enzymes can also modify HDL lipid and apoprotein structure. HDL modification induces generally the loss of their anti-inflammatory and cytoprotective properties. This could play a role in the pathogenesis of atherosclerosis and neurodegenerative diseases such as Alzheimer's disease. PMID:16157342

  1. PROTEOMICS INVESTIGATIONS OF HDL. CHALLENGES AND PROMISE

    PubMed Central

    Vaisar, Tomáš

    2013-01-01

    High density lipoprotein (HDL) is recognized as the major negative risk factor of cardiovascular disease and number of anti-atherogenic functions has been ascribed to HDL. HDL is an assembly of a neutral lipid core and an outer shell consisting of polar lipids and proteins. It has been defined many different way based on various distinct properties including density flotation, protein composition, molecular size, and electrophoretic migration. Overall the studies characterizing HDL clearly demonstrate that it is a complex heterogeneous mixture of particles. Furthermore several studies convincingly demonstrated that certain populations of HDL particles have a distinct functionality suggesting that HDL may serve as a platform for assembly of protein complexes with very specific biological functions. Indeed recent proteomics studies described over 100 proteins associated with HDL. Here we review approaches to isolation and proteomic analysis of HDL and discuss potential problems associated with isolation methods which may confound our understanding of the relation of the HDL composition and its biological function. PMID:22339300

  2. Dialysis Modalities and HDL Composition and Function

    PubMed Central

    Holzer, Michael; Schilcher, Gernot; Curcic, Sanja; Trieb, Markus; Ljubojevic, Senka; Stojakovic, Tatjana; Scharnagl, Hubert; Kopecky, Chantal M.; Rosenkranz, Alexander R.; Heinemann, Akos

    2015-01-01

    Lipid abnormalities may have an effect on clinical outcomes of patients on dialysis. Recent studies have indicated that HDL dysfunction is a hallmark of ESRD. In this study, we compared HDL composition and metrics of HDL functionality in patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) with those in healthy controls. We detected a marked suppression of several metrics of HDL functionality in patients on HD or PD. Compositional analysis revealed that HDL from both dialysis groups shifted toward a more proinflammatory phenotype with profound alterations in the lipid moiety and protein composition. With regard to function, cholesterol efflux and anti-inflammatory and antiapoptotic functions seemed to be more severely suppressed in patients on HD, whereas HDL-associated paraoxonase activity was lowest in patients on PD. Quantification of enzyme activities involved in HDL metabolism suggested that HDL particle maturation and remodeling are altered in patients on HD or PD. In summary, our study provides mechanistic insights into the formation of dysfunctional HDL in patients with ESRD who are on HD or PD. PMID:25745027

  3. Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients

    PubMed Central

    Banach, Maciej

    2016-01-01

    A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high-density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD. PMID:27478466

  4. Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients.

    PubMed

    Rysz-Górzyńska, Magdalena; Banach, Maciej

    2016-08-01

    A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high-density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD. PMID:27478466

  5. HDL and Cognition in Neurodegenerative Disorders

    PubMed Central

    Hottman, David A.; Chernick, Dustin; Cheng, Shaowu; Wang, Zhe; Li, Ling

    2014-01-01

    High-density lipoproteins (HDL) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function. PMID:25131449

  6. Metabolic and functional relevance of HDL subspecies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Though the association of high-density lipoprotein cholesterol (HDL-C) with cardiovascular disease (CVD) was described as early as 1950, HDL’s role in CVD still remains to be fully elucidated. There are numerous publications showing the inverse relationship between HDL-C and CVD risk; however, in t...

  7. HDL to verification logic translator

    NASA Astrophysics Data System (ADS)

    Gambles, J. W.; Windley, P. J.

    The increasingly higher number of transistors possible in VLSI circuits compounds the difficulty in insuring correct designs. As the number of possible test cases required to exhaustively simulate a circuit design explodes, a better method is required to confirm the absence of design faults. Formal verification methods provide a way to prove, using logic, that a circuit structure correctly implements its specification. Before verification is accepted by VLSI design engineers, the stand alone verification tools that are in use in the research community must be integrated with the CAD tools used by the designers. One problem facing the acceptance of formal verification into circuit design methodology is that the structural circuit descriptions used by the designers are not appropriate for verification work and those required for verification lack some of the features needed for design. We offer a solution to this dilemma: an automatic translation from the designers' HDL models into definitions for the higher-ordered logic (HOL) verification system. The translated definitions become the low level basis of circuit verification which in turn increases the designer's confidence in the correctness of higher level behavioral models.

  8. HDL to verification logic translator

    NASA Technical Reports Server (NTRS)

    Gambles, J. W.; Windley, P. J.

    1992-01-01

    The increasingly higher number of transistors possible in VLSI circuits compounds the difficulty in insuring correct designs. As the number of possible test cases required to exhaustively simulate a circuit design explodes, a better method is required to confirm the absence of design faults. Formal verification methods provide a way to prove, using logic, that a circuit structure correctly implements its specification. Before verification is accepted by VLSI design engineers, the stand alone verification tools that are in use in the research community must be integrated with the CAD tools used by the designers. One problem facing the acceptance of formal verification into circuit design methodology is that the structural circuit descriptions used by the designers are not appropriate for verification work and those required for verification lack some of the features needed for design. We offer a solution to this dilemma: an automatic translation from the designers' HDL models into definitions for the higher-ordered logic (HOL) verification system. The translated definitions become the low level basis of circuit verification which in turn increases the designer's confidence in the correctness of higher level behavioral models.

  9. Anion Exchange HPLC Isolation of High-Density Lipoprotein (HDL) and On-Line Estimation of Proinflammatory HDL

    PubMed Central

    Ji, Xiang; Xu, Hao; Zhang, Hao; Hillery, Cheryl A.; Gao, Hai-qing; Pritchard, Kirkwood A.

    2014-01-01

    Proinflammatory high-density lipoprotein (p-HDL) is a biomarker of cardiovascular disease. Sickle cell disease (SCD) is characterized by chronic states of oxidative stress that many consider to play a role in forming p-HDL. To measure p-HDL, apolipoprotein (apo) B containing lipoproteins are precipitated. Supernatant HDL is incubated with an oxidant/LDL or an oxidant alone and rates of HDL oxidation monitored with dichlorofluorescein (DCFH). Although apoB precipitation is convenient for isolating HDL, the resulting supernatant matrix likely influences HDL oxidation. To determine effects of supernatants on p-HDL measurements we purified HDL from plasma from SCD subjects by anion exchange (AE) chromatography, determined its rate of oxidation relative to supernatant HDL. SCD decreased total cholesterol but not triglycerides or HDL and increased cell-free (cf) hemoglobin (Hb) and xanthine oxidase (XO). HDL isolated by AE-HPLC had lower p-HDL levels than HDL in supernatants after apoB precipitation. XO+xanthine (X) and cf Hb accelerated purified HDL oxidation. Although the plate and AE-HPLC assays both showed p-HDL directly correlated with cf-Hb in SCD plasma, the plate assay yielded p-HDL data that was influenced more by cf-Hb than AE-HPLC generated p-HDL data. The AE-HPLC p-HDL assay reduces the influence of the supernatants and shows that SCD increases p-HDL. PMID:24609013

  10. HDL particle number and size as predictors of cardiovascular disease

    PubMed Central

    Kontush, Anatol

    2015-01-01

    Previous studies indicate that reduced concentrations of circulating high-density lipoprotein (HDL) particles can be superior to HDL-cholesterol (HDL-C) levels as a predictor of cardiovascular disease. Measurements of HDL particle numbers, therefore, bear a potential for the improved assessment of cardiovascular risk. Furthermore, such measurement can be relevant for the evaluation of novel therapeutic approaches targeting HDL. Modern in-depth analyses of HDL particle profile may further improve evaluation of cardiovascular risk. Although clinical relevance of circulating concentrations of HDL subpopulations to cardiovascular disease remains controversial, the negative relationship between the number of large HDL particles and cardiovascular disease suggests that assessment of HDL particle profile can be clinically useful. Reduced mean HDL size is equally associated with cardiovascular disease in large-scale clinical studies. Since HDL-C is primarily carried in the circulation by large, lipid-rich HDL particles, the inverse relationship between HDL size and cardiovascular risk can be secondary to those established for plasma levels of HDL particles, HDL-C, and large HDL. The epidemiological data thereby suggest that HDL particle number may represent a more relevant therapeutic target as compared to HDL-C. PMID:26500551

  11. Origin and heterogeneity of HDL subspecies

    SciTech Connect

    Nichols, A.V.; Gong, E.L.; Blanche, P.J.; Forte, T.M.; Shore, V.G.

    1987-09-01

    A major determinant of mature HDL particle size and apolar core content, in the absence of remodeling factors, is most likely the size and apolipoprotein content of the precursor particle. Depending on the number of apoA-I molecules per analog particle, the LCAT-induced transformation follows either a fusion pathway (for precursors with 2 apoA-I per particle) or a pathway (for precursors with more than 2 apoA-I per particle) that conserves the apolipoprotein number. According to our analog results, small nascent HDL probably serve as precursors to the major (apoA-I without apoA-II)-subpopulation in the size interval. Our studies with the large discoidal analog suggest that HDL/sub 2/ (apoA-I without apoA-II)-subpopulations probably originate from the large discoidal nascent HDL that contain a higher number of apolipoprotein molecules per particle than the small nascent HDL. Intermediate transformation products of the large discoidal analog, described in the present study, resemble deformable species found in human lymph and are characterized by a relatively high surface-to-core lipid ratio. Whether large discoidal precursors containing apoE transform in comparable manner but with eventual interchange of apoA-I for apoE (10,15) is under investigation in our laboratory. Likewise, detailed delineation of pathways whereby the (apoA-I with apoA-II)-HDL subpopulations are formed is yet to be accomplished. 23 refs., 6 figs., 2 tabs.

  12. Dysfunctional HDL and atherosclerotic cardiovascular disease.

    PubMed

    Rosenson, Robert S; Brewer, H Bryan; Ansell, Benjamin J; Barter, Philip; Chapman, M John; Heinecke, Jay W; Kontush, Anatol; Tall, Alan R; Webb, Nancy R

    2016-01-01

    High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis. PMID:26323267

  13. ABCA1 and nascent HDL biogenesis.

    PubMed

    Wang, Shuhui; Smith, Jonathan D

    2014-01-01

    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. PMID:25359426

  14. Intestinal nuclear receptors in HDL cholesterol metabolism

    PubMed Central

    Degirolamo, Chiara; Sabbà, Carlo; Moschetta, Antonio

    2015-01-01

    The intestine plays a pivotal role in cholesterol homeostasis by functioning as an absorptive and secretory organ in the reverse cholesterol transport pathway. Enterocytes control cholesterol absorption, apoAI synthesis, HDL biogenesis, and nonbiliary cholesterol fecal disposal. Thus, intestine-based therapeutic interventions may hold promise in the management of diseases driven by cholesterol overload. Lipid-sensing nuclear receptors (NRs) are highly expressed in the intestinal epithelium and regulate transcriptionally the handling of cholesterol by the enterocytes. Here, we discuss the NR regulation of cholesterol fluxes across the enterocytes with special emphasis on NR exploitation as a bona fide novel HDL-raising strategy. PMID:25070952

  15. Intestinal nuclear receptors in HDL cholesterol metabolism.

    PubMed

    Degirolamo, Chiara; Sabbà, Carlo; Moschetta, Antonio

    2015-07-01

    The intestine plays a pivotal role in cholesterol homeostasis by functioning as an absorptive and secretory organ in the reverse cholesterol transport pathway. Enterocytes control cholesterol absorption, apoAI synthesis, HDL biogenesis, and nonbiliary cholesterol fecal disposal. Thus, intestine-based therapeutic interventions may hold promise in the management of diseases driven by cholesterol overload. Lipid-sensing nuclear receptors (NRs) are highly expressed in the intestinal epithelium and regulate transcriptionally the handling of cholesterol by the enterocytes. Here, we discuss the NR regulation of cholesterol fluxes across the enterocytes with special emphasis on NR exploitation as a bona fide novel HDL-raising strategy. PMID:25070952

  16. Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity.

    PubMed

    Vaisar, Tomáš; Tang, Chongren; Babenko, Ilona; Hutchins, Patrick; Wimberger, Jake; Suffredini, Anthony F; Heinecke, Jay W

    2015-08-01

    Recent studies demonstrate that HDL's ability to promote cholesterol efflux from macrophages associates strongly with cardioprotection in humans independently of HDL-cholesterol (HDL-C) and apoA-I, HDL's major protein. However, the mechanisms that impair cholesterol efflux capacity during vascular disease are unclear. Inflammation, a well-established risk factor for cardiovascular disease, has been shown to impair HDL's cholesterol efflux capacity. We therefore tested the hypothesis that HDL's impaired efflux capacity is mediated by specific changes of its protein cargo. Humans with acute inflammation induced by low-level endotoxin had unchanged HDL-C levels, but their HDL-C efflux capacity was significantly impaired. Proteomic analyses demonstrated that HDL's cholesterol efflux capacity correlated inversely with HDL content of serum amyloid A (SAA)1 and SAA2. In mice, acute inflammation caused a marked impairment of HDL-C efflux capacity that correlated with a large increase in HDL SAA. In striking contrast, the efflux capacity of mouse inflammatory HDL was preserved with genetic ablation of SAA1 and SAA2. Our observations indicate that the inflammatory impairment of HDL-C efflux capacity is due in part to SAA-mediated remodeling of HDL's protein cargo. PMID:25995210

  17. [Therapeutic targets in the treatment of dyslipidemia: HDL and non-HDL cholesterol].

    PubMed

    Brea Hernando, Ángel Julián

    2014-07-01

    Atherogenic dyslipidemia (AD) consists of the combination of an increase in very low density lipoproteins (VLDL), which results in increased plasma triglyceride (TG) levels, with a reduction of levels of high-density lipoprotein bound cholesterol (HDL-C), also accompanied by a high proportion of small and dense LDL particles. AD is considered the main cause of the residual risk of experiencing cardiovascular disease (CVD), which is still presented by any patient on treatment with statins despite maintaining low-density lipoprotein bound cholesterol (LDL-C) levels below the values considered to be the objective. Non-HDL cholesterol (non-HDL-c) reflects the number of atherogenic particles present in the plasma. This includes VLDL, intermediate density lipoproteins (IDL) and LDL. Non-HDL-c provides a better estimate of cardiovascular risk than LDL-c, especially in the presence of hypertriglyceridemia or AD. The European guidelines for managing dyslipidemia recommend that non-HDL-c values be less than 100 and 130 mg/dL for individuals with very high and high cardiovascular risk, respectively. However, these guidelines state that there is insufficient evidence to suggest that raising HDL-c levels incontrovertibly results in a reduction in CVD. Therefore, the guidelines do not set recommended HDL-c levels as a therapeutic objective. The guidelines, however, state that individuals with AD on treatment with statins could benefit from an additional reduction in their risk by using fibrates. PMID:25043539

  18. Serum amyloid A impairs the antiinflammatory properties of HDL

    PubMed Central

    Han, Chang Yeop; Tang, Chongren; Guevara, Myriam E.; Wei, Hao; Wietecha, Tomasz; Shao, Baohai; Subramanian, Savitha; Omer, Mohamed; Wang, Shari; O’Brien, Kevin D.; Marcovina, Santica M.; Wight, Thomas N.; Vaisar, Tomas; de Beer, Maria C.; de Beer, Frederick C.; Osborne, William R.; Elkon, Keith B.; Chait, Alan

    2015-01-01

    HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface–associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane. PMID:26642365

  19. Serum amyloid A impairs the antiinflammatory properties of HDL.

    PubMed

    Han, Chang Yeop; Tang, Chongren; Guevara, Myriam E; Wei, Hao; Wietecha, Tomasz; Shao, Baohai; Subramanian, Savitha; Omer, Mohamed; Wang, Shari; O'Brien, Kevin D; Marcovina, Santica M; Wight, Thomas N; Vaisar, Tomas; de Beer, Maria C; de Beer, Frederick C; Osborne, William R; Elkon, Keith B; Chait, Alan

    2016-01-01

    HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface-associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane. PMID:26642365

  20. LDL-apheresis depletes apoE-HDL and pre-β1-HDL in familial hypercholesterolemia: relevance to atheroprotection

    PubMed Central

    Orsoni, Alexina; Saheb, Samir; Levels, Johannes H. M.; Dallinga-Thie, Geesje; Atassi, Marielle; Bittar, Randa; Robillard, Paul; Bruckert, Eric; Kontush, Anatol; Carrié, Alain; Chapman, M. John

    2011-01-01

    Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (−62%) and apoAI (−16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ∼1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ∼1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (−50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (−53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix. PMID:21957200

  1. Relationship between apolipoprotein concentrations and HDL subclasses distribution.

    PubMed

    Tian, Li; Fu, Mingde; Jia, Lianqun; Xu, Yanhua; Long, Shiyin; Tian, Haoming; Tian, Ying

    2007-05-01

    Alterations in plasma apolipoproteins levels can influence the composition, content, and distribution of plasma lipoproteins that affect the risk of atherosclerosis. This study assessed the relationship between plasma apolipoproteins levels, mainly apoAI, and HDL subclass distribution. The contents of plasma HDL subclasses were determined by two-dimensional gel electrophoresis coupled with immunodetection in 545 Chinese subjects. Compared with a low apoAI group, the contents of all HDL subclasses increased significantly both in middle and high apoAI group, and the contents of large-sized HDL(2b) increased more significantly relative to those of small-sized prebeta(1)-HDL in a high apoAI group. When apoAI and HDL-C levels increased simultaneously, in comparison to a low apoAI along with HDL-C concentration group, a significant increase (116%) was shown in HDL2b but only a slight increase (26%) in prebeta1-HDL. In addition, Pearson correlation analysis revealed that apoAI levels were positively and significantly correlated with all HDL subclasses. Multiple liner regression demonstrated that the apoAI concentrations were the most powerful predictor for HDL subclass distribution. With the elevation of apoAI concentrations, the contents of all HDL subclasses increased successively and significantly, especially, an increase in large-sized HDL(2b). Further, when apoAI and HDL-C concentrations increased simultaneously, the shift to larger HDL size was more obvious. Which, in turn, indicated that HDL maturation might be enhanced and, the reverse cholesterol transport might be strengthened along with apoAI levels which might be a more powerful factor influencing the distribution of HDL subclasses. PMID:17476546

  2. Separation of the principal HDL subclasses by iodixanol ultracentrifugation

    PubMed Central

    Harman, Nicola L.; Griffin, Bruce A.; Davies, Ian G.

    2013-01-01

    HDL subclasses detection, in cardiovascular risk, has been limited due to the time-consuming nature of current techniques. We have developed a time-saving and reliable separation of the principal HDL subclasses employing iodixanol density gradient ultracentrifugation (IxDGUC) combined with digital photography. HDL subclasses were separated in 2.5 h from prestained plasma on a three-step iodixanol gradient. HDL subclass profiles were generated by digital photography and gel scan software. Plasma samples (n = 46) were used to optimize the gradient for the resolution of HDL heterogeneity and to compare profiles generated by IxDGUC with gradient gel electrophoresis (GGE); further characterization from participants (n = 548) with a range of lipid profiles was also performed. HDL subclass profiles generated by IxDGUC were comparable to those separated by GGE as indicated by a significant association between areas under the curve for both HDL2 and HDL3 (HDL2, r = 0.896, P < 0.01; HDL3, r = 0.894, P < 0.01). The method was highly reproducible, with intra- and interassay coefficient of variation percentage < 5 for percentage area under the curve HDL2 and HDL3, and < 1% for peak Rf and peak density. The method provides time-saving and cost-effective detection and preparation of the principal HDL subclasses. PMID:23690506

  3. HDL in sepsis – risk factor and therapeutic approach

    PubMed Central

    Morin, Emily E.; Guo, Ling; Schwendeman, Anna; Li, Xiang-An

    2015-01-01

    High-density lipoprotein (HDL) is a key component of circulating blood and plays essential roles in regulation of vascular endothelial function and immunity. Clinical data demonstrate that HDL levels drop by 40–70% in septic patients, which is associated with a poor prognosis. Experimental studies using Apolipoprotein A-I (ApoAI) null mice showed that HDL deficient mice are susceptible to septic death, and overexpressing ApoAI in mice to increase HDL levels protects against septic death. These clinical and animal studies support our hypothesis that a decrease in HDL level is a risk factor for sepsis, and raising circulating HDL levels may provide an efficient therapy for sepsis. In this review, we discuss the roles of HDL in sepsis and summarize the efforts of using synthetic HDL as a potential therapy for sepsis. PMID:26557091

  4. HDL phospholipid content and cholesterol efflux capacity are reduced in patients with very high HDL-C and coronary disease

    PubMed Central

    Agarwala, Anandita P.; Rodrigues, Amrith; Risman, Marjorie; McCoy, Mary; Trindade, Kevin; Qu, Liming; Cuchel, Marina; Billheimer, Jeffrey; Rader, Daniel J.

    2015-01-01

    Objective Plasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with coronary artery disease (CAD), and high HDL-C is generally associated with reduced risk of CAD. Extremely high HDL-C with CAD is an unusual phenotype, and we hypothesized that the HDL in such individuals may have an altered composition and reduced function when compared to controls with similarly high HDL-C and no CAD. Approach 55 subjects with very high HDL-C (mean 86 mg/dL) and onset of CAD around age 60 with no known risk factors for CAD (‘cases’) were identified through systematic recruitment. 120 control subjects without CAD, matched for race, gender, and HDL-C level (‘controls’), were identified. In all subjects, HDL composition was analyzed and HDL cholesterol efflux capacity was assessed. Results HDL phospholipid composition was significantly lower in cases (92 ± 37 mg/dL) than in controls (109 ± 43 mg/dL, p= 0.0095). HDL cholesterol efflux capacity was significantly lower in cases (1.96 ± 0.39) compared with controls (2.11 ± 0.43, p= 0.04). Conclusions In persons with very high HDL-C, reduced HDL phospholipid content and cholesterol efflux capacity is associated with the paradoxical development of CAD. PMID:25838421

  5. Printed Circuit Board Design with HDL Designer

    NASA Technical Reports Server (NTRS)

    Winkert, Thomas K.; LaFourcade, Teresa

    2004-01-01

    Staying up to date with the latest CAD tools both from a cost and time perspective is difficult. Within a given organization there may be experts in Printed Circuit Board Design tools and experts in FPGA/VHDL tools. Wouldn't it be great to have someone familiar with HDL Designer be able to design PCBs without having to learn another tool? This paper describes a limited experiment to do this.

  6. Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

    PubMed Central

    Cilpa-Karhu, Geraldine; Jauhiainen, Matti; Riekkola, Marja-Liisa

    2015-01-01

    Inhibition of cholesterol ester transfer protein (CETP), a protein mediating transfer of neutral lipids between lipoproteins, has been proposed as a means to elevate atheroprotective HDL subpopulations and thereby reduce atherosclerosis. However, off-target and adverse effects of the inhibition have raised doubts about the molecular mechanism of CETP-HDL interaction. Recent experimental findings have demonstrated the penetration of CETP into HDL. However, atomic level resolution of CETP penetration into HDL, a prerequisite for a better understanding of CETP functionality and HDL atheroprotection, is missing. We constructed an HDL particle that mimics the actual human HDL mass composition and investigated for the first time, by large-scale atomistic molecular dynamics, the interaction of an upright CETP with a human HDL-mimicking model. The results demonstrated how CETP can penetrate the HDL particle surface, with the formation of an opening in the N barrel domain end of CETP, put in evidence the major anchoring role of a tryptophan-rich region of this domain, and unveiled the presence of a phenylalanine barrier controlling further access of HDL-derived lipids to the tunnel of CETP. The findings reveal novel atomistic details of the CETP-HDL interaction mechanism and can provide new insight into therapeutic strategies. PMID:25424006

  7. Postmenopausal Women Have Higher HDL and Decreased Incidence of Low HDL than Premenopausal Women with Metabolic Syndrome.

    PubMed

    Fernandez, Maria Luz; Murillo, Ana Gabriela

    2016-01-01

    It is well known that plasma lipids, waist circumference (WC) and blood pressure (BP) increase following menopause. In addition, there is a perceived notion that plasma high-density lipoprotein-cholesterol (HDL-C) concentrations also decrease in postmenopausal women. In this cross-sectional study, we evaluated plasma lipids, fasting glucose, anthropometrics and BP in 88 post and 100 pre-menopausal women diagnosed with metabolic syndrome. No differences were observed in plasma low-density lipoprotein-cholesterol cholesterol, triglycerides, fasting glucose or systolic and diastolic BP between groups. However, plasma HDL-C was higher (p < 0.01) in postmenopausal women and the percentage of women who had low HDL (<50 mg/dL) was higher (p < 0.01) among premenopausal women. In addition, negative correlations were found between WC and HDL-C (r = -0.148, p < 0.05) and BMI and HDL-C (r = -0.258, p < 0.01) for all subjects indicating that increases in weight and abdominal fat have a deleterious effect on plasma HDL-C. Interestingly, there was a positive correlation between age and plasma HDL-C (r = 0.237 p < 0.01). The results from this study suggest that although HDL is decreased by visceral fat and overall weight, low HDL is not a main characteristic of metabolic syndrome in postmenopausal women. Further, HDL appears to increase, not decrease, with age. PMID:27417608

  8. Postmenopausal Women Have Higher HDL and Decreased Incidence of Low HDL than Premenopausal Women with Metabolic Syndrome

    PubMed Central

    Fernandez, Maria Luz; Murillo, Ana Gabriela

    2016-01-01

    It is well known that plasma lipids, waist circumference (WC) and blood pressure (BP) increase following menopause. In addition, there is a perceived notion that plasma high-density lipoprotein-cholesterol (HDL-C) concentrations also decrease in postmenopausal women. In this cross-sectional study, we evaluated plasma lipids, fasting glucose, anthropometrics and BP in 88 post and 100 pre-menopausal women diagnosed with metabolic syndrome. No differences were observed in plasma low-density lipoprotein-cholesterol cholesterol, triglycerides, fasting glucose or systolic and diastolic BP between groups. However, plasma HDL-C was higher (p < 0.01) in postmenopausal women and the percentage of women who had low HDL (<50 mg/dL) was higher (p < 0.01) among premenopausal women. In addition, negative correlations were found between WC and HDL-C (r = −0.148, p < 0.05) and BMI and HDL-C (r = −0.258, p < 0.01) for all subjects indicating that increases in weight and abdominal fat have a deleterious effect on plasma HDL-C. Interestingly, there was a positive correlation between age and plasma HDL-C (r = 0.237 p < 0.01). The results from this study suggest that although HDL is decreased by visceral fat and overall weight, low HDL is not a main characteristic of metabolic syndrome in postmenopausal women. Further, HDL appears to increase, not decrease, with age. PMID:27417608

  9. [HDL cholesterol as a sensitive diagnostic parameter in malaria].

    PubMed

    Kittl, E M; Diridl, G; Lenhart, V; Neuwald, C; Tomasits, J; Pichler, H; Bauer, K

    1992-01-01

    In patients with malaria the lipid parameters triglycerides, cholesterol, and HDL-cholesterol were determined routinely. At the time of admission hypertriglyceridemia, hypocholesterolemia, and an extreme decrease in HDL-cholesterol were found. This dyslipoproteinemia was present in cases of falciparum malaria, as well as in cases of benign tertian malaria. The extent of HDL-cholesterol decrease showed no correlation to the severity of the clinical course of disease. HDL-cholesterol has proven to be an independent diagnostic laboratory finding in cases of suspected malarial infection. This parameter displays high diagnostic sensitivity, but no specificity for malaria. PMID:1546481

  10. 27 CFR 9.195 - Alta Mesa.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ..., photorevised 1979, minor revision 1993. (c) Boundary. The Alta Mesa viticultural area is located in Sacramento County, California, and is entirely within the Lodi viticultural area (27 CFR 9.107). The Alta...

  11. Endothelial lipase is a major determinant of HDL level

    SciTech Connect

    Ishida, Tatsuro; Choi, Sungshin; Kundu, Ramendra K.; Hirata, Ken-Ichi; Rubin, Edward M.; Cooper, Allen D.; Quertermous, Thomas

    2003-01-30

    For the past three decades, epidemiologic studies have consistently demonstrated an inverse relationship between plasma HDL cholesterol (HDL-C) concentrations and coronary heart disease (CHD). Population-based studies have provided compelling evidence that low HDL-C levels are a risk factor for CHD, and several clinical interventions that increased plasma levels of HDL-C were associated with a reduction in CHD risk. These findings have stimulated extensive investigation into the determinants of plasma HDL-C levels. Turnover studies using radiolabeled apolipoprotein A-I, the major protein component of HDL, suggest that plasma HDL-C concentrations are highly correlated with the rate of clearance of apolipoprotein AI. However, the metabolic mechanisms by which HDL are catabolized have not been fully defined. Previous studies in humans with genetic deficiency of cholesteryl ester transfer protein, and in mice lacking the scavenger receptor BI (SR-BI), have demonstrated that these proteins participate in the removal of cholesterol from HDL, while observations in individuals with mutations in hepatic lipase indicate that this enzyme hydrolyzes HDL triglycerides. In this issue of the JCI, reports from laboratories of Tom Quertermous and Dan Rader now indicate that endothelial lipase (LIPG), a newly identified member of the lipase family, catalyzes the hydrolysis of HDL phospholipids and facilitates the clearance of HDL from the circulation. Endothelial lipase was initially cloned by both of these laboratories using entirely different strategies. Quertermous and his colleagues identified endothelial lipase as a transcript that was upregulated in cultured human umbilical vein endothelial cells undergoing tube formation, whereas the Rader group cloned endothelial lipase as a transcript that was upregulated in the human macrophage-like cell line THP-1 exposed to oxidized LDL. Database searches revealed that endothelial lipase shows strong sequence similarity to lipoprotein

  12. Inhibition of cholesteryl ester transfer protein increases cholesteryl ester content of large HDL independently of HDL-to-HDL homotypic transfer: in vitro vs in vivo comparison using anacetrapib and dalcetrapib.

    PubMed

    Johns, Douglas G; Chen, Ying; Wang, Sheng-Ping; Castro-Perez, Jose; Previs, Stephen F; Roddy, Thomas P

    2015-09-01

    The increase in high density lipoprotein (HDL)-cholesterol observed with cholesteryl ester transfer protein (CETP) inhibition is commonly attributed to blockade of cholesteryl ester (CE) transfer from HDL to low density lipoprotein particles. In vitro, it has been observed that CETP can mediate transfer of CE between HDL particles ("homotypic transfer"), and it is postulated that this contributes to HDL remodeling and generation of anti-atherogenic pre-beta HDL. Inhibition of CETP could limit this beneficial remodeling and reduce pre-beta HDL levels. We observed that anacetrapib does not reduce pre-beta HDL in vivo, but the role of HDL homotypic transfer was not examined. This study evaluated the effects of anacetrapib on homotypic transfer from HDL3 to HDL2 in vivo using deuterium-labeled HDL3, and compared this to in vitro settings, where homotypic transfer was previously described. In vitro, both anacetrapib and dalcetrapib inhibited transfer of CE from HDL3 to HDL2 particles. In CETP transgenic mice, anacetrapib did not inhibit the appearance of labeled CE derived from HDL3 in HDL2 particles, but rather promoted the appearance of labeled CE in HDL2. We concluded that inhibition of CETP by anacetrapib promoted HDL particle remodeling, and does not impair the flux of cholesterol ester into larger HDL particles when studied in vivo, which is not consistent with in vitro observations. We further conclude, therefore, that the in vitro conditions used to examine HDL-to-HDL homotypic transfer may not recapitulate the in vivo condition, where multiple mechanisms contribute to cholesteryl ester flux into and out of the HDL pool. PMID:26049012

  13. Printed Circuit Board Design (PCB) with HDL Designer

    NASA Technical Reports Server (NTRS)

    Winkert, Thomas K.; LaFourcade, Teresa

    2004-01-01

    Contents include the following: PCB design with HDL designer, design process and schematic capture - symbols and diagrams: 1. Motivation: time savings, money savings, simplicity. 2. Approach: use single tool PCB for FPGA design, more FPGA designs than PCB designers. 3. Use HDL designer for schematic capture.

  14. Inflammation modulates human HDL composition and function in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans. Our study was designed to investigate this relationship. We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-rel...

  15. A big role for small RNAs in HDL homeostasis

    PubMed Central

    Ouimet, Mireille; Moore, Kathryn J.

    2013-01-01

    High-density lipoproteins play a central role in systemic cholesterol homeostasis by stimulating the efflux of excess cellular cholesterol and transporting it to the liver for biliary excretion. HDL has long been touted as the “good cholesterol” because of the strong inverse correlation of plasma HDL cholesterol levels with coronary heart disease. However, the disappointing outcomes of recent clinical trials involving therapeutic elevations of HDL cholesterol have called this moniker into question and revealed our lack of understanding of this complex lipoprotein. At the same time, the discovery of microRNAs (miRNAs) that regulate HDL biogenesis and function have led to a surge in our understanding of the posttranscriptional mechanisms regulating plasma levels of HDL. Furthermore, HDL has recently been shown to selectively transport miRNAs and thereby facilitate cellular communication by shuttling these potent gene regulators to distal tissues. Finally, that miRNA cargo carried by HDL may be altered during disease states further broadened our perspective of how this lipoprotein can have complex effects on target cells and tissues. The unraveling of how these tiny RNAs govern HDL metabolism and contribute to its actions promises to reveal new therapeutic strategies to optimize cardiovascular health. PMID:23509405

  16. HDL-Mimetic PLGA Nanoparticle To Target Atherosclerosis Plaque Macrophages

    PubMed Central

    Sanchez-Gaytan, Brenda L.; Fay, Francois; Lobatto, Mark E.; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E. M.; van Rijs, Sarian M.; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J.; Langer, Robert; Fayad, Zahi A.; Mulder, Willem J M

    2015-01-01

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA–HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA–HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers. PMID:25650634

  17. Regulation of HDL genes: transcriptional, posttranscriptional, and posttranslational.

    PubMed

    Kardassis, Dimitris; Gafencu, Anca; Zannis, Vassilis I; Davalos, Alberto

    2015-01-01

    HDL regulation is exerted at multiple levels including regulation at the level of transcription initiation by transcription factors and signal transduction cascades; regulation at the posttranscriptional level by microRNAs and other noncoding RNAs which bind to the coding or noncoding regions of HDL genes regulating mRNA stability and translation; as well as regulation at the posttranslational level by protein modifications, intracellular trafficking, and degradation. The above mechanisms have drastic effects on several HDL-mediated processes including HDL biogenesis, remodeling, cholesterol efflux and uptake, as well as atheroprotective functions on the cells of the arterial wall. The emphasis is on mechanisms that operate in physiologically relevant tissues such as the liver (which accounts for 80% of the total HDL-C levels in the plasma), the macrophages, the adrenals, and the endothelium. Transcription factors that have a significant impact on HDL regulation such as hormone nuclear receptors and hepatocyte nuclear factors are extensively discussed both in terms of gene promoter recognition and regulation but also in terms of their impact on plasma HDL levels as was revealed by knockout studies. Understanding the different modes of regulation of this complex lipoprotein may provide useful insights for the development of novel HDL-raising therapies that could be used to fight against atherosclerosis which is the underlying cause of coronary heart disease. PMID:25522987

  18. Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex.

    PubMed

    Huang, Ying; Wu, Zhiping; Riwanto, Meliana; Gao, Shengqiang; Levison, Bruce S; Gu, Xiaodong; Fu, Xiaoming; Wagner, Matthew A; Besler, Christian; Gerstenecker, Gary; Zhang, Renliang; Li, Xin-Min; DiDonato, Anthony J; Gogonea, Valentin; Tang, W H Wilson; Smith, Jonathan D; Plow, Edward F; Fox, Paul L; Shih, Diana M; Lusis, Aldons J; Fisher, Edward A; DiDonato, Joseph A; Landmesser, Ulf; Hazen, Stanley L

    2013-09-01

    Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein-associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr71), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other's function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function. PMID:23908111

  19. HDL as a drug and nucleic acid delivery vehicle

    PubMed Central

    Lacko, Andras G.; Sabnis, Nirupama A.; Nagarajan, Bhavani; McConathy, Walter J.

    2015-01-01

    This review is intended to evaluate the research findings and potential clinical applications of drug transport systems, developed based on the concepts of the structure/function and physiological role(s) of high density lipoprotein type nanoparticles. These macromolecules provide targeted transport of cholesteryl esters (a highly lipophilic payload) in their natural/physiological environment. The ability to accommodate highly water insoluble constituents in their core regions enables High density lipoproteins (HDL) type nanoparticles to effectively transport hydrophobic drugs subsequent to systemic administration. Even though the application of reconstituted HDL in the treatment of a number of diseases is reviewed, the primary focus is on the application of HDL type drug delivery agents in cancer chemotherapy. The use of both native and synthetic HDL as drug delivery agents is compared to evaluate their respective potentials for commercial and clinical development. The current status and future perspectives for HDL type nanoparticles are discussed, including current obstacles and future applications in therapeutics. PMID:26578957

  20. The pleiotropic role of HDL in autoimmune diseases.

    PubMed

    Parra, Sandra; Castro, Antoni; Masana, Luis

    2015-01-01

    As is widely known, the classic function of HDL is reverse cholesterol transport (RCT), thus removing cholesterol from peripheral tissues. Early epidemiological studies, such as Framingham's, stated that increased HDL levels were associated with a significant decrease in relative risk for cardiovascular disease (CVD) mortality. However, those with heightened expectations in recent years for the development of therapeutic targets to increase HDL levels have been disappointed, because efforts have demonstrated the opposite effect on cardiovascular and global mortality. However, in contrast, studies have highlighted the complexity and the intriguing role of HDL in different pathological conditions, such as infections, neoplasms, and autoimmune diseases. In this review an attempt is made to summarize some biological pathways that link HDL function with the immune system, and its possible clinical repercussions in autoimmune diseases. PMID:25444650

  1. Synthesis of HDL apolipoproteins by rat hepatocytes

    SciTech Connect

    Hussain, M.M.; Kelley, M.; Zannis, V.I.

    1986-05-01

    The authors have used 2D-PAGE to study the synthesis, intracellular modification, and secretion of rat HDL apolipoproteins by primary cultures of rat hepatocytes. ApoA-IV, apoA-II and apoE synthesized after a 10 min pulse with /sup 35/S-methionine coincided on 2D-gels with their corresponding plasma forms and they were not modified further intracellularly or following secretion. A fraction (< 10%) of apoE was modified intracellularly to minor isoprotein forms that were insensitive to neuraminidase treatment. These later forms also constituted a minor component of the secreted and plasma rat apoE. The intracellular and newly secreted apoA-I differed from its plasma counterpart by -1 charge as described previously. The intracellular forms of rat apoA-I, apoA-IV and unmodified apoE differed from the products of cell free translation of rat liver mRNA by +1 charge. Their findings (a) establish the charge relationship between nascent and plasma rat apolipoproteins, (b) indicate that rat apoA-I, apoA-II and apoA-IV are not modified intracellularly, (c) suggest that there is a difference in the post-translational modification patterns between the rat and human hepatic apoE.

  2. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.

    PubMed Central

    Van Lenten, B J; Hama, S Y; de Beer, F C; Stafforini, D M; McIntyre, T M; Prescott, S M; La Du, B N; Fogelman, A M; Navab, M

    1995-01-01

    We previously reported that high density lipoprotein (HDL) protects against the oxidative modification of low density lipoprotein (LDL) induced by artery wall cells causing these cells to produce pro-inflammatory molecules. We also reported that enzyme systems associated with HDL were responsible for this anti-inflammatory property of HDL. We now report studies comparing HDL before and during an acute phase response (APR) in both humans and a croton oil rabbit model. In rabbits, from the onset of APR the protective effect of HDL progressively decreased and was completely lost by day three. As serum amyloid A (SAA) levels in acute phase HDL (AP-HDL) increased, apo A-I levels decreased 73%. Concomitantly, paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH) levels in HDL declined 71 and 90%, respectively, from days one to three. After day three, there was some recovery of the protective effect of HDL. AP-HDL from human patients and rabbits but not normal or control HDL (C-HDL) exhibited increases in ceruloplasmin (CP). This increase in CP was not seen in acute phase VLDL or LDL. C-HDL incubated with purified CP and re-isolated (CP-HDL), lost its ability to inhibit LDL oxidation. Northern blot analyses demonstrated enhanced expression of MCP-1 in coculture cells treated with AP-HDL and CP-HDL compared to C-HDL. Enrichment of human AP-HDL with purified PON or PAF-AH rendered AP-HDL protective against LDL modification. We conclude that under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule. Images PMID:8675645

  3. Autoimmune Lymphoproliferative Syndrome: A Rare Cause of Disappearing HDL Syndrome.

    PubMed

    Sriram, Swetha; Joshi, Avni Y; Rodriguez, Vilmarie; Kumar, Seema

    2016-01-01

    The term disappearing HDL syndrome refers to development of severe high density lipoprotein cholesterol (HDL-C) deficiency in noncritically ill patients with previously normal HDL-C and triglyceride levels. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of the immune system due to an inability to regulate lymphocyte homeostasis resulting in lymphadenopathy and hepatosplenomegaly. We describe a 17-year-old boy who was evaluated in the lipid clinic for history of undetectable or low HDL-C and low density lipoprotein cholesterol (LDL-C) levels. Past medical history was significant for ALPS IA diagnosed at 10 years of age when he presented with bilateral cervical adenopathy. He was known to have a missense mutation in one allele of the FAS protein extracellular domain consistent with ALPS type 1A. HDL-C and LDL-C levels had been undetectable on multiple occasions, though lipids had not been measured prior to the diagnosis of ALPS. He had been receiving sirolimus for immunosuppression. The HDL-C and LDL-C levels correlated with disease activity and improved to normal levels during times when the activity of ALPS was controlled. This case highlights the importance of considering ALPS as a cause of low HDL-C and LDL-C levels in a child with evidence of lymphoproliferation. PMID:27579193

  4. Protective Effects of HDL Against Ischemia/Reperfusion Injury

    PubMed Central

    Gomaraschi, Monica; Calabresi, Laura; Franceschini, Guido

    2016-01-01

    Several lines of evidence suggest that, besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma high density lipoprotein (HDL) cholesterol level is also associated with short- and long-term unfavorable prognosis in patients, who have recovered from a myocardial infarction, suggesting a direct detrimental effect of low HDL on post-ischemic myocardial function. Experiments performed in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury have clearly shown that HDL are able to preserve cardiac function when given before ischemia or at reperfusion; the protective effects of HDL against I/R injury have been also confirmed in other tissues and organs, as brain and hind limb. HDL were shown to act on coronary endothelial cells, by limiting the increase of endothelium permeability and promoting vasodilation and neoangiogenesis, on white blood cells, by reducing their infiltration into the ischemic tissue and the release of pro-inflammatory and matrix-degrading molecules, and on cardiomyocytes, by preventing the activation of the apoptotic cascade. Synthetic HDL retains the cardioprotective activity of plasma-derived HDL and may become a useful adjunctive therapy to improve clinical outcomes in patients with acute coronary syndromes or undergoing coronary procedures. PMID:26834639

  5. Autoimmune Lymphoproliferative Syndrome: A Rare Cause of Disappearing HDL Syndrome

    PubMed Central

    Sriram, Swetha; Joshi, Avni Y.; Rodriguez, Vilmarie

    2016-01-01

    The term disappearing HDL syndrome refers to development of severe high density lipoprotein cholesterol (HDL-C) deficiency in noncritically ill patients with previously normal HDL-C and triglyceride levels. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of the immune system due to an inability to regulate lymphocyte homeostasis resulting in lymphadenopathy and hepatosplenomegaly. We describe a 17-year-old boy who was evaluated in the lipid clinic for history of undetectable or low HDL-C and low density lipoprotein cholesterol (LDL-C) levels. Past medical history was significant for ALPS IA diagnosed at 10 years of age when he presented with bilateral cervical adenopathy. He was known to have a missense mutation in one allele of the FAS protein extracellular domain consistent with ALPS type 1A. HDL-C and LDL-C levels had been undetectable on multiple occasions, though lipids had not been measured prior to the diagnosis of ALPS. He had been receiving sirolimus for immunosuppression. The HDL-C and LDL-C levels correlated with disease activity and improved to normal levels during times when the activity of ALPS was controlled. This case highlights the importance of considering ALPS as a cause of low HDL-C and LDL-C levels in a child with evidence of lymphoproliferation.

  6. In vivo effects of anacetrapib on preβ HDL: improvement in HDL remodeling without effects on cholesterol absorption.

    PubMed

    Wang, Sheng-Ping; Daniels, Erin; Chen, Ying; Castro-Perez, Jose; Zhou, Haihong; Akinsanya, Karen O; Previs, Stephen F; Roddy, Thomas P; Johns, Douglas G

    2013-10-01

    Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester and triglyceride between HDL and apoB-containing lipoproteins. Anacetrapib (ANA), a reversible inhibitor of CETP, raises HDL cholesterol and lowers LDL cholesterol in dyslipidemic patients. We previously demonstrated that ANA increases macrophage-to-feces reverse cholesterol transport and fecal cholesterol excretion in hamsters, and increased preβ HDL-dependent cholesterol efflux via ABCA1 in vitro. However, the effects of ANA on in vivo preβ HDL have not been characterized. In vitro, ANA inhibited the formation of preβ, however in ANA-treated dyslipidemic hamsters, preβ HDL levels (measured by two-dimensional gel electrophoresis) were increased, in contrast to in vitro findings. Because changes in plasma preβ HDL have been proposed to potentially affect markers of cholesterol absorption with other CETP inhibitors, a dual stable isotope method was used to directly measure cholesterol absorption in hamsters. ANA treatment of hamsters (on either dyslipidemic or normal diet) had no effect on cholesterol absorption, while dalcetrapib-treated hamsters displayed an increase in cholesterol absorption. Taken together, these data support the notion that ANA promotes preβ HDL functionality in vivo, with no effects on cholesterol absorption. PMID:23898048

  7. Emerging therapies for raising high-density lipoprotein cholesterol (HDL-C) and augmenting HDL particle functionality.

    PubMed

    Barylski, Marcin; Toth, Peter P; Nikolic, Dragana; Banach, Maciej; Rizzo, Manfredi; Montalto, Giuseppe

    2014-06-01

    High-density lipoprotein (HDL) particles are highly complex polymolecular aggregates capable of performing a remarkable range of atheroprotective functions. Considerable research is being performed throughout the world to develop novel pharmacologic approaches to: (1) promote apoprotein A-I and HDL particle biosynthesis; (2) augment capacity for reverse cholesterol transport so as to reduce risk for the development and progression of atherosclerotic disease; and (3) modulate the functionality of HDL particles in order to increase their capacity to antagonize oxidation, inflammation, thrombosis, endothelial dysfunction, insulin resistance, and other processes that participate in arterial wall injury. HDL metabolism and the molecular constitution of HDL particles are highly complex and can change in response to both acute and chronic alterations in the metabolic milieu. To date, some of these interventions have been shown to positively impact rates of coronary artery disease progression. However, none of them have as yet been shown to significantly reduce risk for cardiovascular events. In the next 3-5 years a variety of pharmacologic interventions for modulating HDL metabolism and functionality will be tested in large, randomized, prospective outcomes trials. It is hoped that one or more of these therapeutic approaches will result in the ability to further reduce risk for cardiovascular events once low-density lipoprotein cholesterol and non-HDL-cholesterol targets have been attained. PMID:24840270

  8. [Raising HDL cholesterol: which is the best strategy?].

    PubMed

    Alfonso, John Edwin Feliciano; Ariza, Iván Darío Sierra

    2008-01-01

    After having reached the objective for the LDL cholesterol levels, it becomes imperative to reach the objective for HDL cholesterol, known for its anti-atherogenic properties, generally confirmed in many epidemiological studies. This review deals, in a clear and concise manner, with the different alternatives available in daily clinical practice to raise the HDL cholesterol levels of patients, to achieve better outcomes in terms of morbidity and mortality in cardiovascular disease. PMID:18719798

  9. Origins and determinants of HDL populations and their subpopulations

    SciTech Connect

    Nichols, A.V.; Gong, E.L.

    1990-06-01

    This paper describes the origins and determinants of High Density Lipoproteins (HDL) populations and their subpopulations. Our survey of compositional properties of small HDL particles indicates considerable variation in core lipid content reflecting in large part the origins of such particles. Whether small HDL particles of different core content and apolipoprotein composition differ in their metabolic properties and function in reverse cholesterol transport remains to be established. Our studies demonstrate that lipolysis-derived products can facilitate formation in vitro of small Apolipoprotein (AI) particles with properties approximating those of plasma pre-{beta} HDL. Of particular interest is our observation that small AI particles are an exclusive reassembly product in mixtures containing POPE and FFA. This observation may be relevant to the physiologic origins of PE in lipoprotein structure and its role in metabolism and secretion of nascent HDL. Lastly our observations on the reactivity of small AI particles, containing FFA, with LCAT and LDL suggest further linkages between triglyceride and HDL metabolism. 19 refs., 4 figs., 5 tabs.

  10. Graded effects of proteinuria on HDL structure in nephrotic rats.

    PubMed

    Shearer, Gregory C; Newman, John W; Hammock, Bruce D; Kaysen, George A

    2005-05-01

    Nephrotic syndrome is characterized by increased triglycerides resulting from decreased clearance of VLDL and chylomicrons. These triglyceride-rich lipoproteins are structurally altered by interaction with HDL derived from animals with proteinuria and not as a consequence of hypoalbuminemia. HDL isolated from rats with massive proteinuria is depleted in apolipoprotein E (apoE). It is unknown at what threshold of urinary albumin loss HDL structure is altered, and it is unknown what effects proteinuria has on apolipoproteins other than apoE. Two models of albuminuria were used in Sprague-Dawley rats: Adriamycin and passive Heymann nephritis (HN). The adriamycin group was divided into minimal albumin excretion (MAE) and intermediate albumin excretion (MAE, 1 to 40; intermediate albumin excretion, 60 to 210 mg/d per 100 g body wt). Urinary albumin excretion exceeded 300 mg/d per 100 g body wt in the HN rats. HDL apolipoprotein composition was analyzed with SDS-PAGE densitometry and liquid chromatography-time of flight mass spectrometer mass spectrometry. HDL apoA-IV content relative to apoA-I was reduced at all levels of albuminuria (P < 0.0001). ApoE was not reduced in MAE but was significantly reduced in IAE (72%; P < 0.001). By contrast, apoA-II and apoC-III were each significantly increased with increasing UAE. ApoA-IV and apoE were decreased to approximately 10% of control in HDL isolated from rats with HN, whereas apoA-II, apoC-II, and apoC-III were each significantly increased relative to apoA-I. HDL is structurally altered by levels of albuminuria that are insufficient to change serum albumin levels and is progressively altered as albuminuria increases. PMID:15788471

  11. HDL Cholesterol, Apolipoproteins, and Cardiovascular Risk in Hemodialysis Patients

    PubMed Central

    Genser, Bernd; Drechsler, Christiane; Scharnagl, Hubert; Grammer, Tanja B.; Stojakovic, Tatjana; Krane, Vera; Ritz, Eberhard; Wanner, Christoph; März, Winfried

    2015-01-01

    High concentrations of HDL cholesterol are considered to indicate efficient reverse cholesterol transport and to protect from atherosclerosis. However, HDL has been suggested to be dysfunctional in ESRD. Hence, our main objective was to investigate the effect of HDL cholesterol on outcomes in maintenance hemodialysis patients with diabetes. Moreover, we investigated the associations between the major protein components of HDL (apoA1, apoA2, and apoC3) and end points. We performed an exploratory, post hoc analysis with 1255 participants (677 men and 578 women) of the German Diabetes Dialysis study. The mean age was 66.3 years and the mean body mass index was 28.0 kg/m2. The primary end point was a composite of cardiac death, myocardial infarction, and stroke. The secondary end point included all-cause mortality. The mean duration of follow-up was 3.9 years. A total of 31.3% of the study participants reached the primary end point and 49.1% died from any cause. HDL cholesterol and apoA1 and apoC3 quartiles were not related to end points. However, there was a trend toward an inverse association between apoA2 and all-cause mortality. The hazard ratio for death from any cause in the fourth quartile compared with the first quartile of apoA2 was 0.63 (95% confidence interval, 0.40 to 0.89). The lack of an association between HDL cholesterol and cardiovascular risk may support the concept of dysfunctional HDL in hemodialysis. The possible beneficial effect of apoA2 on survival requires confirmation in future studies. PMID:25012163

  12. Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1.

    PubMed

    Givvimani, Srikanth; Kundu, Sourav; Pushpakumar, Sathnur; Doyle, Vivian; Narayanan, Nithya; Winchester, Lee J; Veeranki, Sudhakar; Metreveli, Naira; Tyagi, Suresh C

    2015-09-01

    Paraoxanase-1 (PON1) is an HDL-associated enzyme that contributes to the antioxidant and antiatherosclerotic properties of HDL. Lack of PON1 results in dysfunctional HDL. HHcy is a risk factor for cardiovascular disorders, and instigates vascular dysfunction and ECM remodeling. Although studies have reported HHcy during atherosclerosis, the exact mechanism is unclear. Here, we hypothesize that dysfunctional HDL due to lack of PON1 contributes to endothelial impairment and atherogenesis through HHcy-induced ECM re-modeling. To verify this hypothesis, we used C57BL6/J and PON1 knockout mice (KO) and fed them an atherogenic diet. The expression of Akt, ADMA, and DDAH, as well as endothelial gap junction proteins such as Cx-37 and Cx-40 and eNOS was measured for vascular dysfunction and inflammation. We observed that cardiac function was decreased and plasma Hcy levels were increased in PON1 KO mice fed the atherogenic diet compared with the controls. Expression of Akt, eNOS, DDAH, Cx-37, and Cx-40 was decreased, and the expression of MMP-9 and ADMA was increased in PON1 KO mice fed an atherogenic diet compared with the controls. Our results suggest that HHcy plays an intricate role in dysfunctional HDL, owing to the lack of PON1. This contributes to vascular endothelial impairment and atherosclerosis through MMP-9-induced vascular remodeling. PMID:26176406

  13. Modular hardware synthesis using an HDL. [Hardware Description Language

    NASA Technical Reports Server (NTRS)

    Covington, J. A.; Shiva, S. G.

    1981-01-01

    Although hardware description languages (HDL) are becoming more and more necessary to automated design systems, their application is complicated due to the difficulty in translating the HDL description into an implementable format, nonfamiliarity of hardware designers with high-level language programming, nonuniform design methodologies and the time and costs involved in transfering HDL design software. Digital design language (DDL) suffers from all of the above problems and in addition can only by synthesized on a complete system and not on its subparts, making it unsuitable for synthesis using standard modules or prefabricated chips such as those required in LSI or VLSI circuits. The present paper presents a method by which the DDL translator can be made to generate modular equations that will allow the system to be synthesized as an interconnection of lower-level modules. The method involves the introduction of a new language construct called a Module which provides for the separate translation of all equations bounded by it.

  14. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo

    PubMed Central

    Sacks, Frank M.; Rudel, Lawrence L.; Conner, Adam; Akeefe, Hassibullah; Kostner, Gerhard; Baki, Talal; Rothblat, George; de la Llera-Moya, Margarita; Asztalos, Bela; Perlman, Timothy; Zheng, Chunyu; Alaupovic, Petar; Maltais, Jo-Ann B.; Brewer, H. Bryan

    2009-01-01

    Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small α, preβ-1, and other preβ forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Preβ-1-like HDL had a plasma residence time of 8 ± 6 h and was converted entirely to large α-HDL having residence times of 13–14 h. Small α-HDL was converted entirely to large α-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis. PMID:19144994

  15. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo.

    PubMed

    Sacks, Frank M; Rudel, Lawrence L; Conner, Adam; Akeefe, Hassibullah; Kostner, Gerhard; Baki, Talal; Rothblat, George; de la Llera-Moya, Margarita; Asztalos, Bela; Perlman, Timothy; Zheng, Chunyu; Alaupovic, Petar; Maltais, Jo-Ann B; Brewer, H Bryan

    2009-05-01

    Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small alpha, prebeta-1, and other prebeta forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Prebeta-1-like HDL had a plasma residence time of 8 +/- 6 h and was converted entirely to large alpha-HDL having residence times of 13-14 h. Small alpha-HDL was converted entirely to large alpha-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis. PMID:19144994

  16. Volumetric determination of apolipoprotein stoichiometry of circulating HDL subspecies1[S

    PubMed Central

    Segrest, Jere P.; Cheung, Marian C.; Jones, Martin K.

    2013-01-01

    Although HDL is inversely correlated with coronary heart disease, elevated HDL-cholesterol is not always protective. Additionally, HDL has biological functions that transcend any antiatherogenic role: shotgun proteomics show that HDL particles contain 84 proteins (latest count), many correlating with antioxidant and anti-inflammatory properties of HDL. ApoA-I has been suggested to serve as a platform for the assembly of these protein components on HDL with specific functions - the HDL proteome. However, the stoichiometry of apoA-I in HDL subspecies is poorly understood. Here we use a combination of immunoaffinity chromatography data and volumetric analysis to evaluate the size and stoichiometry of LpA-I and LpA-I,A-II particles. We conclude that there are three major LpA-I subspecies: two major particles, HDL[4] in the HDL3 size range (d = 85.0 ± 1.2 Å) and HDL[7] in the HDL2 size range (d = 108.5 ± 3.8 Å) with apoA-I stoichiometries of 3 and 4, respectively, and a small minor particle, HDL[1] (d = 73.8 ± 2.1Å) with an apoA-I stoichiometry of 2. Additionally, we conclude that the molar ratio of apolipoprotein to surface lipid is significantly higher in circulating HDL subspecies than in reconstituted spherical HDL particles, presumably reflecting a lack of phospholipid transfer protein in reconstitution protocols. PMID:23883582

  17. 27 CFR 9.195 - Alta Mesa.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... County, California, and is entirely within the Lodi viticultural area (27 CFR 9.107). The Alta Mesa... Grant Line Road to Wilton Road at the hamlet of Sheldon, and then continue southeast on Wilton Road...

  18. HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications

    PubMed Central

    Levkau, Bodo

    2015-01-01

    Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid contained in High-density lipoproteins (HDL) and has drawn considerable attention in the lipoprotein field as numerous studies have demonstrated its contribution to several functions inherent to HDL. Some of them are partly and some entirely due to the S1P contained in HDL (HDL-S1P). Despite the presence of over 1000 different lipids in HDL, S1P stands out as it possesses its own cell surface receptors through which it exercises key physiological functions. Most of the S1P in human plasma is associated with HDL, and the amount of HDL-S1P influences the quality and quantity of HDL-dependent functions. The main binding partner of S1P in HDL is apolipoprotein M but others may also exist particularly under conditions of acute S1P elevations. HDL not only exercise functions through their S1P content but have also an impact on genuine S1P signaling by influencing S1P bioactivity and receptor presentation. HDL-S1P content is altered in human diseases such as atherosclerosis, coronary artery disease, myocardial infarction, renal insufficiency and diabetes mellitus. Low HDL-S1P has also been linked to impaired HDL functions associated with these disorders. Although the pathophysiological and molecular reasons for such disease-associated shifts in HDL-S1P are little understood, there have been successful approaches to circumvent their adverse implications by pharmacologically increasing HDL-S1P as means to improve HDL function. This mini-review will cover the current understanding of the contribution of HDL-S1P to physiological HDL function, its alteration in disease and ways for its restoration to correct HDL dysfunction. PMID:26539121

  19. Design time optimization for hardware watermarking protection of HDL designs.

    PubMed

    Castillo, E; Morales, D P; García, A; Parrilla, L; Todorovich, E; Meyer-Baese, U

    2015-01-01

    HDL-level design offers important advantages for the application of watermarking to IP cores, but its complexity also requires tools automating these watermarking algorithms. A new tool for signature distribution through combinational logic is proposed in this work. IPP@HDL, a previously proposed high-level watermarking technique, has been employed for evaluating the tool. IPP@HDL relies on spreading the bits of a digital signature at the HDL design level using combinational logic included within the original system. The development of this new tool for the signature distribution has not only extended and eased the applicability of this IPP technique, but it has also improved the signature hosting process itself. Three algorithms were studied in order to develop this automated tool. The selection of a cost function determines the best hosting solutions in terms of area and performance penalties on the IP core to protect. An 1D-DWT core and MD5 and SHA1 digital signatures were used in order to illustrate the benefits of the new tool and its optimization related to the extraction logic resources. Among the proposed algorithms, the alternative based on simulated annealing reduces the additional resources while maintaining an acceptable computation time and also saving designer effort and time. PMID:25861681

  20. HDL abnormalities in nephrotic syndrome and chronic kidney disease.

    PubMed

    Vaziri, Nosratola D

    2016-01-01

    Normal HDL activity confers cardiovascular and overall protection by mediating reverse cholesterol transport and through its potent anti-inflammatory, antioxidant, and antithrombotic functions. Serum lipid profile, as well as various aspects of HDL metabolism, structure, and function can be profoundly altered in patients with nephrotic range proteinuria or chronic kidney disease (CKD). These abnormalities can, in turn, contribute to the progression of cardiovascular complications and various other comorbidities, such as foam cell formation, atherosclerosis, and/or glomerulosclerosis, in affected patients. The presence and severity of proteinuria and renal insufficiency, as well as dietary and drug regimens, pre-existing genetic disorders of lipid metabolism, and renal replacement therapies (including haemodialysis, peritoneal dialysis, and renal transplantation) determine the natural history of lipid disorders in patients with kidney disease. Despite the adverse effects associated with dysregulated reverse cholesterol transport and advances in our understanding of the underlying mechanisms, safe and effective therapeutic interventions are currently lacking. This Review provides an overview of HDL metabolism under normal conditions, and discusses the features, mechanisms, and consequences of HDL abnormalities in patients with nephrotic syndrome or advanced CKD. PMID:26568191

  1. Design Time Optimization for Hardware Watermarking Protection of HDL Designs

    PubMed Central

    Castillo, E.; Morales, D. P.; García, A.; Parrilla, L.; Todorovich, E.; Meyer-Baese, U.

    2015-01-01

    HDL-level design offers important advantages for the application of watermarking to IP cores, but its complexity also requires tools automating these watermarking algorithms. A new tool for signature distribution through combinational logic is proposed in this work. IPP@HDL, a previously proposed high-level watermarking technique, has been employed for evaluating the tool. IPP@HDL relies on spreading the bits of a digital signature at the HDL design level using combinational logic included within the original system. The development of this new tool for the signature distribution has not only extended and eased the applicability of this IPP technique, but it has also improved the signature hosting process itself. Three algorithms were studied in order to develop this automated tool. The selection of a cost function determines the best hosting solutions in terms of area and performance penalties on the IP core to protect. An 1D-DWT core and MD5 and SHA1 digital signatures were used in order to illustrate the benefits of the new tool and its optimization related to the extraction logic resources. Among the proposed algorithms, the alternative based on simulated annealing reduces the additional resources while maintaining an acceptable computation time and also saving designer effort and time. PMID:25861681

  2. Implication of Low HDL-c Levels in Patients with Average LDL-c Levels: A Focus on Oxidized LDL, Large HDL Subpopulation, and Adiponectin

    PubMed Central

    Mascarenhas-Melo, Filipa; Sereno, José; Teixeira-Lemos, Edite; Marado, Daniela; Palavra, Filipe; Pinto, Rui; Rocha-Pereira, Petronila; Teixeira, Frederico; Reis, Flávio

    2013-01-01

    To evaluate the impact of low levels of high density lipoprotein cholesterol (HDL-c) on patients with LDL-c average levels, focusing on oxidative, lipidic, and inflammatory profiles. Patients with cardiovascular risk factors (n = 169) and control subjects (n = 73) were divided into 2 subgroups, one of normal HDL-c and the other of low HDL-c levels. The following data was analyzed: BP, BMI, waist circumference and serum glucose Total-c, TGs, LDL-c, oxidized LDL, total HDL-c and subpopulations (small, intermediate, and large), paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF-α, adiponectin, VEGF, and iCAM1. In the control subgroup with low HDL-c levels, significantly higher values of BP and TGs and lower values of PON1 activity and adiponectin were found, versus control normal HDL-c subgroup. However, differences in patients' subgroups were clearly more pronounced. Indeed, low HDL-c subgroup presented increased HbA1c, TGs, non-HDL-c, Ox-LDL, hsCRP, VEGF, and small HDL-c and reduced adiponectin and large HDL. In addition, Ox-LDL, large-HDL-c, and adiponectin presented interesting correlations with classical and nonclassical markers, mainly in the normal HDL-c patients' subgroup. In conclusion, despite LDL-c average levels, low HDL-c concentrations seem to be associated with a poor cardiometabolic profile in a population with cardiovascular risk factors, which is better evidenced by traditional and nontraditional CV biomarkers, including Ox-LDL, large HDL-c, and adiponectin. PMID:24282340

  3. Mechanism of transfer of LDL-derived free cholesterol to HDL subfractions in human plasma

    SciTech Connect

    Miida, T.; Fielding, C.J.; Fielding, P.E. )

    1990-11-01

    The transfer of ({sup 3}H)cholesterol in low-density lipoprotein (LDL) to different high-density lipoprotein (HDL) species in native human plasma was determined by using nondenaturing two-dimensional electrophoresis. Transfer from LDL had a t{sub 1/2} at 37{degree}C of 51 {plus minus} 8 min and an activation energy of 18.0 kCal mol{sup {minus}1}. There was unexpected specificity among HDL species as acceptors of LDL-derived labeled cholesterol. The largest fraction of the major {alpha}-migrating class (HDL{sub 2b}) was the major initial acceptor of LDL-derived cholesterol. Kinetic analysis indicated a rapid secondary transfer from HDL{sub 2b} to smaller {alpha}HDL (particularly HDL{sub 3}) driven enzymatically by the lecithin-cholesterol acyltransferase reaction. Rates of transfer among {alpha}HDL were most rapid from the largest {alpha}HDL fraction (HDL{sub 2b}), suggesting possible protein-mediated facilitation. Simultaneous measurements of the transport of LDL-derived and cell-derived isotopic cholesterol indicated that the former preferably utilized the {alpha}HDL pathyway, with little label in pre-{beta}HDL. The same experiments confirmed earlier data that cell-derived cholesterol is preferentially channeled through pre-{beta}HDL. The authors suggest that the functional heterogeneity of HDL demonstrated here includes the ability to independently process cell- and LDL-derived free cholesterol.

  4. HDL and Atherosclerosis Regression: Evidence from Pre-clinical and Clinical Studies

    PubMed Central

    Feig, Jonathan E.; Hewing, Bernd; Smith, Jonathan D.; Hazen, Stanley L.; Fisher, Edward A.

    2014-01-01

    High density lipoprotein particles (HDL) transport, among other molecules, cholesterol (HDL-C). In epidemiologic studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease (CVD). It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, a number of recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased CVD risk, giving rise to a controversy over whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. On balance, the evidence from pre-clinical and (limited) clinical studies show that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. While more research will be needed on basic mechanisms and to establish that these changes translate clinically to reduced CVD events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent, but emphasizes the important distinction between HDL function and plasma levels of HDL-C. PMID:24385513

  5. HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

    PubMed Central

    Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mili; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry-Anne; Qiu, Xiayang; Johns, Douglas G.; Charles, M. Arthur; Ren, Gang

    2015-01-01

    Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL. PMID:25737239

  6. HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

    DOE PAGESBeta

    Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mili; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry-Anne; Qiu, Xiayang; et al

    2015-03-04

    Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobicmore » environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.« less

  7. HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

    SciTech Connect

    Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mili; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry-Anne; Qiu, Xiayang; Johns, Douglas G.; Charles, M. Arthur; Ren, Gang

    2015-03-04

    Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

  8. HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

    NASA Astrophysics Data System (ADS)

    Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mili; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry-Anne; Qiu, Xiayang; Johns, Douglas G.; Charles, M. Arthur; Ren, Gang

    2015-03-01

    Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

  9. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

    The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials. In addition to HDL infusion therapy an alternative way to exploit beneficial cardiovascular effects of HDL/ApoA-1 is to use gene transfer. Preclinical studies have shown evidence of benefit using this approach; however clinical validation is yet lacking. This review summarizes our current knowledge of the aforementioned strategies. PMID:26388776

  10. High Pre-β1 HDL Concentrations and Low Lecithin: Cholesterol Acyltransferase Activities Are Strong Positive Risk Markers for Ischemic Heart Disease and Independent of HDL-Cholesterol

    PubMed Central

    Sethi, Amar A.; Sampson, Maureen; Warnick, Russell; Muniz, Nehemias; Vaisman, Boris; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Remaley, Alan T.

    2016-01-01

    BACKGROUND We hypothesized that patients with high HDL-cholesterol (HDL-C) and ischemic heart disease (IHD) may have dysfunctional HDL or unrecognized nonconventional risk factors. METHODS Individuals with IHD (Copenhagen University Hospital) and either high HDL-C (n = 53; women ≥735 mg/L; men ≥619 mg/L) or low HDL-C (n = 42; women ≤387 mg/L; men ≤341 mg/L) were compared with individuals without IHD (Copenhagen City Heart Study) matched by age, sex, and HDL-C concentrations (n = 110). All participants had concentrations within reference intervals for LDL-C (<1600 mg/L) and triglyceride (<1500 mg/L), and none were treated with lipid-lowering medications. Pre-β1 HDL and phospholipid transfer protein concentrations were measured by using commercial kits and lecithin:cholesterol acyltransferase (LCAT) activity by using a proteoliposome cholesterol esterification assay. RESULTS Pre-β1 HDL concentrations were 2-fold higher in individuals with IHD vs no IHD in both the high [63 (5.7) vs 35 (2.3) mg/L; P < 0.0001] and low HDL-C [49 (5.0) vs 27 (1.5) mg/L; P = 0.001] groups. Low LCAT activity was also associated with IHD in the high [95.2 (6.7) vs 123.0 (5.3) μmol · L−1 · h−1; P = 0.002] and low [93.4 (8.3) vs 113.5 (4.9) μmol · L−1 · h−1; P = 0.03] HDL-C groups. ROC curves for pre-β1 HDL in the high–HDL-C groups yielded an area under the curve of 0.71 (95% CI: 0.61–0.81) for predicting IHD, which increased to 0.92 (0.87–0.97) when LCAT was included. Similar results were obtained for low HDL-C groups. An inverse correlation between LCAT activity and pre-β1 HDL was observed (r2 = 0.30; P < 0.0001) in IHD participants, which was stronger in the low HDL-C group (r2 = 0.56; P < 0.0001). CONCLUSIONS IHD was associated with high pre-β1 HDL concentrations and low LCAT levels, yielding correct classification in more than 90% of the IHD cases for which both were measured, thus making pre-β1 HDL concentration and LCAT activity level potentially

  11. HDL-Mediated Cellular Cholesterol Efflux Assay Method.

    PubMed

    Hafiane, Anouar; Genest, Jacques

    2015-01-01

    Biomarkers of high-density lipoprotein (HDL) function may provide mechanistic insights and better cardiovascular risk discrimination than HDL-cholesterol mass. The purpose of this work is to describe a simplified experimental protocol that can be used in the determination of cholesterol efflux from macrophages cultured cells and be brought to a medium throughput volume. The cellular cholesterol efflux assay is designed to quantify the rate of cholesterol efflux from cultured cells to an acceptor particle or to plasma. This assay is multi step, cell based assay. Various factors, if not carefully controlled may influence the accuracy and reproducibility of the assay. Attempts were made to address factors influencing this assay and to provide a standardized method that is relatively rapid and scalable. We demonstrate that further centrifugation of the HDL fraction is necessary to avoid apolipoprotein B contamination when using polyethylene glycol (PEG) method. We demonstrate also no effect on cholesterol efflux efficiency when using PEG with plasma or serum. This method has been previously applied in our laboratory in context of cardiovascular research, cardiovascular disease and pharmacologic therapies. PMID:26663796

  12. HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype.

    PubMed

    Shroff, Rukshana; Speer, Thimoteus; Colin, Sophie; Charakida, Marietta; Zewinger, Stephen; Staels, Bart; Chinetti-Gbaguidi, Giulia; Hettrich, Inga; Rohrer, Lucia; O'Neill, Francis; McLoughlin, Eve; Long, David; Shanahan, Catherine M; Landmesser, Ulf; Fliser, Danilo; Deanfield, John E

    2014-11-01

    Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2-5 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation. PMID:24854267

  13. HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity.

    PubMed

    Borja, Mark S; Ng, Kit F; Irwin, Angela; Hong, Jaekyoung; Wu, Xing; Isquith, Daniel; Zhao, Xue-Qiao; Prazen, Bryan; Gildengorin, Virginia; Oda, Michael N; Vaisar, Tomáš

    2015-10-01

    HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT. PMID:26254308

  14. HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A growing body of evidence from epidemiological data, animal studies, and clinical trials supports HDL as the next target to reduce residual cardiovascular risk in statin-treated, high-risk patients. For more than 3 decades, HDL cholesterol has been employed as the principal clinical measure of HDL ...

  15. HDL function and subclinical atherosclerosis in juvenile idiopathic arthritis

    PubMed Central

    Mani, Preethi; Uno, Kiyoko; Duong, MyNgan; Wolski, Kathy; Spalding, Steven; Husni, M. Elaine

    2016-01-01

    Background Increasing evidence suggests that inflammation adversely impacts the protective properties of high-density lipoproteins (HDL) and progression of atherosclerosis. The impact of early chronic inflammatory conditions on HDL function and vascular risk has not been well investigated. Methods We compared measures of HDL particle distribution and functionality, in addition to measures of carotid intima-medial thickness (cIMT) in patients with juvenile idiopathic arthritis (JIA) and age matched controls. Results JIA patients demonstrated lower levels of HDL cholesterol [47.0 (40.0, 56.0) vs. 56.0 (53.0, 61.0) mg/dL, P=0.04], total HDL [29.5 (27.9, 32.3) vs. 32.9 (31.6, 36.3) mg/dL, P=0.05] and large HDL [5.1 (3.7, 7.3) vs. 8.0 (6.7, 9.7) mg/dL, P=0.04] particles. In association JIA patients demonstrated greater cholesterol efflux mediated via ATP binding cassette A1 (ABCA1) [17.3% (12.8, 19.7) vs. 10.0% (5.8, 16.0), P=0.05] and less efflux mediated via ATP binding cassette G-1 (ABCG1) [3.2% (2.0, 3.9) vs. 4.8% (3.5, 5.8), P=0.01] and SR-B1 [6.9% (6.0, 8.4) vs. 9.1% (8.6, 10.2), P=0.002] compared with controls. Exposure of macrophages to serum from JIA patients resulted in a smaller increase in mRNA expression of ABCA1 (2.0±0.95 vs. 7.1±5.7 fold increase, P=0.01) and greater increases in expression of ABCG1 [1.4 (0.9, 1.5) vs. 0.8 (0.7, 1.1) fold increase, P=0.04] and SR-B1 (1.3±0.47 vs. 0.7±0.3 fold increase, P=0.001) compared with controls. Arylesterase (128.9±27.6 vs. 152.0±45.2 umoles/min/mL, P=0.04) activity and endothelial cell migration (491.2±68.9 vs. 634.2±227.4 cells/field, P=0.01) were less in JIA patients. No differences in cIMT were observed between JIA patients and controls. Conclusions The presence of JIA was associated with alterations in HDL particle distribution, cholesterol efflux and non-lipid transporting activities. The ultimate implication of these findings for cardiovascular risk requires further investigation. PMID:26885490

  16. Distinct composition of human fetal HDL attenuates its anti-oxidative capacity.

    PubMed

    Sreckovic, Ivana; Birner-Gruenberger, Ruth; Obrist, Britta; Stojakovic, Tatjana; Scharnagl, Hubert; Holzer, Michael; Scholler, Monika; Philipose, Sonia; Marsche, Gunther; Lang, Uwe; Desoye, Gernot; Wadsack, Christian

    2013-04-01

    In human high-density lipoprotein (HDL) represents the major cholesterol carrying lipoprotein class in cord blood, while cholesterol is mainly carried by low-density lipoprotein in maternal serum. Additionally, to carrying cholesterol, HDL also associates with a range of proteins as cargo. We tested the hypothesis that fetal HDL carries proteins qualitatively and quantitatively different from maternal HDL. These differences then contribute to distinct HDL functionality in both circulations. Shotgun proteomics and biochemical analyses were used to assess composition/function of fetal and maternal HDL isolated from uncomplicated human pregnancies at term of gestation. The pattern of analyzed proteins that were statistically elevated in fetal HDL (apoE, proteins involved in coagulation, transport processes) suggests a particle characteristic for the light HDL2 sub-fraction. In contrast, proteins that were enriched in maternal HDL (apoL, apoF, PON1, apoD, apoCs) have been described almost exclusively in the dense HDL3 fraction and relevant to its anti-oxidative function and role in innate immunity. Strikingly, PON1 mass and activity were 5-fold lower (p<0.01) in the fetus, which was accompanied by attenuation of anti-oxidant capacity of fetal HDL. Despite almost equal quantity of CETP in maternal and fetal HDL, its enzymatic activity was 55% lower (p<0.001) in the fetal circulation, whereas LCAT activity was not altered. These findings indicate that maternally derived HDL differs from fetal HDL with respect to its proteome, size and function. Absence of apoA-1, apoL and PON1 on fetal HDL is associated with decreased anti-oxidative properties together with deficiency in innate immunity collectively indicating distinct HDLs in fetuses. PMID:23321267

  17. Regional variations in HDL metabolism in human fat cells: effect of cell size

    SciTech Connect

    Despres, J.; Fong, B.S.; Julien, P.; Jimenez, J.; Angel, A.

    1987-05-01

    Abdominal obesity is related to reduced plasma high-density lipoprotein (HDL) cholesterol, and both are associated with cardiovascular disease risk. The authors have observed that plasma membranes from abdominal subcutaneous adipocytes have a greater HDL binding capacity than omental fat cell plasma membranes. The present study examined whether these binding characteristics could be due to differences in fat cell size or cholesterol concentration between the two adipose depots. Abdominal subcutaneous and deep omental fat were obtained from massively obese patients at surgery. Subcutaneous abdominal fat cells were significantly larger and their cellular cholesterol content greater than omental adipocytes. The uptake of HDL by collagenase-isolated fat cells was studied by incubating the cells for 2 h at 37/sup 0/C with 10 ..mu..g/ml /sup 125/I-HDL/sub 2/ or /sup 125/I-HDL/sub 3/. In both depots, the cellular uptake of /sup 125/I-HDL/sub 2/ and /sup 125/I-HDL/sub 3/ was specifically inhibited by addition of 25-fold excess unlabeled HDL and a close correlation was observed between the cellular uptake of /sup 125/I-HDL/sub 2/ and /sup 125/I-HDL/sub 3/. In obese patients, the uptake of /sup 125/I-HDL was higher in subcutaneous cells than in omental cells. The cellular /sup 125/I-HDL uptake was significantly correlated with adipocyte size and fat cell cholesterol content but not with adipocyte cholesterol concentration. These results suggest that the higher HDL uptake observed in subcutaneous cells compared with omental cells in obesity is the result of differences in adipocyte size rather than differences in the cholesterol concentration (cholesterol-to-triglyceride ratio). The increased interaction of HDL with hypertrophied abdominal adipocytes may play an important role in determining the lipid composition of HDL in obesity.

  18. 27 CFR 9.195 - Alta Mesa.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... County, California, and is entirely within the Lodi viticultural area (27 CFR 9.107). The Alta Mesa... line's intersection with the 105-foot contour line and an unimproved extension of Blake Road, section 9, T6N, R7E (Sloughhouse Quadrangle); then (9) Proceed west 0.3 mile on the unimproved extension of...

  19. 27 CFR 9.195 - Alta Mesa.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... County, California, and is entirely within the Lodi viticultural area (27 CFR 9.107). The Alta Mesa... line's intersection with the 105-foot contour line and an unimproved extension of Blake Road, section 9, T6N, R7E (Sloughhouse Quadrangle); then (9) Proceed west 0.3 mile on the unimproved extension of...

  20. 27 CFR 9.195 - Alta Mesa.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... County, California, and is entirely within the Lodi viticultural area (27 CFR 9.107). The Alta Mesa... line's intersection with the 105-foot contour line and an unimproved extension of Blake Road, section 9, T6N, R7E (Sloughhouse Quadrangle); then (9) Proceed west 0.3 mile on the unimproved extension of...

  1. Bile acids reduce endocytosis of high-density lipoprotein (HDL) in HepG2 cells.

    PubMed

    Röhrl, Clemens; Eigner, Karin; Fruhwürth, Stefanie; Stangl, Herbert

    2014-01-01

    High-density lipoprotein (HDL) transports lipids to hepatic cells and the majority of HDL-associated cholesterol is destined for biliary excretion. Cholesterol is excreted into the bile directly or after conversion to bile acids, which are also present in the plasma as they are effectively reabsorbed through the enterohepatic cycle. Here, we provide evidence that bile acids affect HDL endocytosis. Using fluorescent and radiolabeled HDL, we show that HDL endocytosis was reduced in the presence of high concentrations of taurocholate, a natural non-cell-permeable bile acid, in human hepatic HepG2 and HuH7 cells. In contrast, selective cholesteryl-ester (CE) uptake was increased. Taurocholate exerted these effects extracellularly and independently of HDL modification, cell membrane perturbation or blocking of endocytic trafficking. Instead, this reduction of endocytosis and increase in selective uptake was dependent on SR-BI. In addition, cell-permeable bile acids reduced HDL endocytosis by farnesoid X receptor (FXR) activation: chenodeoxycholate and the non-steroidal FXR agonist GW4064 reduced HDL endocytosis, whereas selective CE uptake was unaltered. Reduced HDL endocytosis by FXR activation was independent of SR-BI and was likely mediated by impaired expression of the scavenger receptor cluster of differentiation 36 (CD36). Taken together we have shown that bile acids reduce HDL endocytosis by transcriptional and non-transcriptional mechanisms. Further, we suggest that HDL endocytosis and selective lipid uptake are not necessarily tightly linked to each other. PMID:25010412

  2. Effect of alcohol on hepatic receptor of high density lipoproteins (HDL)

    SciTech Connect

    Lin, R.C.; Miller, B.M. V.A. Medical Center, Indianapolis, IN )

    1991-03-11

    Moderate alcohol intake has been shown to increase HDL cholesterol and proteins. The seemingly protective effect' of moderate alcohol drinking against cardiovascular diseases has been attributed to an increase in serum HDL. In this study, the authors show that a receptor for HDL is present in rat liver. Rat liver membrane was prepared by stepwise ultracentrifugation. Apo Al was iodinated using {sup 125}I-NaI and IODO-beads. HDL was labeled by incubating with {sup 125}I-apo Al then refloated be centrifugation. Binding of {sup 125}I-HDL to rat liver membrane reached equilibrium by 2-3 h and was saturable at 37C. The binding was inhibited 80% by excess unlabeled HDL, but was inhibited only 25% by excess LDL. It could also be inhibited by preincubating HDL with anti-apo Al or anti-apo E antisera but not with anti-apo AIV or control sera. The binding affinity of HDL to the liver membrane of rats fed alcohol for 5 wk was 50% that of their pair-fed controls. Thus a decrease in the binding of HDL to liver membrane due to alcohol-drinking may result in a slower clearance of HDL by the liver and consequently a higher HDL concentration in the serum.

  3. The effects of apolipoprotein B depletion on HDL subspecies composition and function.

    PubMed

    Davidson, W Sean; Heink, Anna; Sexmith, Hannah; Melchior, John T; Gordon, Scott M; Kuklenyik, Zsuzsanna; Woollett, Laura; Barr, John R; Jones, Jeffrey I; Toth, Christopher A; Shah, Amy S

    2016-04-01

    HDL cholesterol (HDL-C) efflux function may be a more robust biomarker of coronary artery disease risk than HDL-C. To study HDL function, apoB-containing lipoproteins are precipitated from serum. Whether apoB precipitation affects HDL subspecies composition and function has not been thoroughly investigated. We studied the effects of four common apoB precipitation methods [polyethylene glycol (PEG), dextran sulfate/magnesium chloride (MgCl2), heparin sodium/manganese chloride (MnCl2), and LipoSep immunoprecipitation (IP)] on HDL subspecies composition, apolipoproteins, and function (cholesterol efflux and reduction of LDL oxidation). PEG dramatically shifted the size distribution of HDL and apolipoproteins (assessed by two independent methods), while leaving substantial amounts of reagent in the sample. PEG also changed the distribution of cholesterol efflux and LDL oxidation across size fractions, but not overall efflux across the HDL range. Dextran sulfate/MgCl2, heparin sodium/MnCl2, and LipoSep IP did not change the size distribution of HDL subspecies, but altered the quantity of a subset of apolipoproteins. Thus, each of the apoB precipitation methods affected HDL composition and/or size distribution. We conclude that careful evaluation is needed when selecting apoB depletion methods for existing and future bioassays of HDL function. PMID:26908829

  4. High-Density Lipoproteins (HDL) – Nature’s Multi-Functional Nanoparticles

    PubMed Central

    Kuai, Rui; Li, Dan; Chen, Y. Eugene; Moon, James J.; Schwendeman, Anna

    2016-01-01

    High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well known as the ―good‖ cholesterol because it not only removes excess cholesterol from atherosclerotic plaques but also has anti-inflammatory and anti-oxidative properties, which protect the cardiovascular system. Circulating HDL also transports endogenous proteins, vitamins, hormones, and microRNA to various organs. Compared with other synthetic nanocarriers, such as liposomes, micelles, inorganic and polymeric nanoparticles, HDL has unique features that allow them to deliver cargo to specific targets more efficiently. These attributes include their ultra-small size (8-12 nm in diameter), high tolerability in humans (up to 8 g of protein per infusion), long circulating half-life (12-24 hours), and intrinsic targeting properties to different recipient cells. Various recombinant ApoA proteins and ApoA mimetic peptides have been recently developed for the preparation of reconstituted HDL that exhibits properties similar to endogenous HDL and has a potential for industrial scale-up. In this review, we will summarize: a) clinical pharmacokinetics and safety of reconstituted HDL products, b) comparison of HDL with inorganic and other organic nanoparticles, c) the rationale for using HDL as drug delivery vehicles for important therapeutic indications, d) the current state-of-the-art in HDL production, and e) HDL-based drug delivery strategies for small molecules, peptides/proteins, nucleic acids, and imaging agents targeted to various organs. PMID:26889958

  5. [New perspectives in cardiovascular risk reduction: focus on HDL].

    PubMed

    Paolillo, Stefania; Della Ratta, Giuseppe Luca; Vitagliano, Alice; Cirillo, Annapaola; Lardino, Elisabetta; Formisano, Tiziana; Fabiani, Irma; Pellegrino, Angela Maria; Riello, Pietro; Filardi, Pasquale Perrone

    2013-03-01

    Cardiovascular diseases represent the leading cause of morbidity and mortality worldwide, mostly contributing to hospitalizations and health care costs. Dyslipidemias represent one of the major cardiovascular risk factor and its management, throughout life-style modifications and pharmacological interventions, has shown to reduce cardiac events. The risk of adverse cardiovascular events is related not only to elevated LDL blood levels, but also to decreased HDL concentrations, that exhibit protective effects in the development of atherosclerotic process. Aim of this review is to summarize current evidences about defensing effects of such lipoproteins and to show the most recent pharmacological strategies to reduce cardiovascular risk through the increase of their circulating levels. PMID:23923587

  6. Lipoprotein hydrophobic core lipids are partially extruded to surface in smaller HDL: “Herniated” HDL, a common feature in diabetes

    PubMed Central

    Amigó, Núria; Mallol, Roger; Heras, Mercedes; Martínez-Hervás, Sergio; Blanco-Vaca, Francisco; Escolà-Gil, Joan Carles; Plana, Núria; Yanes, Óscar; Masana, Lluís; Correig, Xavier

    2016-01-01

    Recent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects. PMID:26778677

  7. Expression of the human apolipoprotein A-I gene in transgenic mice alters high density lipoprotein (HDL) particle size distribution and diminishes selective uptake of HDL cholesteryl esters

    SciTech Connect

    Chajekshaul, T.; Hayek, T.; Walsh, A.; Breslow, J.L. )

    1991-08-01

    Transgenic mice carrying the human apolipoprotein (apo) A-I gene (HuAITg mice) were used to examine the effects of overexpression of the human gene on high density lipoprotein (HDL) particle size distribution and metabolism. On a chow diet, control mice had HDL cholesterol and apo A-I levels of 49 {plus minus} 2 and 137 {plus minus} 12 mg/dl of plasma, respectively. HuAITg mice had HDL cholesterol, human apo A-I, and mouse apo A-I levels of 88 {plus minus} 2, 255 {plus minus} 19, and 16 {plus minus} 2 mg/dl, respectively. Nondenaturing gradient gel electrophoresis revealed control mouse plasma HDL to be primarily monodisperse with a particle diameter of 10.2 nm, whereas HuAITg mouse plasma HDL was polydisperse with particles of diameter 11.4, 10.2, and 8.7 nm, which correspond in size to human HDL1, HDL2, and HDL3, respectively. In vivo turnover studies of HDL labeled with (3H)cholesteryl linoleyl ether and 125I-apo A-I were performed. In control animals, the fractional catabolic rate (FCR) for HDL cholesteryl ester was significantly more than the apo A-I FCR. In the HuAITg mice, the HDL cholesteryl ester FCR was the same as the apo A-I FCR. There were no significant differences between control and HuAITg animals in the sites of tissue removal of HDL cholesteryl ester, with the liver extracting most of the injected radioactivity. Control and HuAITg animals had comparable liver and intestinal cholesterol synthesis and LDL FCR. In conclusion, HuAITg mice have principally human and not mouse apo A-I in their plasma. This apparently causes a change in HDL particle size distribution in the transgenic mice to one resembling the human pattern. The replacement of mouse by human apo A-I also apparently causes the loss of the selective uptake pathway of HDL cholesteryl esters present in control mice.

  8. The mouse plasma PAF acetylhydrolase: II. It consists of two enzymes both associated with the HDL.

    PubMed

    Tsaoussis, V; Vakirtzi-Lemonias, C

    1994-05-01

    The PAF acetylhydrolase (PAF-AH) of mouse plasma was characterised as to its lipoprotein subclass and apolipoprotein association. Association with plasma lipoproteins was established by cholesteryl-hemisuccinate agarose affinity chromatography while electrophoretic and electrofocusing studies demonstrated almost exclusive association with the HDL-VHDL. Fractionation of [4-14C]cholesterol-labelled plasma on a Bio-Gel A-5m column established that 1% of the enzymic activity was associated with the VLDL-LDL, 4.5% with the HDL1, 80% with the HDL2-HDL3 and 15% with the VHDL. Electrophoresis of the solubilised, HDL2-HDL3 bound enzyme gave two peaks of activity with mobilities of 0.29 and 0.49 and a distribution of the recovered activity of 78 and 22%, respectively. The VHDL associated activity on similar analysis gave a 25 and 75% distribution. These findings showed that two enzymes, both associated with the HDL and VHDL fractions, constitute the PAF-AH activity of mouse plasma. Further fractionation of the HDL2-HDL3 bound activity on heparin-agarose established that 70% of the recovered activity was bound to the apo-E containing HDL. PMID:7921790

  9. Plasma levels of HDL and carotenoids are lower in dementia patients with vascular comorbidities.

    PubMed

    Dias, Irundika H K; Polidori, Maria Cristina; Li, Li; Weber, Daniela; Stahl, Wilhelm; Nelles, Gereon; Grune, Tilman; Griffiths, Helen R

    2014-01-01

    Elevated serum cholesterol concentrations in mid-life increase risk for Alzheimer's disease (AD) in later life. However, lower concentrations of cholesterol-carrying high density lipoprotein (HDL) and its principal apolipoprotein A1 (ApoA1) correlate with increased risk for AD. As HDL transports oxocarotenoids, which are scavengers of peroxynitrite, we have investigated the hypothesis that lower HDL and oxocarotenoid concentrations during AD may render HDL susceptible to nitration and oxidation and in turn reduce the efficiency of reverse cholesterol transport (RCT) from lipid-laden cells. Fasting blood samples were obtained from subjects with (1) AD without cardiovascular comorbidities and risk factors (AD); (2) AD with cardiovascular comorbidities and risk factors (AD Plus); (3) normal cognitive function; for carotenoid determination by HPLC, analysis of HDL nitration and oxidation by ELISA, and 3H-cholesterol export to isolated HDL. HDL concentration in the plasma from AD Plus patients was significantly lower compared to AD or control subject HDL levels. Similarly, lutein, lycopene, and zeaxanthin concentrations were significantly lower in AD Plus patients compared to those in control subjects or AD patients, and oxocarotenoid concentrations correlated with Mini-Mental State Examination scores. At equivalent concentrations of ApoA1, HDL isolated from all subjects irrespective of diagnosis was equally effective at mediating RCT. HDL concentration is lower in AD Plus patients' plasma and thus capacity for RCT is compromised. In contrast, HDL from patients with AD-only was not different in concentration, modifications, or function from HDL of healthy age-matched donors. The relative importance of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia should be investigated in patients with early signs of dementia. PMID:24448787

  10. Why Targeting HDL Should Work as a Therapeutic Tool, but Hasn’t

    PubMed Central

    Sorci-Thomas, Mary G.; Thomas, Michael J.

    2013-01-01

    Atherosclerosis is one of the most common causes of death and disability in US today despite the availability of statins which reduce hyperlipidemia, a risk factor that predisposes individuals to this disease. Epidemiology of human populations has overwhelmingly demonstrated an inverse correlation between the concentration of plasma HDL cholesterol (HDL-C) and the likelihood of developing cardiovascular disease (CVD). Decades of observations and mechanistic studies suggest that one protective function of HDL is its central role in reverse cholesterol transport (RCT). In this pathway the ATP-binding cassette transporter (ABCA1) releases intracellular cholesterol, which is packaged by apolipoprotein A-I (apoA-I) into nascent HDL (nHDL) particles and released from the plasma membrane. Further lipidation and maturation of HDL occurs in plasma with the eventual uptake by the liver where cholesterol is removed. It is generally accepted that CVD risk can be reduced if plasma HDL-C levels are elevated. Several different pharmacological approaches have been tried, the most popular approach targets the movement of cholesteryl ester from HDL to triglyceride rich particles by cholesteryl ester transfer protein (CETP). Inhibition of CETP increases plasma HDL-C concentration, however, beneficial effects have yet to be demonstrated, likely the result of off-target effects. These revelations have led to a reevaluation of how elevating HDL concentration could decrease risk. A recent, landmark study showed that the inherent cholesterol efflux capacity of an individual’s plasma was a better predictor of CVD status than overall HDL-C concentration. Even more provocative are recent studies showing that apoA-I, the principle protein component of HDL, functions as a modulator of cellular inflammation and oxidation. The following will review all of these potential routes explaining how HDL apoA-I can reduce the risk of CVD. PMID:23743767

  11. Tailoring of Biomimetic High-Density Lipoprotein (HDL) Nanostructures Changes Cholesterol Binding and Efflux

    PubMed Central

    Luthi, Andrea J.; Zhang, Heng; Kim, Dongwoo; Giljohann, David A.; Mirkin, Chad A.; Thaxton, C. Shad

    2014-01-01

    Gold nanoparticles (Au NPs) were employed as templates to synthesize spherical, high-density lipoprotein (HDL) biomimics (HDL Au NPs) of different sizes and surface chemistries. The effect of size and surface chemistry on the cholesterol binding properties and the ability of the HDL Au NPs to efflux cholesterol from macrophage cells were measured. Results demonstrate that Au NPs may be utilized as templates to generate nanostructures with different physical characteristics that mimic natural HDL. Furthermore, the properties of the HDL Au NPs may be tailored to modulate the ability to bind cholesterol in solution and efflux cholesterol from macrophages. From the conjugates tested, the optimum size and surface chemistry for preparing functional Au NP-templated HDL biomimics were identified. PMID:22117189

  12. The improvement of large High-Density Lipoprotein (HDL) particle levels, and presumably HDL metabolism, depend on effects of low-carbohydrate diet and weight loss

    PubMed Central

    Finelli, C.; Crispino, P.; Gioia, S.; La Sala, N.; D'amico, L.; La Grotta, M.; Miro, O.; Colarusso, D.

    2016-01-01

    Depressed levels of atheroprotective large HDL particles are common in obesity and cardiovascular disease (CVD). Increases in large HDL particles are favourably associated with reduced CVD event risk and coronary plaque burden. The objective of the study is to compare the effectiveness of low-carbohydrate diets and weight loss for increasing blood levels of large HDL particles at 1 year. This study was performed by screening for body mass index (BMI) and metabolic syndrome in 160 consecutive subjects referred to our out-patient Metabolic Unit in South Italy. We administered dietary advice to four small groups rather than individually. A single team comprised of a dietitian and physician administered diet-specific advice to each group. Large HDL particles at baseline and 1 year were measured using two-dimensional gel electrophoresis. Dietary intake was assessed via 3-day diet records. Although 1-year weight loss did not differ between diet groups (mean 4.4 %), increases in large HDL particles paralleled the degree of carbohydrate restriction across the four diets (p<0.001 for trend). Regression analysis indicated that magnitude of carbohydrate restriction (percentage of calories as carbohydrate at 1 year) and weight loss were each independent predictors of 1-year increases in large HDL concentration. Changes in HDL cholesterol concentration were modestly correlated with changes in large HDL particle concentration (r=0.47, p=.001). In conclusion, reduction of excess dietary carbohydrate and body weight improved large HDL levels. Comparison trials with cardiovascular outcomes are needed to more fully evaluate these findings. PMID:27103896

  13. Synthetic High-Density Lipoprotein (sHDL) Inhibits Steroid Production in HAC15 Adrenal Cells.

    PubMed

    Taylor, Matthew J; Sanjanwala, Aalok R; Morin, Emily E; Rowland-Fisher, Elizabeth; Anderson, Kyle; Schwendeman, Anna; Rainey, William E

    2016-08-01

    High density lipoprotein (HDL) transported cholesterol represents one of the sources of substrate for adrenal steroid production. Synthetic HDL (sHDL) particles represent a new therapeutic option to reduce atherosclerotic plaque burden by increasing cholesterol efflux from macrophage cells. The effects of the sHDL particles on steroidogenic cells have not been explored. sHDL, specifically ETC-642, was studied in HAC15 adrenocortical cells. Cells were treated with sHDL, forskolin, 22R-hydroxycholesterol, or pregnenolone. Experiments included time and concentration response curves, followed by steroid assay. Quantitative real-time RT-PCR was used to study mRNA of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, lanosterol 14-α-methylase, cholesterol side-chain cleavage enzyme, and steroid acute regulatory protein. Cholesterol assay was performed using cell culture media and cell lipid extracts from a dose response experiment. sHDL significantly inhibited production of cortisol. Inhibition occurred in a concentration- and time-dependent manner and in a concentration range of 3μM-50μM. Forskolin (10μM) stimulated cortisol production was also inhibited. Incubation with 22R-hydroxycholesterol (10μM) and pregnenolone (10μM) increased cortisol production, which was unaffected by sHDL treatment. sHDL increased transcript levels for the rate-limiting cholesterol biosynthetic enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. Extracellular cholesterol assayed in culture media showed a positive correlation with increasing concentration of sHDL, whereas intracellular cholesterol decreased after treatment with sHDL. The current study suggests that sHDL inhibits HAC15 adrenal cell steroid production by efflux of cholesterol, leading to an overall decrease in steroid production and an adaptive rise in adrenal cholesterol biosynthesis. PMID:27253994

  14. Quantification of HDL Proteins, Cardiac Events, and Mortality in Patients with Type 2 Diabetes on Hemodialysis

    PubMed Central

    Kopecky, Chantal; Genser, Bernd; Drechsler, Christiane; Krane, Vera; Kaltenecker, Christopher C.; Hengstschläger, Markus; März, Winfried; Wanner, Christoph; Säemann, Marcus D.

    2015-01-01

    Background and objectives Impairment of HDL function has been associated with cardiovascular events in patients with kidney failure. The protein composition of HDLs is altered in these patients, presumably compromising the cardioprotective effects of HDLs. This post hoc study assessed the relation of distinct HDL-bound proteins with cardiovascular outcomes in a dialysis population. Design, setting, participants, & measurements The concentrations of HDL-associated serum amyloid A (SAA) and surfactant protein B (SP-B) were measured in 1152 patients with type 2 diabetes mellitus on hemodialysis participating in The German Diabetes Dialysis Study who were randomly assigned to double-blind treatment of 20 mg atorvastatin daily or matching placebo. The association of SAA(HDL) and SP-B(HDL) with cardiovascular outcomes was assessed in multivariate regression models adjusted for known clinical risk factors. Results High concentrations of SAA(HDL) were significantly and positively associated with the risk of cardiac events (hazard ratio per 1 SD higher, 1.09; 95% confidence interval, 1.01 to 1.19). High concentrations of SP-B(HDL) were significantly associated with all-cause mortality (hazard ratio per 1 SD higher, 1.10; 95% confidence interval, 1.02 to 1.19). Adjustment for HDL cholesterol did not affect these associations. Conclusions In patients with diabetes on hemodialysis, SAA(HDL) and SP-B(HDL) were related to cardiac events and all-cause mortality, respectively, and they were independent of HDL cholesterol. These findings indicate that a remodeling of the HDL proteome was associated with a higher risk for cardiovascular events and mortality in patients with ESRD. PMID:25424990

  15. Association between Triglyceride to HDL-C Ratio (TG/HDL-C) and Insulin Resistance in Chinese Patients with Newly Diagnosed Type 2 Diabetes Mellitus

    PubMed Central

    Ren, Xingxing; Chen, Zeng.ai; Zheng, Shuang; Han, Tingting; Li, Yangxue; Liu, Wei; Hu, Yaomin

    2016-01-01

    Objectives To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus. Methods Patients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman’s correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance. Results TG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman’s correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74–3.70); T2: 2.96(2.29–4.56); T3: 3.09(2.30–4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02(1.86–8.71); T3: 4.30(1.99–9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference. Conclusions TG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches. PMID:27115999

  16. HDL-level automated watermarking of IP cores

    NASA Astrophysics Data System (ADS)

    Castillo, E.; Meyer-Baese, U.; Parrilla, L.; García, A.; Lloris, A.

    2008-04-01

    This paper presents significant improvements to our previous watermarking technique for Intellectual Property Protection (IPP) of IP cores. The technique relies on hosting the bits of a digital signature at the HDL design level using resources included within the original system. Thus, any attack trying to change or remove the digital signature will damage the design. The technique also includes a procedure for secure signature extraction requiring minimal modifications to the system. The new advances refer to increasing the applicability of this watermarking technique to any design, not only to those including look-ups, and the provision of an automatic tool for signature hosting purposes. Synthesis results show that the application of the proposed watermarking strategy results in negligible degradation of system performance and very low area penalties and that the use of the automated tool, in addition to easy the signature hosting, leads to reduced area penalties.

  17. Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice.

    PubMed

    Kim, Myung-Hee; de Beer, Maria C; Wroblewski, Joanne M; Charnigo, Richard J; Ji, Ailing; Webb, Nancy R; de Beer, Frederick C; van der Westhuyzen, Deneys R

    2016-06-01

    The acute phase (AP) reactant serum amyloid A (SAA), an HDL apolipoprotein, exhibits pro-inflammatory activities, but its physiological function(s) are poorly understood. Functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are unclear. Mice deficient in either isoform were used to investigate plasma isoform effects on HDL structure, composition, and apolipoprotein catabolism. Lack of either isoform did not affect the size of HDL, normally enlarged in the AP, and did not significantly change HDL composition. Plasma clearance rates of HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCRs) of apoA-I, apoA-II, and SAA were distinct, indicating that HDL is not cleared as intact particles. The FCRs of SAA1.1 and SAA2.1 in AP mice were similar, suggesting that the selective deposition of SAA1.1 in amyloid plaques is not associated with a difference in the rates of plasma clearance of the isoforms. Although the clearance rate of SAA was reduced in the absence of the HDL receptor, scavenger receptor class B type I (SR-BI), it remained significantly faster compared with that of apoA-I and apoA-II, indicating a relatively minor role of SR-BI in SAA's rapid clearance. These studies enhance our understanding of SAA metabolism and SAA's effects on AP-HDL composition and catabolism. PMID:27018443

  18. Pleiotropy and genotype by diet interaction: A multivariate genetic analysis of HDL-C subfractions

    SciTech Connect

    Mahaney, M.C.; Blangero, J.; Comuzzie, A.G.

    1994-09-01

    Reduced high density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease in humans. Both major genes and major genotype by diet interaction have been reported for HDL-C, but the genetics of the HDL-C subfractions are less well known. In a baboon model for human atherosclerosis, we investigated the pleiotropic effects of genes on normal quantitative variation in three HDL-C subfractions (HDL{sub 1}-C, HDL{sub 2}-C, and HDL{sub 3}-C) in two dietary environments -- a basal diet and a 7 week high cholesterol, saturated fat (HCSF) diet. We analyzed data on serum HDL-C subfraction levels, quantified by gradient gel eletrophoresis, for 942 baboons (Papo hamadryas, sensu lato) from 17 pedigrees. We used multivariate maximum likelihood methods to simultaneously estimate phenotypic means, standard deviations, and heritabilities (h{sup 2}); effects of sex, age-by-sex, age{sup 2}-by-sex, percent subspecies admixture, and infant feeding modality; plus estimated significant h{sup 2} values for all three subfractions on both diets. When tested within dietary environments, we obtained significant genetic correlations between all three subfractions [i.e., P({rho}{sub G} = 0) < 0.001] and evidence of complete pleiotropy [i.e., P({vert_bar}{rho}{sub G}{vert_bar} = 1.0) > 0.1] between HDL{sub 1}-C and HDL{sub 3}-C ({rho}{sub G} = 0.81) on the basal diet. On the HCSF diet, only the genetic correlation between HDL{sub 1}-C and HDL{sub 3}-C ({rho}{sub g} = 0.61) was significant (p > 0.1). Complete pleiotropy was observed for each of the three subfractions between both diets. Given these results, we reject genotype by diet interaction for HDL{sub 1}-C, HDL{sub 2}-C or HDL{sub 3}-C; i.e., the same genes influence variation in each subfraction to the same degree on either diet. However, the apparent disruption of pleiotropy between HDL{sub 2}-C and the other two subfractions needs to be investigated further.

  19. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.

    PubMed

    Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B; Hancock-Cerutti, William F; Millar, John S; Cuchel, Marina; DerOhannessian, Stephanie; Kontush, Anatol; Surendran, Praveen; Saleheen, Danish; Trompet, Stella; Jukema, J Wouter; De Craen, Anton; Deloukas, Panos; Sattar, Naveed; Ford, Ian; Packard, Chris; Majumder, Abdullah al Shafi; Alam, Dewan S; Di Angelantonio, Emanuele; Abecasis, Goncalo; Chowdhury, Rajiv; Erdmann, Jeanette; Nordestgaard, Børge G; Nielsen, Sune F; Tybjærg-Hansen, Anne; Schmidt, Ruth Frikke; Kuulasmaa, Kari; Liu, Dajiang J; Perola, Markus; Blankenberg, Stefan; Salomaa, Veikko; Männistö, Satu; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Müller-Nurasyid, Martina; Ferrario, Marco; Kee, Frank; Willer, Cristen J; Samani, Nilesh; Schunkert, Heribert; Butterworth, Adam S; Howson, Joanna M M; Peloso, Gina M; Stitziel, Nathan O; Danesh, John; Kathiresan, Sekar; Rader, Daniel J

    2016-03-11

    Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant). PMID:26965621

  20. HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells

    PubMed Central

    Tabet, Fatiha; Vickers, Kasey C.; Cuesta Torres, Luisa F.; Wiese, Carrie B.; Shoucri, Bassem M.; Lambert, Gilles; Catherinet, Claire; Prado-Lourenco, Leonel; Levin, Michael G.; Thacker, Seth; Sethupathy, Praveen; Barter, Philip J.; Remaley, Alan T.; Rye, Kerry-Anne

    2014-01-01

    High-density lipoproteins (HDL) have many biological functions, including reducing endothelial activation and adhesion molecule expression. We recently reported that HDL transport and deliver functional microRNAs (miRNA). Here we show that HDL suppresses expression of intercellular adhesion molecule 1 (ICAM-1) through the transfer of miR-223 to endothelial cells. After incubation of endothelial cells with HDL, mature miR-223 levels are significantly increased in endothelial cells and decreased on HDL. However, miR-223 is not transcribed in endothelial cells and is not increased in cells treated with HDL from miR-223−/− mice. HDL inhibit ICAM-1 protein levels, but not in cells pretreated with miR-223 inhibitors. ICAM-1 is a direct target of HDL-transferred miR-223 and this is the first example of an extracellular miRNA regulating gene expression in cells where it is not transcribed. Collectively, we demonstrate that HDL’s anti-inflammatory properties are conferred, in part, through HDL-miR-223 delivery and translational repression of ICAM-1 in endothelial cells. PMID:24576947

  1. Advances in the Study of the Antiatherogenic Function and Novel Therapies for HDL

    PubMed Central

    Cao, Peiqiu; Pan, Haitao; Xiao, Tiancun; Zhou, Ting; Guo, Jiao; Su, Zhengquan

    2015-01-01

    The hypothesis that raising high-density lipoprotein cholesterol (HDL-C) levels could improve the risk for cardiovascular disease (CVD) is facing challenges. There is multitudinous clear clinical evidence that the latest failures of HDL-C-raising drugs show no clear association with risks for CVD. At the genetic level, recent research indicates that steady-state HDL-C concentrations may provide limited information regarding the potential antiatherogenic functions of HDL. It is evident that the newer strategies may replace therapeutic approaches to simply raise plasma HDL-C levels. There is an urgent need to identify an efficient biomarker that accurately predicts the increased risk of atherosclerosis (AS) in patients and that may be used for exploring newer therapeutic targets. Studies from recent decades show that the composition, structure and function of circulating HDL are closely associated with high cardiovascular risk. A vast amount of data demonstrates that the most important mechanism through which HDL antagonizes AS involves the reverse cholesterol transport (RCT) process. Clinical trials of drugs that specifically target HDL have so far proven disappointing, so it is necessary to carry out review on the HDL therapeutics. PMID:26225968

  2. Serum Opacity Factor Enhances HDL-Mediated Cholesterol Efflux, Esterification and Anti Inflammatory Effects

    PubMed Central

    Tchoua, Urbain; Rosales, Corina; Tang, Daming; Gillard, Baiba K.; Vaughan, Ashley; Lin, Hu Yu; Courtney, Harry S.

    2011-01-01

    Serum opacity factor (SOF) is a streptococcal protein that disrupts the structure of human high density lipoproteins (HDL) releasing lipid-free apo A-I while forming a large cholesteryl ester-rich particle and a small neo HDL. Given its low cholesterol and high phospholipid contents, we tested the hypotheses that neo HDL is a better substrate for cholesterol esterification via lecithin:cholesterol acyltransferase (LCAT), better than HDL as an acceptor of THP-1 macrophage cholesterol efflux, and improves reduction of oxidized LDL-induced production of inflammatory markers. We observed that both cholesterol efflux and esterification were improved by recombinant (r)SOF treatment of whole plasma and that the underlying cause of the improved cholesterol esterification in plasma and macrophage cholesterol efflux to rSOF-treated plasma was due to the rSOF-mediated conversion of HDL to neo HDL. Moreover, the reduction of secretion of TNF-α and IL-6 by THP-1 cells by neo HDL was twice that of HDL. Studies in BHK cells overexpressing cholesterol transporters showed that efflux to neo HDL occurred primarily via ABCA1 not ABCG1. Thus, rSOF improves two steps in reverse cholesterol transport with a concomitant reduction in the release of macrophage markers of inflammation. We conclude that rSOF catalyzes a novel reaction that might be developed as a new therapy that prevents or reverses atherosclerosis via improved reverse cholesterol transport. PMID:20972840

  3. Population-Based Resequencing of LIPG and ZNF202 Genes in Subjects with Extreme HDL Levels.

    PubMed

    Razzaghi, Hamid; Santorico, Stephanie A; Kamboh, M Ilyas

    2012-01-01

    Endothelial lipase (LIPG) and zinc finger protein 202 (ZNF202) are two pivotal genes in high density lipoprotein (HDL metabolism). We sought to determine their genetic contribution to variation in HDL-cholesterol levels by comprehensive resequencing of both genes in 235 individuals with high or low HDL-C levels. The selected subjects were 141 Whites (High HDL Group: n = 68, [Formula: see text] Low HDL Group: n = 73, [Formula: see text]) and 94 Hispanics (High HDL Group: n = 46, [Formula: see text] Low HDL Group: n = 48, [Formula: see text]). We identified a total of 185 and 122 sequence variants in LIPG and ZNF202, respectively. We found only two missense variants in LIPG (T111I and N396S) and two in ZNF202 (A154V and K259E). In both genes, there were several variants unique to either the low or high HDL group. For LIPG, the proportion of unique variants differed between the high and low HDL groups in both Whites (p = 0.022) and Hispanics (p = 0.017), but for ZNF202 this difference was observed only in Hispanics (p = 0.021). We also identified a common haplotype in ZNF202 among Whites that was significantly associated with the high HDL group (p = 0.013). These findings provide insights into the genetics of LIPG and ZNF202, and suggest that sequence variants occurring with high frequency in non-exonic regions may play a prominent role in modulating HDL-C levels in the general population. PMID:22723803

  4. Role of LCAT in HDL Remodeling: Investigation of LCAT Deficiency States

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To better understand the role of LCAT in HDL metabolism, we compared HDL subpopulations in subjects with homozygous (n 5 11) and heterozygous (n 5 11) LCAT deficiency with controls (n 5 22). Distribution and concentrations of apolipoprotein A-I (apoA-I)-, apoA-II-, apoA-IV-, apoC-I-, apoC-III-, and ...

  5. Hepatic ACAT2 Knock Down Increases ABCA1 and Modifies HDL Metabolism in Mice

    PubMed Central

    Degirolamo, Chiara; Gomaraschi, Monica; Graham, Mark; Ossoli, Alice; Larsson, Lilian; Calabresi, Laura; Gustafsson, Jan-Åke; Steffensen, Knut R.; Eriksson, Mats; Parini, Paolo

    2014-01-01

    Objectives ACAT2 is the exclusive cholesterol-esterifying enzyme in hepatocytes and enterocytes. Hepatic ABCA1 transfers unesterified cholesterol (UC) to apoAI, thus generating HDL. By changing the hepatic UC pool available for ABCA1, ACAT2 may affect HDL metabolism. The aim of this study was to reveal whether hepatic ACAT2 influences HDL metabolism. Design WT and LXRα/β double knockout (DOKO) mice were fed a western-type diet for 8 weeks. Animals were i.p. injected with an antisense oligonucleotide targeted to hepatic ACAT2 (ASO6), or with an ASO control. Injections started 4 weeks after, or concomitantly with, the beginning of the diet. Results ASO6 reduced liver cholesteryl esters, while not inducing UC accumulation. ASO6 increased hepatic ABCA1 protein independently of the diet conditions. ASO6 affected HDL lipids (increased UC) only in DOKO, while it increased apoE-containing HDL in both genotypes. In WT mice ASO6 led to the appearance of large HDL enriched in apoAI and apoE. Conclusions The use of ASO6 revealed a new pathway by which the liver may contribute to HDL metabolism in mice. ACAT2 seems to be a hepatic player affecting the cholesterol fluxes fated to VLDL or to HDL, the latter via up-regulation of ABCA1. PMID:24695360

  6. A disposable electrochemical sensor based on protein G for High-Density Lipoprotein (HDL) detection.

    PubMed

    Chammem, H; Hafaid, I; Bohli, N; Garcia, A; Meilhac, O; Abdelghani, A; Mora, L

    2015-11-01

    In this work, two biosensors were developed for the detection of High-Density Lipoproteins (HDL) particles, which are biomarkers inversely correlated with cardiovascular risk and which represent therapeutic targets for atherosclerosis. The electrochemical properties of the grafted antibody on interdigitated gold electrode were achieved by Impedance Spectroscopy (IS). The used deposition method was based on oriented antibody Anti-ApoA1 with an intermediate thin layer of protein G. The developed biosensor was able to detect both native plasma HDL and reconstituted HDL (rHDL) particles respectively with the detection limit of 50n g/mL and 1 ng/mL, respectively. Dynamic contact angle and atomic force microscopy were used. The developed biosensors are able to differentiate the HDL particles according to their differences in size and interactions with the immobilized antibody. PMID:26452849

  7. Atheroprotective role of high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P).

    PubMed

    Potì, Francesco; Simoni, Manuela; Nofer, Jerzy-Roch

    2014-08-01

    Numerous epidemiological studies documented an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and the extent of atherosclerotic disease. However, clinical interventions targeting HDL cholesterol failed to show clinical benefits with respect to cardiovascular risk reduction, suggesting that HDL components distinct from cholesterol may account for anti-atherogenic effects attributed to this lipoprotein. Sphingosine-1-phosphate (S1P)-a lysosphingolipid exerting its biological activity via binding to specific G protein-coupled receptors and regulating a wide array of biological responses in a variety of different organs and tissues including the cardiovascular system-has been identified as an integral constituent of HDL particles. In the present review, we discuss current evidence from epidemiological studies, experimental approaches in vitro, and animal models of atherosclerosis, suggesting that S1P contributes to atheroprotective effects exerted by HDL particles. PMID:24891400

  8. A biochemical fluorometric method for assessing the oxidative properties of HDL[S

    PubMed Central

    Kelesidis, Theodoros; Currier, Judith S.; Huynh, Diana; Meriwether, David; Charles-Schoeman, Christina; Reddy, Srinivasa T.; Fogelman, Alan M.; Navab, Mohamad; Yang, Otto O.

    2011-01-01

    Most current assays of HDL functional properties are cell-based. We have developed a fluorometric biochemical assay based on the oxidation of dihydrorhodamine 123 (DHR) by HDL. This cell-free assay assesses the intrinsic ability of HDL to be oxidized by measuring increasing fluorescence due to DHR oxidation over time. The assay distinguishes the oxidative potential of HDL taken from different persons, and the results are reproducible. Direct comparison of this measurement correlated well with results obtained using a validated cell-based assay (r2 = 0.62, P < 0.001). The assay can be scaled from a 96-well format to a 384-well format and, therefore, is suitable for high-throughput implementation. This new fluorometric method offers an inexpensive, accurate, and rapid means for determining the oxidative properties of HDL that is applicable to large-scale clinical studies. PMID:21957198

  9. HDL Cholesterol and Cancer Risk Among Patients With Type 2 Diabetes

    PubMed Central

    Zhao, Wenhui; Guan, Jing; Horswell, Ronald; Li, Weiqin; Wang, Yujie; Wu, Xiaocheng

    2014-01-01

    OBJECTIVE To investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients. RESEARCH DESIGN AND METHODS We performed a retrospective cohort study of 14,169 men and 23,176 women with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of various levels of HDL cholesterol (HDL-C) with cancer risk. RESULTS During a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30–39.9, 40–49.9, 50–59.9, 60–69.9, 70–79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (Ptrend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (Ptrend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up. CONCLUSIONS The study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation. PMID:25216507

  10. Biophysical characterization of the interaction of high-density lipoprotein (HDL) with endotoxins.

    PubMed

    Brandenburg, Klaus; Jürgens, Gudrun; Andrä, Jörg; Lindner, Buko; Koch, Michel H J; Blume, Alfred; Garidel, Patrick

    2002-12-01

    The interaction of bacterial endotoxins [lipopolysaccharide (LPS) and the 'endotoxic principle' lipid A], with high-density lipoprotein (HDL) from serum was investigated with a variety of physical techniques and biological assays. HDL exhibited an increase in the gel to liquid crystalline phase transition temperature Tc and a rigidification of the acyl chains of the endotoxins as measured by Fourier-transform infrared spectroscopy and differential scanning calorimetry. The functional groups of the endotoxins interacting with HDL are the phosphates and the diglucosamine backbone. The finding of phosphates as target groups is in accordance to measurements of the electrophoretic mobility showing that the zeta potential decreases from -50 to -60 mV to -20 mV at binding saturation. The importance of the sugar backbone as further target structure is in accordance with the remaining negative potential and competition experiments with polymyxin B (PMB) and phase transition data of the system PMB/dephosphorylated LPS. Furthermore, endotoxin binding to HDL influences the secondary structure of the latter manifesting in a change from a mixed alpha-helical/beta-sheet structure to a predominantly alpha-helical structure. The aggregate structure of the lipid A moiety of the endotoxins as determined by small-angle X-ray scattering shows a change of a unilamellar/inverted cubic into a multilamellar structure in the presence of HDL. Fluorescence resonance energy transfer data indicate an intercalation of pure HDL, and of [LPS]-[HDL] complexes into phospholipid liposomes. Furthermore, HDL may enhance the lipopolysaccharide-binding protein-induced intercalation of LPS into phospholipid liposomes. Parallel to these observations, the LPS-induced cytokine production of human mononuclear cells and the reactivity in the Limulus test are strongly reduced by the addition of HDL. These data allow to develop a model of the [endotoxin]/[HDL] interaction. PMID:12444987

  11. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial

    PubMed Central

    Mietus-Snyder, Michele L.; Shigenaga, Mark K.; Suh, Jung H.; Shenvi, Swapna V.; Lal, Ashutosh; McHugh, Tara; Olson, Don; Lilienstein, Joshua; Krauss, Ronald M.; Gildengoren, Ginny; McCann, Joyce C.; Ames, Bruce N.

    2012-01-01

    Dietary intake modulates disease risk, but little is known how components within food mixtures affect pathophysiology. A low-calorie, high-fiber, fruit-based nutrient-dense bar of defined composition (e.g., vitamins and minerals, fruit polyphenolics, β-glucan, docosahexaenoic acid) appropriate for deconstruction and mechanistic studies is described and evaluated in a pilot trial. The bar was developed in collaboration with the U.S. Department of Agriculture. Changes in cardiovascular disease and diabetes risk biomarkers were measured after 2 wk twice-daily consumption of the bar, and compared against baseline controls in 25 healthy adults. Plasma HDL-cholesterol (HDL-c) increased 6.2% (P=0.001), due primarily to a 28% increase in large HDL (HDL-L; P<0.0001). Total plasma homocysteine (Hcy) decreased 19% (P=0.017), and glutathione (GSH) increased 20% (P=0.011). The changes in HDL and Hcy are in the direction associated with decreased risk of cardiovascular disease and cognitive decline; increased GSH reflects improved antioxidant defense. Changes in biomarkers linked to insulin resistance and inflammation were not observed. A defined food-based supplement can, within 2 wk, positively impact metabolic biomarkers linked to disease risk. These results lay the groundwork for mechanistic/deconstruction experiments to identify critical bar components and putative synergistic combinations responsible for observed effects.—Mietus-Snyder, M. L., Shigenaga, M. K., Suh, J. H., Shenvi, S. V., Lal, A., McHugh, T., Olson, D., Lilienstein, J., Krauss, R. M., Gildengoren, G., McCann, J. C., Ames, B. N. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial. PMID:22549511

  12. World Wide Web Search Engines: AltaVista and Yahoo.

    ERIC Educational Resources Information Center

    Machovec, George S., Ed.

    1996-01-01

    Examines the history, structure, and search capabilities of Internet search tools AltaVista and Yahoo. AltaVista provides relevance-ranked feedback on full-text searches. Yahoo indexes Web "citations" only but does organize information hierarchically into predefined categories. Yahoo has recently become a publicly held company and currently…

  13. Beneficial Effect of Higher Dietary Fiber Intake on Plasma HDL-C and TC/HDL-C Ratio among Chinese Rural-to-Urban Migrant Workers

    PubMed Central

    Zhou, Quan; Wu, Jiang; Tang, Jie; Wang, Jia-Ji; Lu, Chu-Hong; Wang, Pei-Xi

    2015-01-01

    Research has shown that high-dose supplemental dietary fiber intake has beneficial effects on cardiovascular risk factors. To clarify such a relationship, we examined the association between daily dietary fiber intake and plasma lipids using a cross-sectional design including 1034 (M 502, F 532) rural-to-urban workers in China. We found a dose-response relationship between increased dietary fiber intakes and increase of HDL cholesterol in male workers. There was also a dose-response relationship between increased dietary fiber intake and decreased total cholesterol to HDL cholesterol (TC/HDL-C) ratio in both male and female workers, after adjusting for potential confounders (p for trend, all p < 0.05). When the average dietary fiber intake increased from less than 18 g/day to over 30 g/day, the average HDL cholesterol level increased by 10.1%, and the TC/HDL-C ratio decreased by 14.4% for males (p = 0.020) and by 11.1% for females (p = 0.048). In conclusion, higher daily dietary fiber consumption is associated with beneficial effect on cholesterol for rural-to-urban workers in China, suggesting its potential beneficial effect on decreasing the risk of cardiovascular diseases. PMID:25938914

  14. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial.

    PubMed

    Mietus-Snyder, Michele L; Shigenaga, Mark K; Suh, Jung H; Shenvi, Swapna V; Lal, Ashutosh; McHugh, Tara; Olson, Don; Lilienstein, Joshua; Krauss, Ronald M; Gildengoren, Ginny; McCann, Joyce C; Ames, Bruce N

    2012-08-01

    Dietary intake modulates disease risk, but little is known how components within food mixtures affect pathophysiology. A low-calorie, high-fiber, fruit-based nutrient-dense bar of defined composition (e.g., vitamins and minerals, fruit polyphenolics, β-glucan, docosahexaenoic acid) appropriate for deconstruction and mechanistic studies is described and evaluated in a pilot trial. The bar was developed in collaboration with the U.S. Department of Agriculture. Changes in cardiovascular disease and diabetes risk biomarkers were measured after 2 wk twice-daily consumption of the bar, and compared against baseline controls in 25 healthy adults. Plasma HDL-cholesterol (HDL-c) increased 6.2% (P=0.001), due primarily to a 28% increase in large HDL (HDL-L; P<0.0001). Total plasma homocysteine (Hcy) decreased 19% (P=0.017), and glutathione (GSH) increased 20% (P=0.011). The changes in HDL and Hcy are in the direction associated with decreased risk of cardiovascular disease and cognitive decline; increased GSH reflects improved antioxidant defense. Changes in biomarkers linked to insulin resistance and inflammation were not observed. A defined food-based supplement can, within 2 wk, positively impact metabolic biomarkers linked to disease risk. These results lay the groundwork for mechanistic/deconstruction experiments to identify critical bar components and putative synergistic combinations responsible for observed effects. PMID:22549511

  15. Multiple apolipoprotein kinetics measured in human HDL by high-resolution/accurate mass parallel reaction monitoring.

    PubMed

    Singh, Sasha A; Andraski, Allison B; Pieper, Brett; Goh, Wilson; Mendivil, Carlos O; Sacks, Frank M; Aikawa, Masanori

    2016-04-01

    Endogenous labeling with stable isotopes is used to study the metabolism of proteins in vivo. However, traditional detection methods such as GC/MS cannot measure tracer enrichment in multiple proteins simultaneously, and multiple reaction monitoring MS cannot measure precisely the low tracer enrichment in slowly turning-over proteins as in HDL. We exploited the versatility of the high-resolution/accurate mass (HR/AM) quadrupole Orbitrap for proteomic analysis of five HDL sizes. We identified 58 proteins in HDL that were shared among three humans and that were organized into five subproteomes according to HDL size. For seven of these proteins, apoA-I, apoA-II, apoA-IV, apoC-III, apoD, apoE, and apoM, we performed parallel reaction monitoring (PRM) to measure trideuterated leucine tracer enrichment between 0.03 to 1.0% in vivo, as required to study their metabolism. The results were suitable for multicompartmental modeling in all except apoD. These apolipoproteins in each HDL size mainly originated directly from the source compartment, presumably the liver and intestine. Flux of apolipoproteins from smaller to larger HDL or the reverse contributed only slightly to apolipoprotein metabolism. These novel findings on HDL apolipoprotein metabolism demonstrate the analytical breadth and scope of the HR/AM-PRM technology to perform metabolic research. PMID:26862155

  16. The macrophage and its related cholesterol efflux as a HDL function index in atherosclerosis.

    PubMed

    Yamamoto, Suguru; Narita, Ichiei; Kotani, Kazuhiko

    2016-06-01

    The macrophage and its related cholesterol efflux are considered to be a key player in atherosclerotic formation in relation to the function of high-density lipoprotein (HDL). The HDL function can be evaluated by the reaction between lipid-loaded macrophages and lipid-acceptors in the HDL fraction from the plasma, apolipoprotein B-depleted serum, and/or whole serum/plasma. Recent studies have reported that an impaired cholesterol efflux of HDL is observed in patients with cardiometabolic diseases, such as dyslipidemia, diabetes mellitus, and chronic kidney disease. A population-based cohort study has reported an inverse association between the cholesterol efflux capacity of HDL and the incidence of atherosclerotic disease, regardless of the serum HDL-cholesterol level. Moreover, in this paper, when we summarized several clinical interventional studies of statin treatment that examined cholesterol efflux, a potential increase in the efflux in patients treated with statins was implied. However, the effect was not fully defined in the current situation because of the small sample sizes, lack of a unified protocol for measuring the efflux, and short-term intervention periods without cardiovascular outcomes in available studies. Further investigation is necessary to determine the effect of drugs on cholesterol efflux. With additional advanced studies, cholesterol efflux is a promising laboratory index to understand the HDL function. PMID:27087419

  17. Restoration of renal function does not correct impairment of uremic HDL properties.

    PubMed

    Kopecky, Chantal; Haidinger, Michael; Birner-Grünberger, Ruth; Darnhofer, Barbara; Kaltenecker, Christopher C; Marsche, Gunther; Holzer, Michael; Weichhart, Thomas; Antlanger, Marlies; Kovarik, Johannes J; Werzowa, Johannes; Hecking, Manfred; Säemann, Marcus D

    2015-03-01

    Cardiovascular disease remains the leading cause of death in renal transplant recipients, but the underlying causative mechanisms for this important problem remain elusive. Recent work has indicated that qualitative alterations of HDL affect its functional and compositional properties in ESRD. Here, we systematically analyzed HDL from stable renal transplant recipients, according to graft function, and from patients with ESRD to determine whether structural and functional properties of HDL remain dysfunctional after renal transplantation. Cholesterol acceptor capacity and antioxidative activity, representing two key cardioprotective mechanisms of HDL, were profoundly suppressed in kidney transplant recipients independent of graft function and were comparable with levels in patients with ESRD. Using a mass spectroscopy approach, we identified specific remodeling of transplant HDL with highly enriched proteins, including α-1 microglobulin/bikunin precursor, pigment epithelium-derived factor, surfactant protein B, and serum amyloid A. In conclusion, this study demonstrates that HDL from kidney recipients is uniquely altered at the molecular and functional levels, indicating a direct pathologic role of HDL that could contribute to the substantial cardiovascular risk in the transplant population. PMID:25071090

  18. Restoration of Renal Function Does Not Correct Impairment of Uremic HDL Properties

    PubMed Central

    Kopecky, Chantal; Haidinger, Michael; Birner-Grünberger, Ruth; Darnhofer, Barbara; Kaltenecker, Christopher C.; Marsche, Gunther; Holzer, Michael; Weichhart, Thomas; Antlanger, Marlies; Kovarik, Johannes J.; Werzowa, Johannes; Hecking, Manfred

    2015-01-01

    Cardiovascular disease remains the leading cause of death in renal transplant recipients, but the underlying causative mechanisms for this important problem remain elusive. Recent work has indicated that qualitative alterations of HDL affect its functional and compositional properties in ESRD. Here, we systematically analyzed HDL from stable renal transplant recipients, according to graft function, and from patients with ESRD to determine whether structural and functional properties of HDL remain dysfunctional after renal transplantation. Cholesterol acceptor capacity and antioxidative activity, representing two key cardioprotective mechanisms of HDL, were profoundly suppressed in kidney transplant recipients independent of graft function and were comparable with levels in patients with ESRD. Using a mass spectroscopy approach, we identified specific remodeling of transplant HDL with highly enriched proteins, including α-1 microglobulin/bikunin precursor, pigment epithelium-derived factor, surfactant protein B, and serum amyloid A. In conclusion, this study demonstrates that HDL from kidney recipients is uniquely altered at the molecular and functional levels, indicating a direct pathologic role of HDL that could contribute to the substantial cardiovascular risk in the transplant population. PMID:25071090

  19. Impact of HDL oxidation by the myeloperoxidase system on sterol efflux by the ABCA1 pathway.

    PubMed

    Shao, Baohai; Heinecke, Jay W

    2011-10-19

    Protein oxidation by phagocytic white blood cells is implicated in tissue injury during inflammation. One important target might be high-density lipoprotein (HDL), which protects against atherosclerosis by removing excess cholesterol from artery wall macrophages. In the human artery wall, cholesterol-laden macrophages are a rich source of myeloperoxidase (MPO), which uses hydrogen peroxide for oxidative reactions in the extracellular milieu. Levels of two characteristic products of MPO-chlorotyrosine and nitrotyrosine-are markedly elevated in HDL from human atherosclerotic lesions. Here, we describe how MPO-dependent chlorination impairs the ability of apolipoprotein A-I (apoA-I), HDL's major protein, to transport cholesterol by the ATP-binding cassette transporter A1 (ABCA1) pathway. Faulty interactions between apoA-I and ABCA1 are involved. Tandem mass spectrometry and investigations of mutated forms of apoA-I demonstrate that tyrosine residues in apoA-I are chlorinated in a site-specific manner by chloramine intermediates on suitably juxtaposed lysine residues. Plasma HDL isolated from subjects with coronary artery disease (CAD) also contains higher levels of chlorinated and nitrated tyrosine residues than HDL from healthy subjects. Thus, the presence of chlorinated HDL might serve as a marker of CAD risk. Because HDL damaged by MPO in vitro becomes dysfunctional, inhibiting MPO in vivo might be cardioprotective. PMID:21501700

  20. HDL cholesterol and bone mineral density: Is there a genetic link?

    PubMed Central

    Ackert-Bicknell, Cheryl L.

    2011-01-01

    Overwhelming evidence has linked cardiovascular disease and osteoporosis, but the shared root cause of these two diseases of the elderly remains unknown. Low levels of high-density lipoprotein cholesterol (HDL) and bone mineral density (BMD) are risk factors for cardiovascular disease and osteoporosis respectively. A number of correlation studies have attempted to determine if there is a relationship between serum HDL and BMD but these studies are confounded by a number of variables including age, diet, genetic background, gender and hormonal status. Collectively, these data suggest that there is a relationship between these two phenotypes, but that the nature of this relationship is context specific. Studies in mice plainly demonstrate that genetic loci for BMD and HDL co-map and transgenic mouse models have been used to show that a single gene can affect both serum HDL and BMD. Work completed to date has demonstrated that HDL can interact directly with both osteoblasts and osteoclasts, but no direct evidence links bone back to the regulation of HDL levels. Understanding the genetic relationship between BMD and HDL has huge implications for understanding the clinical relationship between CVD and osteoporosis and for the development of safe treatment options for both diseases. PMID:21810493

  1. PLTP activity in premenopausal women. Relationship with lipoprotein lipase, HDL, LDL, body fat, and insulin resistance.

    PubMed

    Murdoch, S J; Carr, M C; Hokanson, J E; Brunzell, J D; Albers, J J

    2000-02-01

    Plasma phospholipid transfer protein (PLTP) is thought to play a major role in the facilitated transfer of phospholipids between lipoproteins and in the modulation of high density lipoprotein (HDL) particle size and composition. However, little has been reported concerning the relationships of PLTP with plasma lipoprotein parameters, lipolytic enzymes, body fat distribution, insulin, and glucose in normolipidemic individuals, particularly females. In the present study, 50 normolipidemic healthy premenopausal females were investigated. The relationships between the plasma PLTP activity and selected variables were assessed. PLTP activity was significantly and positively correlated with low density lipoprotein (LDL) cholesterol (r(s) = 0.53), apoB (r(s) = 0.44), glucose (r(s) = 0.40), HDL cholesterol (r(s) = 0.38), HDL(3) cholesterol (r(s) = 0.37), lipoprotein lipase activity (r(s) = 0.36), insulin (r(s) = 0.33), subcutaneous abdominal fat (r(s) = 0.36), intra-abdominal fat (r(s) = 0.29), and body mass index (r(s) = 0.29). HDL(2) cholesterol, triglyceride, and hepatic lipase were not significantly related to PLTP activity. As HDL(2) can be decreased by hepatic lipase and hepatic lipase is increased in obesity with increasing intra-abdominal fat, the participants were divided into sub-groups of non-obese (n = 35) and obese (n = 15) individuals and the correlation of PLTP with HDL(2) cholesterol was re-examined. In the non-obese subjects, HDL(2) cholesterol was found to be significantly and positively related to PLTP activity (r(s) = 0.44). Adjustment of the HDL(2) values for the effect of hepatic lipase activity resulted in a significant positive correlation between PLTP and HDL(2) (r(s) = 0.41), indicating that the strength of the relationship between PLTP activity and HDL(2) can be reduced by the opposing effect of hepatic lipase on HDL(2) concentrations. We conclude that PLTP-facilitated lipid transfer activity is related to HDL and LDL metabolism, as well as

  2. A thiocarbamate inhibitor of endothelial lipase raises HDL cholesterol levels in mice.

    PubMed

    Greco, M N; Connelly, M A; Leo, G C; Olson, M W; Powell, E; Huang, Z; Hawkins, M; Smith, C; Schalk-Hihi, C; Darrow, A L; Xin, H; Lang, W; Damiano, B P; Hlasta, D J

    2013-05-01

    By screening directed libraries of serine hydrolase inhibitors using the cell surface form of endothelial lipase (EL), we identified a series of carbamate-derived (EL) inhibitors. Compound 3 raised plasma HDL-C levels in the mouse, and a correlation was found between HDL-C and plasma compound levels. Spectroscopic and kinetic studies support a covalent mechanism of inhibition. Our findings represent the first report of EL inhibition as an effective means for increasing HDL-C in an in vivo model. PMID:23528297

  3. Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile.

    PubMed

    Wang, Jing; Bie, Jinghua; Ghosh, Shobha

    2016-09-01

    While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, but also enhance elimination of cholesterol into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased hydrolysis of HDL-[(3)H]CE, reduced resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, the flux of [(3)H]cholesterol from HDL-[(3)H]CE to biliary bile acids was increased by overexpression of SCP2 or FABP1 in vivo and reduced in SCP2(-/-) mice. Increased flux of HDL-[(3)H]CE to biliary FC was noted with FABP1 overexpression and in SCP2(-/-) mice that have increased FABP1 expression. Lack of a significant decrease in the flux of HDL-[(3)H]CE to biliary FC or bile acids in FABP1(-/-) mice indicates the likely compensation of its function by an as yet unidentified mechanism. Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination. PMID:27381048

  4. Nascent HDL formation by hepatocytes is reduced by the concerted action of serum amyloid A and endothelial lipase.

    PubMed

    Wroblewski, Joanne M; Jahangiri, Anisa; Ji, Ailing; de Beer, Frederick C; van der Westhuyzen, Deneys R; Webb, Nancy R

    2011-12-01

    Inflammation is associated with significant decreases in plasma HDL-cholesterol (HDL-C) and apoA-I levels. Endothelial lipase (EL) is known to be an important determinant of HDL-C in mice and in humans and is upregulated during inflammation. In this study, we investigated whether serum amyloid A (SAA), an HDL apolipoprotein highly induced during inflammation, alters the ability of EL to metabolize HDL. We determined that EL hydrolyzes SAA-enriched HDL in vitro without liberating lipid-free apoA-I. Coexpression of SAA and EL in mice by adenoviral vector produced a significantly greater reduction in HDL-C and apoA-I than a corresponding level of expression of either SAA or EL alone. The loss of HDL occurred without any evidence of HDL remodeling to smaller particles that would be expected to have more rapid turnover. Studies with primary hepatocytes demonstrated that coexpression of SAA and EL markedly impeded ABCA1-mediated lipidation of apoA-I to form nascent HDL. Our findings suggest that a reduction in nascent HDL formation may be partly responsible for reduced HDL-C during inflammation when both EL and SAA are known to be upregulated. PMID:21957202

  5. Where Are We With HDL Raising and Inhibition of Cholesteryl Ester Transfer for Heart Disease Risk Reduction?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose: To review recent research in the area of high density lipoprotein (HDL) raising and coronary heart disease (CHD) risk reduction. Recent Findings: It is known that a decreased HDL cholesterol is an important CHD risk factor, and that raising HDL cholesterol has been associated with CHD risk...

  6. Hemorheological and Glycemic Parameters and HDL Cholesterol for the Prediction of Cardiovascular Events

    PubMed Central

    Cho, Sung Woo; Kim, Byung Gyu; Kim, Byung Ok; Byun, Young Sup; Goh, Choong Won; Rhee, Kun Joo; Kwon, Hyuck Moon; Lee, Byoung Kwon

    2016-01-01

    Background Hemorheological and glycemic parameters and high density lipoprotein (HDL) cholesterol are used as biomarkers of atherosclerosis and thrombosis. Objective To investigate the association and clinical relevance of erythrocyte sedimentation rate (ESR), fibrinogen, fasting glucose, glycated hemoglobin (HbA1c), and HDL cholesterol in the prediction of major adverse cardiovascular events (MACE) and coronary heart disease (CHD) in an outpatient population. Methods 708 stable patients who visited the outpatient department were enrolled and followed for a mean period of 28.5 months. Patients were divided into two groups, patients without MACE and patients with MACE, which included cardiac death, acute myocardial infarction, newly diagnosed CHD, and cerebral vascular accident. We compared hemorheological and glycemic parameters and lipid profiles between the groups. Results Patients with MACE had significantly higher ESR, fibrinogen, fasting glucose, and HbA1c, while lower HDL cholesterol compared with patients without MACE. High ESR and fibrinogen and low HDL cholesterol significantly increased the risk of MACE in multivariate regression analysis. In patients with MACE, high fibrinogen and HbA1c levels increased the risk of multivessel CHD. Furthermore, ESR and fibrinogen were significantly positively correlated with HbA1c and negatively correlated with HDL cholesterol, however not correlated with fasting glucose. Conclusion Hemorheological abnormalities, poor glycemic control, and low HDL cholesterol are correlated with each other and could serve as simple and useful surrogate markers and predictors for MACE and CHD in outpatients. PMID:26690693

  7. Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

    PubMed Central

    Edmondson, Andrew C.; Brown, Robert J.; Kathiresan, Sekar; Cupples, L. Adrienne; Demissie, Serkalem; Manning, Alisa Knodle; Jensen, Majken K.; Rimm, Eric B.; Wang, Jian; Rodrigues, Amrith; Bamba, Vaneeta; Khetarpal, Sumeet A.; Wolfe, Megan L.; DerOhannessian, Stephanie; Li, Mingyao; Reilly, Muredach P.; Aberle, Jens; Evans, David; Hegele, Robert A.; Rader, Daniel J.

    2009-01-01

    Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG) is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C. PMID:19287092

  8. Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway[S

    PubMed Central

    Pamir, Nathalie; Hutchins, Patrick; Ronsein, Graziella; Vaisar, Tomas; Reardon, Catherine A.; Getz, Godfrey S.; Lusis, Aldons J.; Heinecke, Jay W.

    2016-01-01

    Cholesterol efflux capacity associates strongly and negatively with the incidence and prevalence of human CVD. We investigated the relationships of HDL’s size and protein cargo with its cholesterol efflux capacity using APOB-depleted serum and HDLs isolated from five inbred mouse strains with different susceptibilities to atherosclerosis. Like humans, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. HDL’s content of specific proteins strongly correlated with its size and cholesterol efflux capacity, suggesting that its protein cargo regulates its function. Cholesterol efflux capacity with macrophages strongly and positively correlated with retinol binding protein 4 (RBP4) and PLTP, but not APOA1. In contrast, ABCA1-specific cholesterol efflux correlated strongly with HDL’s content of APOA1, APOC3, and APOD, but not RBP4 and PLTP. Unexpectedly, APOE had a strong negative correlation with ABCA1-specific cholesterol efflux capacity. Moreover, the ABCA1-specific cholesterol efflux capacity of HDL isolated from APOE-deficient mice was significantly greater than that of HDL from wild-type mice. Our observations demonstrate that the HDL-associated APOE regulates HDL’s ABCA1-specific cholesterol efflux capacity. These findings may be clinically relevant because HDL’s APOE content associates with CVD risk and ABCA1 deficiency promotes unregulated cholesterol accumulation in human macrophages. PMID:26673204

  9. Remarkable quantitative and qualitative differences in HDL after niacin or fenofibrate therapy in type 2 diabetic patients.

    PubMed

    Masana, Luís; Cabré, Anna; Heras, Mercedes; Amigó, Núria; Correig, Xavier; Martínez-Hervás, Sergio; Real, José T; Ascaso, Juan F; Quesada, Helena; Julve, Josep; Palomer, Xavier; Vázquez-Carrera, Manuel; Girona, Josefa; Plana, Núria; Blanco-Vaca, Francisco

    2015-02-01

    HDL-increasing drugs such as fenofibrate and niacin have failed to decrease the cardiovascular risk in patients with type 2 diabetes. Drug-mediated quantitative and qualitative HDL modifications could be involved in these negative results. To evaluate the quantitative and qualitative effects of niacin and fenofibrate on HDL in patients with type 2 diabetes, a prospective, randomised controlled intervention trial was conducted. Thirty type 2 diabetic patients with low HDL were randomised to receive either fenofibrate (FFB) or niacin + laropiprant (ERN/LPR) as an add-on to simvastatin treatment for 12 weeks according to a crossover design. At the basal point and after each intervention period, physical examinations and comprehensive standard biochemical determinations and HDL metabolomics were performed. Thirty nondiabetic patients with normal HDL were used as a basal control group. ERN/LRP, but not FFB, significantly increased HDL cholesterol. Neither ERN/LRP nor FFB reversed the HDL particle size or particle number to normal. ERN/LRP increased apoA-I but not apoA-II, whereas FFB produced the opposite effect. FFB significantly increased Preβ1-HDL, whereas ERN/LRP tended to lower Preβ1-HDL. CETP and LCAT activities were significantly decreased only by ERN/LRP. PAF-AH activity in HDL and plasma decreased with the use of both agents. Despite their different actions on antioxidant parameters, none of the treatments induced detectable antioxidant improvements. ERN/LRP and FFB had strikingly different effects on HDL quantity and quality, as well as on HDL cholesterol concentrations. When prescribing HDL cholesterol increasing drugs, this differential action should be considered. PMID:25528430

  10. The Alta schist, North Norway: unique rock with unique history

    NASA Astrophysics Data System (ADS)

    Heldal, Tom; Aasly, Kari; Meyer, Gurli

    2015-04-01

    Near the small town of Alta, northernmost Norway, are more than thousand small and large schist quarries, some of them dating back to the 1850's. It was the need for roofing material on a local church and a hospital that triggered the production. Since then, the Alta schist has been widely applied in Norway and abroad, known for its quality for roofing material and hard floor covering. The quality lies in the processes behind the formation of the schist. Emplacement of thrust nappes during the Caledonian mountain chain formation in the Silurian caused deformation and metamorphism of the rocks. The Alta schist is situated in one such nappe sheet, where arkosic sandstone where flattened and transformed into mylonite. This made fine mica layers along which the rock can be split, rythmically spaced and separated by quartz-dominated bands. The production of the Alta schist is still characterized by old craft traditions, reflecting a rich history and culture around the schist production.

  11. Nicotinic Acid Accelerates HDL Cholesteryl Ester Turnover in Obese Insulin-Resistant Dogs

    PubMed Central

    Le Bloc'h, Jérôme; Leray, Véronique; Nazih, Hassan; Gauthier, Olivier; Serisier, Samuel; Magot, Thierry; Krempf, Michel; Nguyen, Patrick; Ouguerram, Khadija

    2015-01-01

    Aim Nicotinic acid (NA) treatment decreases plasma triglycerides and increases HDL cholesterol, but the mechanisms involved in these change are not fully understood. A reduction in cholesteryl ester transfer protein (CETP) activity has been advanced to explain most lipid-modulating effects of NA. However, due to the central role of CETP in reverse cholesterol transport in humans, other effects of NA may have been hidden. As dogs have no CETP activity, we conducted this study to examine the specific effects of extended-release niacin (NA) on lipids and high-density lipoprotein (HDL) cholesteryl ester (CE) turnover in obese Insulin-Resistant dogs with increase plasma triglycerides. Methods HDL kinetics were assessed in fasting dogs before and four weeks after NA treatment through endogenous labeling of cholesterol and apolipoprotein AI by simultaneous infusion of [1,2 13C2] acetate and [5,5,5 2H3] leucine for 8 h. Kinetic data were analyzed by compartmental modeling. In vitro cell cholesterol efflux of serum from NA-treated dogs was also measured. Results NA reduced plasma total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides (TG), and very-low-density lipoprotein TG concentrations (p < 0.05). The kinetic study also showed a higher cholesterol esterification rate (p < 0.05). HDL-CE turnover was accelerated (p < 0.05) via HDL removal through endocytosis and selective CE uptake (p < 0.05). We measured an elevated in vitro cell cholesterol efflux (p < 0.05) with NA treatment in accordance with a higher cholesterol esterification. Conclusion NA decreased HDL cholesterol but promoted cholesterol efflux and esterification, leading to improved reverse cholesterol transport. These results highlight the CETP-independent effects of NA in changes of plasma lipid profile. PMID:26366727

  12. Impaired HDL cholesterol efflux in metabolic syndrome is unrelated to glucose tolerance status: the CODAM study

    PubMed Central

    Annema, Wijtske; Dikkers, Arne; de Boer, Jan Freark; van Greevenbroek, Marleen M. J.; van der Kallen, Carla J. H.; Schalkwijk, Casper G.; Stehouwer, Coen D. A.; Dullaart, Robin P. F.; Tietge, Uwe J. F.

    2016-01-01

    Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) increase atherosclerotic cardiovascular disease risk. Cholesterol efflux capacity (CEC) is a key metric of the anti-atherosclerotic functionality of high-density lipoproteins (HDL). The present study aimed to delineate if T2DM and MetS cross-sectionally associate with altered CEC in a large high cardiometabolic risk population. CEC was determined from THP-1 macrophage foam cells towards apolipoprotein B-depleted plasma from 552 subjects of the CODAM cohort (288 controls, 126 impaired glucose metabolism [IGM], 138 T2DM). MetS was present in 297 participants. CEC was not different between different glucose tolerance categories but was lower in MetS (P < 0.001), at least partly attributable to lower HDL cholesterol (HDL-C) and apoA-I levels (P < 0.001 for each). Low grade inflammation was increased in IGM, T2DM and MetS as determined by a score comprising 8 different biomarkers (P < 0.05-< 0.001; n = 547). CEC inversely associated with low-grade inflammation taking account of HDL-C or apoA-I in MetS (P < 0.02), but not in subjects without MetS (interaction: P = 0.015). This study demonstrates that IGM and T2DM do not impact the HDL CEC function, while efflux is lower in MetS, partly dependent on plasma HDL-C levels. Enhanced low-grade inflammation in MetS may conceivably impair CEC even independent of HDL-C and apoA-I. PMID:27270665

  13. The Effect of Natural LCAT Mutations on the Biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Kuivenhoven, Jan Albert; Dafnis, Eugene; Kardassis, Dimitris; Zannis, Vassilis I

    2015-06-01

    We have investigated how the natural LCAT[T147I] and LCAT[P274S] mutations affect the pathway of biogenesis of HDL. Gene transfer of WT LCAT in LCAT(-/-) mice increased 11.8-fold the plasma cholesterol, whereas the LCAT[T147I] and LCAT[P274S] mutants caused a 5.2- and 2.9-fold increase, respectively. The LCAT[P274S] and the WT LCAT caused a monophasic distribution of cholesterol in the HDL region, whereas the LCAT[T147I] caused a biphasic distribution of cholesterol in the LDL and HDL region. Fractionation of plasma showed that the expression of WT LCAT increased plasma apoE and apoA-IV levels and shifted the distribution of apoA-I to lower densities. The LCAT[T147I] and LCAT[P274S] mutants restored partially apoA-I in the HDL3 fraction and LCAT[T147I] increased apoE in the VLD/IDL/LDL fractions. The in vivo functionality of LCAT was further assessed based on is its ability to correct the aberrant HDL phenotype that was caused by the apoA-I[L159R]FIN mutation. Co-infection of apoA-I(-/-) mice with this apoA-I mutant and either of the two mutant LCAT forms restored only partially the HDL biogenesis defect that was caused by the apoA-I[L159R]FIN and generated a distinct aberrant HDL phenotype. PMID:25948084

  14. Effect of HDL-Raising Drugs on Cardiovascular Outcomes: A Systematic Review and Meta-Regression

    PubMed Central

    Shafiq, Nusrat; Reddy, Srinivas; Kaur, Harpreet; Chadha, Neelima; Malhotra, Samir

    2014-01-01

    Background Substantial residual cardiovascular risk remains after optimal LDL lowering in patients of established coronary artery disease. A number of therapeutic agents that raise HDL-C have been tested in clinical trials to cover this risk. However, the results of clinical trials are conflicting. Objectives To determine whether raising HDL-C with pharmacologic therapies translates into beneficial cardiovascular outcomes and to find out if this change was proportional to the percentage change in HDL levels. Methods Electronic and printed sources were searched up to August, 2013 for randomised controlled trials (RCTs) using at least one of the HDL raising therapies for secondary prevention of adverse cardiovascular events over optimal LDL levels. Data from eligible studies were pooled for the following outcomes: all cause mortality, cardiovascular disease mortality, hospitalization for unstable angina, non-fatal myocardial infarction, coronary revascularization and ischemic stroke. Mantel Haensnzel fixed effect model was used preferentially. Meta-regression was done to see the correlation of change in HDL levels and cardiovascular outcomes. Pooled odds ratios with 95% confidence interval (CI) were calculated. Results A total of 12 RCTs including 26,858 patients with follow up period ranging from 1 year to 6.2 years were included in the analysis. Pooled analysis showed no significant difference in all-cause mortality between the treatment and control group (Pooled OR 1.07; 95% CI 0.98–1.16, p = 0.15). No significant difference was found between the groups for any of the secondary outcomes. Similarly no correlation was seen between percentage change in HDL and adverse cardiovascular outcomes on meta-regression analysis. Conclusion Increasing HDL levels via pharmacological manipulation beyond optimal lipid lowering therapy for secondary prevention is not beneficial. PMID:24728455

  15. Impaired HDL cholesterol efflux in metabolic syndrome is unrelated to glucose tolerance status: the CODAM study.

    PubMed

    Annema, Wijtske; Dikkers, Arne; de Boer, Jan Freark; van Greevenbroek, Marleen M J; van der Kallen, Carla J H; Schalkwijk, Casper G; Stehouwer, Coen D A; Dullaart, Robin P F; Tietge, Uwe J F

    2016-01-01

    Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) increase atherosclerotic cardiovascular disease risk. Cholesterol efflux capacity (CEC) is a key metric of the anti-atherosclerotic functionality of high-density lipoproteins (HDL). The present study aimed to delineate if T2DM and MetS cross-sectionally associate with altered CEC in a large high cardiometabolic risk population. CEC was determined from THP-1 macrophage foam cells towards apolipoprotein B-depleted plasma from 552 subjects of the CODAM cohort (288 controls, 126 impaired glucose metabolism [IGM], 138 T2DM). MetS was present in 297 participants. CEC was not different between different glucose tolerance categories but was lower in MetS (P < 0.001), at least partly attributable to lower HDL cholesterol (HDL-C) and apoA-I levels (P < 0.001 for each). Low grade inflammation was increased in IGM, T2DM and MetS as determined by a score comprising 8 different biomarkers (P < 0.05-< 0.001; n = 547). CEC inversely associated with low-grade inflammation taking account of HDL-C or apoA-I in MetS (P < 0.02), but not in subjects without MetS (interaction: P = 0.015). This study demonstrates that IGM and T2DM do not impact the HDL CEC function, while efflux is lower in MetS, partly dependent on plasma HDL-C levels. Enhanced low-grade inflammation in MetS may conceivably impair CEC even independent of HDL-C and apoA-I. PMID:27270665

  16. Interactions of Six SNPs in ABCA1gene and Obesity in Low HDL-C Disease in Kazakh of China

    PubMed Central

    Yao, Ming-hong; Guo, Heng; He, Jia; Yan, Yi-zhong; Ma, Ru-lin; Ding, Yu-song; Zhang, Jing-yu; Liu, Jia-ming; Zhang, Mei; Li, Shu-gang; Xu, Shang-zhi; Niu, Qiang; Ma, Jiao-long; Guo, Shu-xia

    2016-01-01

    Objective: To detect the interactions between six functional polymorphisms in ABCA1 and obesity in Kazakhs with low HDL-C levels. Methods: A total of 204 patients with low HDL-C and 207 health control subjects, which were randomly selected from among 5692 adult Kazakhs, were matched for age and sex. We genotyped ABCA1 single nucleotide polymorphisms of rs2515602, rs3890182, rs2275542, rs2230806, rs1800976, and rs4149313. Results: (1) The genotypic and allelic frequencies of rs2515602, rs2230806 and rs4149313 were different between normal HDL-C and low HDL-C subjects, the genotypic frequency of rs2275542 was also different between normal HDL-C and low HDL-C subjects (p < 0.05); (2) the level of HDL-C (rs2515602 and rs2275542) in normal HDL-C subjects were different among the genotypes (p < 0.05); the levels of TC, LDL-C (rs2515602, rs4149313); TG (rs2515602, rs1800976, rs4149313) in low HDL-C patients were different among the genotypes (p < 0.05); (3) interactions between the rs3890182, rs2275542, rs180096, and rs4149313 polymorphisms in ABCA1 gene and obesity may be associated with low HDL-C disease; (4) the C-C-C-A-A-G, T-C-C-A-A-A, T-C-C-A-A-G, C-C-C-A-A-A, C-T-G-G-A-A, and T-T-C-G-A-A haplotypes were significant between the subjects with normal HDL-C and low HDL-C level (p < 0.05). Conclusions: The differences in serum lipid levels between normal HDL-C and low HDL-C subjects among Kazakhs might partly result from ABCA1 gene polymorphisms; ABCA1 gene polymorphisms may be associated with low HDL-C disease; the low HDL-C disease might partly result from interactions between ABCA1 gene polymorphisms and obesity; the C-C-C-A-A-G, T-C-C-A-A-A, and T-C-C-A-A-G haplotypes may serve as risk factors of low HDL-C disease among Kazakhs, the C-C-C-A-A-A, C-T-G-G-A-A, and T-T-C-G-A-A haplotypes may serve as protective factor of low HDL-C disease among Kazakhs. PMID:26828509

  17. Evidence for a role of CETP in HDL remodeling and cholesterol efflux: role of cysteine 13 of CETP.

    PubMed

    Maugeais, Cyrille; Perez, Anne; von der Mark, Elisabeth; Magg, Christine; Pflieger, Philippe; Niesor, Eric J

    2013-11-01

    Cholesteryl ester transfer protein (CETP), a key regulator of high-density lipoprotein (HDL) metabolism, induces HDL remodeling by transferring lipids between apolipoprotein B-containing lipoproteins and HDL, and/or by promoting lipid transfer between HDL subparticles. In this study, we investigated the mechanism as to how CETP induces the generation of lipid-poor particles (pre-β-HDL) from HDL, which increases ATP-binding cassette transporter 1-mediated cholesterol efflux. This CETP-dependent HDL remodeling is enhanced by the CETP modulator dalcetrapib both in plasma and isolated HDL. The interaction of dalcetrapib with cysteine 13 of CETP is required, since this effect was abolished when using mutant CETP in which cysteine 13 was substituted for a serine residue. Other thiol-containing compounds were identified as CETP modulators interacting with cysteine 13 of CETP. In order to mimic dalcetrapib-bound CETP, mutant CETP proteins were prepared by replacing cysteine 13 with the bulky amino acid tyrosine or tryptophan. The resultant mutants showed virtually no CETP-dependent lipid transfer activity but demonstrated preserved CETP-dependent pre-β-HDL generation. Overall, these data demonstrate that the two functions of CETP i.e., cholesteryl ester transfer and HDL remodeling can be uncoupled by interaction of thiol-containing compounds with cysteine 13 of CETP or by introducing large amino acid residues in place of cysteine 13. PMID:23872476

  18. Effects of Carbohydrate and Dietary Fiber Intake, Glycemic Index and Glycemic Load on HDL Metabolism in Asian Populations

    PubMed Central

    Yanai, Hidekatsu; Katsuyama, Hisayuki; Hamasaki, Hidetaka; Abe, Shinichi; Tada, Norio; Sako, Akahito

    2014-01-01

    High-density lipoprotein (HDL) is a lipoprotein which has anti-atherogenic property by reverse cholesterol transport from the peripheral tissues to liver. Low HDL-cholesterol (HDL-C) levels are associated with the development of coronary artery diseases (CADs). Various epidemiological studies have suggested that the development of CAD increase in individuals with less than 40 mg/dL of HDL-C. In spite of accumulation of evidences which suggest a significant association between low HDL-C and cardiovascular diseases, effects of dietary factors on HDL metabolism remained largely unknown. There may be interracial differences in effects of dietary factors on HDL metabolism. Here we reviewed published articles about effects of carbohydrate and dietary fiber intake, glycemic index (GI) and glycemic load (GL), on HDL-C metabolism, regarding meta-analyses and clinical studies performed in Asian population as important articles. Low carbohydrate intake, GI and GL may be beneficially associated with HDL metabolism. Dietary fiber intake may be favorably associated with HDL metabolism in Asian populations. PMID:25110535

  19. HDL derived from the different phases of conjugated diene formation reduces membrane fluidity and contributes to a decrease in free cholesterol efflux from human THP-1 macrophages.

    PubMed

    Girona, Josefa; LaVille, Agnes E; Solà, Rosa; Motta, Claude; Masana, Lluís

    2003-09-22

    Oxidized HDL (ox-HDL) has been reported to reduce free cholesterol efflux from cells. In this study we investigate the effect of different stages of ox-HDL on macrophage membrane fluidity and its effect on free cholesterol efflux from macrophages as a cell function influenced by ox-HDL. HDL was oxidized by means of conjugated diene production using copper as a prooxidant. Fluidity of HDL and human THP-1 macrophage membranes was evaluated by changes in fluorescence anisotropy (r) by DPH probe where lower (r) values give higher fluidity. We found that ox-HDL derived from the propagation phase (PP-HDL) and the decomposition phase (DP-HDL) became less fluid ((r): 0.263+/-0.001, 0.279+/-0.002, respectively) than HDL from the lag phase (LP-HDL) and native HDL (nat-HDL) ((r): 0.206+/-0.001) (P<0.05). Macrophages incubated with PP-HDL and DP-HDL had less fluid membranes ((r): 0.231+/-0.001, 0.243+/-0.002, respectively) than those incubated with LP-HDL and nat-HDL ((r): 0.223+/-0.001) (P<0.05). Consequently, fluidity was reduced not only in ox-HDL but also in the cell membranes exposed to ox-HDL. A significant negative correlation was observed between macrophage membrane fluorescence anisotropy (r) and free cholesterol efflux from these cells (-0.876; P<0.05). Thus, lower membrane fluidity was associated with lower free cholesterol efflux from cells. In conclusion, the increase in the HDL oxidation process leads to a lost of macrophage membrane fluidity that could contribute to an explanation of the reduction of free cholesterol efflux from cells by ox-HDL. PMID:14499733

  20. HDL subfractions and very early CAD: novel findings from untreated patients in a Chinese cohort.

    PubMed

    Zhang, Yan; Zhu, Cheng-Gang; Xu, Rui-Xia; Li, Sha; Li, Xiao-Lin; Guo, Yuan-Lin; Wu, Na-Qiong; Gao, Ying; Qing, Ping; Cui, Chuan-Jue; Sun, Jing; Li, Jian-Jun

    2016-01-01

    Coronary artery disease (CAD) in very young individuals is a rare disease associated with poor prognosis. However, the role of specific lipoprotein subfractions in very young CAD patients (≤45 years) is not established yet. A total of 734 consecutive CAD subjects were enrolled and were classified as very early (n = 81, ≤45), early (n = 304, male: 45-55; female: 45-65), and late (n = 349, male: >55; female: >65) groups. Meanwhile, a group of non-CAD subjects were also enrolled as controls (n = 56, ≤45). The lipoprotein separation was performed using Lipoprint System. As a result, the very early CAD patients have lower large high-density lipoprotein (HDL) subfraction and higher small low-density lipoprotein (LDL) subfraction (p < 0.05). Although body mass index was inversely related to large HDL subfraction, overweight did not influence its association with very early CAD. In the logistic regression analysis, large HDL was inversely [OR 95% CI: 0.872 (0.825-0.922)] while small LDL was positively [1.038 (1.008-1.069)] related to very early CAD. However, after adjusting potential confounders, the association was only significant for large HDL [0.899 (0.848-0.954)]. This study firstly demonstrated that large HDL subfraction was negatively related to very early CAD suggestive of its important role in very early CAD incidence. PMID:27489174

  1. Beneficial effects of raloxifene and atorvastatin on serum lipids and HDL phospholipids levels of postmenopausal women.

    PubMed

    Piperi, Christina; Kalofoutis, C; Skenderi, Katerina; Economidou, Olga; Kalofoutis, A

    2004-06-01

    Selective oestrogen receptor modulators (raloxifene) and statins (atorvastatin) have been shown to reduce the risk of cardiovascular disease associated with the postmenopausal status. Their beneficial effects may be mediated partly by favourable changes in serum lipids and particular on HDL phospholipid composition. In the present study, individual administration of either raloxifene (Group A) or atorvastatin (Group B) or both (Group C) was compared for a period of 3 months and their effects on total lipids and HDL phospholipids were evaluated. The combined treatment of raloxifene and atorvastatin resulted in profound changes in the majority of serum lipids, including a significant reduction in total cholesterol and triglycerides (P<0.001), a rise in total phospholipids (P<0.01) and a reduction in LDL-C and Apo B levels (P<0.001). Furthermore, Apo A-I was elevated (P<0.001) whereas total HDL phospholipids were significantly increased (P<0.05). Specifically, HDL phosphatidylcholine levels were markedly increased (P<0.001) and HDL lysophosphatidylcholine, sphingomyelin and phosphatidylinositol levels were reduced (P<0.05). A further attempt to evaluate each treatment group was performed and the significance of these results is discussed. PMID:15203583

  2. Radiolabeled cholesteryl ethers trace LDL cholesteryl esters but not HDL cholesteryl esters in the rat.

    PubMed

    Terpstra, A H

    1995-01-01

    The intravascular metabolism of cholesteryl [1-14C]oleoyl ester and [1,2-3H(N)]cholesteryl palmityl ether was compared in the rat, an animal species without plasma cholesteryl ester transfer activity (CETA). The tracers had identical plasma disappearance rates when they were incorporated into human or rat low density lipoproteins (LDL). Fractional catabolic rates (FCR) were 0.081 +/- 0.014 h-1 and 0.080 +/- 0.013 h-1 for human LDL ester and ether and 0.098 +/- 0.007 h-1 and 0.101 +/- 0.007 h-1 for rat LDL ester and ether, respectively. In contrast, the ether had plasma disappearance rates that were 24%-25% lower than the ester when they were incorporated into human or rat high density lipoproteins (HDL). FCR were 0.230 +/- 0.020 and 0.173 +/- 0.030 h-1 for human HDL ester and ether and 0.131 +/- 0.020 h-1 and 0.100 +/- 0.017 h-1 for rat HDL ester and ether respectively. Biological screening of the rat HDL preparations did not affect these differences. The results of these studies indicate that in the absence of plasma CETA, cholesteryl ethers can be used to trace LDL cholesteryl esters but not to trace HDL cholesteryl esters. PMID:7772060

  3. HDL subfractions and very early CAD: novel findings from untreated patients in a Chinese cohort

    PubMed Central

    Zhang, Yan; Zhu, Cheng-Gang; Xu, Rui-Xia; Li, Sha; Li, Xiao-Lin; Guo, Yuan-Lin; Wu, Na-Qiong; Gao, Ying; Qing, Ping; Cui, Chuan-Jue; Sun, Jing; Li, Jian-Jun

    2016-01-01

    Coronary artery disease (CAD) in very young individuals is a rare disease associated with poor prognosis. However, the role of specific lipoprotein subfractions in very young CAD patients (≤45 years) is not established yet. A total of 734 consecutive CAD subjects were enrolled and were classified as very early (n = 81, ≤45), early (n = 304, male: 45–55; female: 45–65), and late (n = 349, male: >55; female: >65) groups. Meanwhile, a group of non-CAD subjects were also enrolled as controls (n = 56, ≤45). The lipoprotein separation was performed using Lipoprint System. As a result, the very early CAD patients have lower large high-density lipoprotein (HDL) subfraction and higher small low-density lipoprotein (LDL) subfraction (p < 0.05). Although body mass index was inversely related to large HDL subfraction, overweight did not influence its association with very early CAD. In the logistic regression analysis, large HDL was inversely [OR 95% CI: 0.872 (0.825–0.922)] while small LDL was positively [1.038 (1.008–1.069)] related to very early CAD. However, after adjusting potential confounders, the association was only significant for large HDL [0.899 (0.848–0.954)]. This study firstly demonstrated that large HDL subfraction was negatively related to very early CAD suggestive of its important role in very early CAD incidence. PMID:27489174

  4. Differing rates of cholesterol absorption among inbred mouse strains yield differing levels of HDL-cholesterol.

    PubMed

    Sontag, Timothy J; Chellan, Bijoy; Getz, Godfrey S; Reardon, Catherine A

    2013-09-01

    Inbred strains of mice with differing susceptibilities to atherosclerosis possess widely varying plasma HDL levels. Cholesterol absorption and lipoprotein formation were compared between atherosclerosis-susceptible, low-HDL C57BL6/J mice and atherosclerosis-resistant, high-HDL FVBN/J mice. [(3)H]cholesterol and triglyceride appeared in the plasma of FVB mice gavaged with cholesterol in olive oil at a much higher rate than in C57 mice. The plasma cholesterol was found almost entirely as HDL-cholesterol in both strains. Inhibition of lipoprotein catabolism with Tyloxapol revealed that the difference in the rate of [(3)H]cholesterol appearance in the plasma was due entirely to a greater rate of chylomicron secretion from the intestine of the FVB mice. Lipid absorption into the 2nd quarter of the small intestine is greater in the FVB mice and indicates that this region may contain the factors that give rise to the differences in absorption observed between the two mouse strains. Additionally, ad libitum feeding prior to cholesterol gavage accentuates the absorption rate differences compared with fasting. The resultant remodeling of the increased levels of chylomicron in the plasma may contribute to increased plasma HDL. Intestinal gene expression analysis reveals several genes that may play a role in these differences, including microsomal triglyceride transfer protein and ABCG8. PMID:23812556

  5. Adiponectin and the mediation of HDL-cholesterol change with improved lifestyle: the Look AHEAD Study.

    PubMed

    Belalcazar, L Maria; Lang, Wei; Haffner, Steven M; Hoogeveen, Ron C; Pi-Sunyer, F Xavier; Schwenke, Dawn C; Balasubramanyam, Ashok; Tracy, Russell P; Kriska, Andrea P; Ballantyne, Christie M

    2012-12-01

    Adipose tissue dysfunction plays a key role in the development of the metabolic abnormalities characteristic of type 2 diabetes (T2DM) and participates actively in lipid metabolism. Adiponectin, found abundantly in circulation and a marker of adipose health, is decreased in obese persons with T2DM. We investigated whether the changes in adiponectin with an intensive lifestyle intervention (ILI) for weight loss could potentially mediate the increase in low HDL-cholesterol (HDL-C) with ILI. Adiponectin and its fractions were determined using an ELISA with selective protease treatment in 1,397 participants from Look AHEAD, a trial examining whether ILI will reduce cardiovascular events in overweight/obese subjects with T2DM when compared with a control arm, diabetes support and education (DSE). Multivariable regression and mediational analyses were performed for adiponectin and its high-molecular-weight (HMW) and non-HMW fractions. ILI increased baseline HDL-C by 9.7% and adiponectin by 11.9%; changes with DSE were 1.3% and 0.2%, respectively (P < 0.0001). In a model including changes in weight, fitness, triglycerides, and glucose control and that adjusted for demographics and medical history, adiponectin changes remained significantly associated with HDL-C change. Data supported the contribution of changes in both HMW- and non-HMW-adiponectin to the improvement in HDL-C with ILI. PMID:22956782

  6. Imaging and force measurement of LDL and HDL by AFM in air and liquid

    PubMed Central

    Gan, Chaoye; Ao, Meiying; Liu, Zhanghua; Chen, Yong

    2015-01-01

    The size and biomechanical properties of lipoproteins are tightly correlated with their structures/functions. While atomic force microscopy (AFM) has been used to image lipoproteins the force measurement of these nano-sized particles is missing. We detected that the sizes of LDL and HDL in liquid are close to the commonly known values. The Young’s modulus of LDL or HDL is ∼0.4 GPa which is similar to that of some viral capsids or nanovesicles but greatly larger than that of various liposomes. The adhesive force of LDL or HDL is small (∼200 pN). The comparison of AFM detection in air and liquid was also performed which is currently lacking. Our data may provide useful information for better understanding and AFM detection of lipoproteins. PMID:25893163

  7. Hepatic lipase- and endothelial lipase-deficiency in mice promotes macrophage-to-feces RCT and HDL antioxidant properties.

    PubMed

    Escolà-Gil, Joan Carles; Chen, Xiangyu; Julve, Josep; Quesada, Helena; Santos, David; Metso, Jari; Tous, Monica; Jauhiainen, Matti; Blanco-Vaca, Francisco

    2013-04-01

    Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol (HDLc) levels and presumably could affect two main HDL atheroprotective functions, macrophage-to-feces reverse cholesterol transport (RCT) and HDL antioxidant properties. In this study, we assessed the effects of both HL and EL deficiency on macrophage-specific RCT process and HDL ability to protect against LDL oxidation. HL- and EL-deficient and wild-type mice were injected intraperitoneally with [(3)H]cholesterol-labeled mouse macrophages, after which the appearance of [(3)H]cholesterol in plasma, liver, and feces was determined. The degree of HDL oxidation and the protection of oxidative modification of LDL co-incubated with HDL were evaluated by measuring conjugated diene kinetics. Plasma levels of HDLc, HDL phospholipids, apoA-I, and platelet-activated factor acetyl-hydrolase were increased in both HL- and EL-deficient mice. These genetically modified mice displayed increased levels of radiolabeled, HDL-bound [(3)H]cholesterol 48h after the label injection. The magnitude of macrophage-derived [(3)H]cholesterol in feces was also increased in both the HL- and EL-deficient mice. HDL from the HL- and EL-deficient mice was less prone to oxidation and had a higher ability to protect LDL from oxidation, compared with the HDL derived from the wild-type mice. These changes were correlated with plasma apoA-I and apoA-I/HDL total protein levels. In conclusion, targeted inactivation of both HL and EL in mice promoted macrophage-to-feces RCT and enhanced HDL antioxidant properties. PMID:23328279

  8. Adrenal steroidogenesis disruption caused by HDL/cholesterol suppression in diethylstilbestrol-treated adult male rat.

    PubMed

    Haeno, Satoko; Maeda, Naoyuki; Yamaguchi, Kousuke; Sato, Michiko; Uto, Aika; Yokota, Hiroshi

    2016-04-01

    The synthetic estrogen diethylstilbestrol is used to prevent miscarriages and as a therapeutic treatment for prostate cancer, but it has been reported to have adverse effects on endocrine homeostasis. However, the toxicity mechanism is poorly understood. Recently, we reported that diethylstilbestrol impairs adrenal steroidogenesis via cholesterol insufficiency in adult male rats. In the present study, we found that the adrenal cholesterol level was significantly reduced without of the decrease in other precursors in the adrenal steroidogenesis 24 h after a single dose of diethylstilbestrol (0.33 μg/g body mass). The serum HDL/cholesterol level was also reduced only 12 h after the diethylstilbestrol exposure. The level of Apo E, which is indispensable for HDL/cholesterol maturation, was decreased in both the HDL and VLDL/LDL fractions, whereas the level of Apo A1, which is an essential constituent of HDL, was not altered in the HDL fraction. Because the liver is a major source of Apo E and Apo A1, the secretion rates of these proteins were examined using a liver perfusion experiment. The secretion rate of Apo A1 from the liver was consistent between DES-treated and control rats, but that of Apo E was comparatively suppressed in the DES-treated rats. The disruption of adrenal steroidogenesis by diethylstilbestrol was caused by a decrease in serum HDL/cholesterol, which is the main source of adrenal steroidogenesis, due to the inhibition of Apo E secretion from the liver. PMID:26349937

  9. The effect of HDL-bound and free PON1 on copper-induced LDL oxidation.

    PubMed

    Bayrak, Ahmet; Bayrak, Tülin; Bodur, Ebru; Kılınç, Kamer; Demirpençe, Ediz

    2016-09-25

    Oxidative modification of LDL plays an important role in the development of atherosclerosis. High-density lipoprotein (HDL) confers protection against atherosclerosis and the antioxidative properties of paraoxonase 1 (PON1) has been suggested to contribute to this effect of HDL. The PON1 exist in two major polymorphic forms (Q and R), which regulate the concentration and activity of the enzyme and alter its ability to prevent lipid oxidation. However, the association of Q192R polymorphism with PON1's capacity to protect against LDL lipoperoxidation is controversial. The aim of this study was to evaluate the effects of the purified PON1 Q192R and the partially purified HDL-bound PON1 Q192R isoenzymes (HDL-PON1 Q192R) on LDL oxidation, with respect to their arylesterase/homocysteine thiolactonase (HTLase) activities. Cupric ion-induced LDL oxidation was reduced up to 48% by purified PON1 Q192, but only 33% by an equivalent activity of PON1 R192. HDL-PON1 Q192 isoenzyme caused a 65% reduction, whereas HDL-PON1 R192 isoenzyme caused only 46% reduction in copper ion-induced LDL oxidation. These findings reflect the fact that PON1 Q and PON1 R allozymes may have different protective characteristics against LDL oxidation. The protection against LDL oxidation provided by HDL-PON1 Q192R isoenzymes is more prominent than the purified soluble enzymes. Inhibition of the Ca(+2)-dependent PON1 Q192R arylesterase/HTLase by the metal chelator EDTA, did not alter PON1's ability to inhibit LDL oxidation. These studies indicate that the active site involvement of the purified enzyme is not similar to the HDL-bound one, in terms of both PON1 arylesterase/HTLase activity and the protection of LDL from copper ion-induced oxidation. Moreover, PON1's ability to protect LDL from oxidation does not seem to require calcium. PMID:27510818

  10. Velodyne HDL-64E lidar for unmanned surface vehicle obstacle detection

    NASA Astrophysics Data System (ADS)

    Halterman, Ryan; Bruch, Michael

    2010-04-01

    The Velodyne HDL-64E is a 64 laser 3D (360×26.8 degree) scanning LIDAR. It was designed to fill perception needs of DARPA Urban Challenge vehicles. As such, it was principally intended for ground use. This paper presents the performance of the HDL-64E as it relates to the marine environment for unmanned surface vehicle (USV) obstacle detection and avoidance. We describe the sensor's capacity for discerning relevant objects at sea- both through subjective observations of the raw data and through a rudimentary automated obstacle detection algorithm. We also discuss some of the complications that have arisen with the sensor.

  11. Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice.

    PubMed

    Huang, LinZhang; Fan, BaoYan; Ma, Ang; Shaul, Philip W; Zhu, HaiBo

    2015-05-01

    ABCA1 plays a key role in the initial lipidation of apoA-I, which generates circulating HDL cholesterol. Whereas it is known that the transcriptional upregulation of ABCA1 promotes HDL formation and reverse cholesterol transport (RCT), it is not known how the inhibition of ABCA1 protein degradation impacts HDL function. Employing the small molecule triacetyl-3-hydroxyphenyladenosine (IMM-H007), we determined how the attenuation of ABCA1 protein degradation affects HDL cholesterol efflux capacity, RCT, and atherosclerotic lesion formation. Pulse-chase analysis revealed that IMM-H007 inhibits ABCA1 degradation and facilitates its cell-surface localization in macrophages, and additional studies in macrophages showed that IMM-H007 thereby promotes cholesterol efflux. IMM-H007 treatment of Paigen diet-fed mice caused an increase in circulating HDL level, it increased the cholesterol efflux capacity of HDL, and it enhanced in vivo RCT from macrophages to the plasma, liver, and feces. Furthermore, ABCA1 degradation suppression by IMM-H007 reduced atherosclerotic plaque formation in apoE(-/-) mice. Thus, via effects on both ABCA1-expressing cells and circulating HDL function, the inhibition of ABCA1 protein degradation by IMM-H007 promotes HDL cholesterol efflux capacity and RCT and attenuates atherogenesis. IMM-H007 potentially represents a lead compound for the development of agents to augment HDL function. PMID:25761370

  12. Reflex Testing for Carbohydrate-Deficient Transferrin (CDT) in Insurance Applicants with Elevated High Density Lipoprotein Cholesterol (HDL).

    PubMed

    Singh, Gurmukh

    2015-01-01

    Objectives .- Ascertain the utility of testing carbohydrate deficient transferrin (CDT) levels in insurance applicants with elevated high density lipoprotein cholesterol (HDL) levels. Background .- Chronic alcoholism is not uncommon and is a risk factor for health and longevity and thus of interest to providers of insurance. A number of tests serve as markers of alcohol use, eg, blood alcohol level, elevated liver enzymes, ethyl glucuronide in urine, whole blood associated aldehyde (WBAA), macrocytosis, elevated HDL, elevated CDT and others. WBAA and CDT are usually only done, if some other screening test suggests alcohol use. HDL testing is routinely done for assessing cardiac risk, however, chronic alcohol intake tends to raise HDL and some insurance providers reflex to CDT testing when HDL is elevated. Methods .- A number of the clients of Heritage Labs Inc. have rules in place to test for CDT levels in specimens showing elevated HDL levels. The commonest HDL level that serves as the trigger for reflex testing for CDT is 80mg/dL. The results of this practice were analyzed to assess the utility of reflex testing for CDT to identify chronic alcohol abusers among the applicants. Results .- In examining the results of CDT levels done as a reflex test due to elevated HDL levels, about 2% of the applicants, 0.7% of women and 3% of men, tested positive for elevated CDT levels. Conclusions .- The incidence of elevated CDT levels is high enough to warrant routinely testing for this analyte in applicants, especially men, with high HDL levels. PMID:27584808

  13. Emergent Biomarkers of Residual Cardiovascular Risk in Patients with Low HDL-c and/or High Triglycerides and Average LDL-c Concentrations: Focus on HDL Subpopulations, Oxidized LDL, Adiponectin, and Uric Acid

    PubMed Central

    Mascarenhas-Melo, Filipa; Sereno, José; Freitas, Isabel; Isabel-Mendonça, Maria; Pinto, Rui; Teixeira, Frederico

    2013-01-01

    This study intended to determine the impact of HDL-c and/or TGs levels on patients with average LDL-c concentration, focusing on lipidic, oxidative, inflammatory, and angiogenic profiles. Patients with cardiovascular risk factors (n = 169) were divided into 4 subgroups, combining normal and low HDL-c with normal and high TGs patients. The following data was analyzed: BP, BMI, waist circumference and serum glucose, Total-c, TGs, LDL-c, oxidized-LDL, total HDL-c and HDL subpopulations, paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF-α, adiponectin, VEGF, and iCAM1. The two populations with increased TGs levels, regardless of the normal or low HDL-c, presented obesity and higher waist circumference, Total-c, LDL-c, Ox-LDL, and uric acid. Adiponectin concentration was significantly lower and VEGF was higher in the population with cumulative low values of HDL-c and high values of TGs, while HDL quality was reduced in the populations with impaired values of HDL-c and/or TGs, viewed by reduced large and increased small HDL subfractions. In conclusion, in a population with cardiovascular risk factors, low HDL-c and/or high TGs concentrations seem to be associated with a poor cardiometabolic profile, despite average LDL-c levels. This condition, often called residual risk, is better evidenced by using both traditional and nontraditional CV biomarkers, including large and small HDL subfractions, Ox-LDL, adiponectin, VEGF, and uric acid. PMID:24319364

  14. Associations of high HDL cholesterol level with all-cause mortality in patients with heart failure complicating coronary heart disease

    PubMed Central

    Cai, Anping; Li, Xida; Zhong, Qi; Li, Minming; Wang, Rui; Liang, Yingcong; Chen, Wenzhong; Huang, Tehui; Li, Xiaohong; Zhou, Yingling; Li, Liwen

    2016-01-01

    Abstract The aim of the present study was to evaluate the association between HDL cholesterol level and all-cause mortality in patients with ejection fraction reduced heart failure (EFrHF) complicating coronary heart disease (CHD). A total of 323 patients were retrospectively recruited. Patients were divided into low and high HDL cholesterol groups. Between-group differences and associations between HDL cholesterol level and all-cause mortality were assessed. Patients in the high HDL cholesterol group had higher HDL cholesterol level and other lipid components (P <0.05 for all comparison). Lower levels of alanine aminotransferase (ALT), high-sensitivity C-reactive protein (Hs-CRP), and higher albumin (ALB) level were observed in the high HDL cholesterol group (P <0.05 for all comparison). Although left ventricular ejection fraction (LVEF) were comparable (28.8 ± 4.5% vs 28.4 ± 4.6%, P = 0.358), mean mortality rate in the high HDL cholesterol group was significantly lower (43.5% vs 59.1%, P = 0.007). HDL cholesterol level was positively correlated with ALB level, while inversely correlated with ALT, Hs-CRP, and NYHA classification. Logistic regression analysis revealed that after extensively adjusted for confounding variates, HDL cholesterol level remained significantly associated with all-cause mortality although the magnitude of association was gradually attenuated with odds ratio of 0.007 (95% confidence interval 0.001–0.327, P = 0.012). Higher HDL cholesterol level is associated with better survival in patients with EFrHF complicating CHD, and future studies are necessary to demonstrate whether increasing HDL cholesterol level will confer survival benefit in these populations of patients. PMID:27428188

  15. Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci.

    PubMed

    Wang, Xiaosong; Le Roy, Isabelle; Nicodeme, Edwige; Li, Renhua; Wagner, Richard; Petros, Christina; Churchill, Gary A; Harris, Stephen; Darvasi, Ariel; Kirilovsky, Jorge; Roubertoux, Pierre L; Paigen, Beverly

    2003-07-01

    Mapping quantitative trait loci (QTLs) with high resolution facilitates identification and positional cloning of the underlying genes. The novel approach of advanced intercross lines (AILs) generates many more recombination events and thus can potentially narrow QTLs significantly more than do conventional backcrosses and F2 intercrosses. In this study, we carried out QTL analyses in (C57BL/6J x NZB/BlNJ) x C57BL/6J backcross progeny fed either chow or an atherogenic diet to detect QTLs that regulate high-density lipoprotein cholesterol (HDL)concentrations, and in (C57BL/6J x NZB/BlNJ) F11 AIL progeny to confirm and narrow those QTLs. QTLs for HDL concentrations were found on chromosomes 1, 5, and 16. AIL not only narrowed the QTLs significantly more than did a conventional backcross but also resolved a chromosome 5 QTL identified in the backcross into two QTLs, the peaks of both being outside the backcross QTL region. We tested 27 candidate genes and found significant mRNA expression differences for 12 (Nr1i3, Apoa2, Sap, Tgfb2, Fgfbp1, Prom, Ppargc1, Tcf1, Ncor2, Srb1, App, and Ifnar). Some of these underlay the same QTL, indicating that expression differences are common and not sufficient to identify QTL genes. All the major HDL QTLs in our study had homologous counterparts in humans, implying that their underlying genes regulate HDL in humans. PMID:12805272

  16. Using Advanced Intercross Lines for High-Resolution Mapping of HDL Cholesterol Quantitative Trait Loci

    PubMed Central

    Wang, Xiaosong; Le Roy, Isabelle; Nicodeme, Edwige; Li, Renhua; Wagner, Richard; Petros, Christina; Churchill, Gary A.; Harris, Stephen; Darvasi, Ariel; Kirilovsky, Jorge; Roubertoux, Pierre L.; Paige, Beverly

    2003-01-01

    Mapping quantitative trait loci (QTLs)with high resolution facilitates identification and positional cloning of the underlying genes. The novel approach of advanced intercross lines (AILs) generates many more recombination events and thus can potentially narrow QTLs significantly more than do conventional backcrosses and F2 intercrosses. In this study, we carried out QTL analyses in (C57BL/6J × NZB/BlNJ)× C57BL/6J backcross progeny fed either chow or an atherogenic diet to detect QTLs that regulate high-density lipoprotein cholesterol (HDL)concentrations, and in (C57BL/6J × NZB/BlNJ)F11 AIL progeny to confirm and narrow those QTLs. QTLs for HDL concentrations were found on chromosomes 1, 5, and 16. AIL not only narrowed the QTLs significantly more than did a conventional backcross but also resolved a chromosome 5 QTL identified in the backcross into two QTLs, the peaks of both being outside the backcross QTL region. We tested 27 candidate genes and found significant mRNA expression differences for 12 (Nr1i3, Apoa2, Sap, Tgfb2, Fgfbp1, Prom, Ppargc1, Tcf1, Ncor2, Srb1, App, and Ifnar). Some of these underlay the same QTL, indicating that expression differences are common and not sufficient to identify QTL genes. All the major HDL QTLs in our study had homologous counterparts in humans, implying that their underlying genes regulate HDL in humans. PMID:12805272

  17. The implementation of thermal image visualization by HDL based on pseudo-color

    NASA Astrophysics Data System (ADS)

    Zhu, Yong; Zhang, JiangLing

    2004-11-01

    The pseudo-color method which maps the sampled data to intuitive perception colors is a kind of powerful visualization way. And the all-around system of pseudo-color visualization, which includes the primary principle, model and HDL (Hardware Description Language) implementation for the thermal images, is expatiated on in the paper. The thermal images whose signal is modulated as video reflect the temperature distribution of measured object, so they have the speciality of mass and real-time. The solution to the intractable problem is as follows: First, the reasonable system, i.e. the combining of global pseudo-color visualization and local special area accurate measure, muse be adopted. Then, the HDL pseudo-color algorithms in SoC (System on Chip) carry out the system to ensure the real-time. Finally, the key HDL algorithms for direct gray levels connection coding, proportional gray levels map coding and enhanced gray levels map coding are presented, and its simulation results are showed. The pseudo-color visualization of thermal images implemented by HDL in the paper has effective application in the aspect of electric power equipment test and medical health diagnosis.

  18. Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics.

    PubMed

    Larach, Daniel B; Cuchel, Marina; Rader, Daniel J

    2013-12-01

    Identification of the CETP, LIPG (encoding endothelial lipase) and APOC3 genes, and ana lysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeutic efficacy. The case of endothelial lipase exemplifies the importance of utilizing population-wide genetic studies of rare variants in potential therapeutic targets to gain information on cardiovascular disease end points. Similar population-wide studies of cardiovascular end points make apoC-III a potentially attractive target for lipid-related drug discovery. These three cases illustrate the positives and negatives of single-gene studies relating to HDL-related cardiovascular drug discovery; such studies should focus not only on HDL cholesterol and other components of the lipid profile, but also on the effect genetic variants have on cardiovascular end points. PMID:25374625

  19. Regulation of the expression of key genes involved in HDL metabolism by unsaturated fatty acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of this study was to determine the effects, and possible mechanisms of action, of unsaturated fatty acids on the expression of genes involved in HDL metabolism in HepG2 cells. The mRNA concentration of target genes was assessed by real time PCR. Protein concentrations were determined by wes...

  20. A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis[S

    PubMed Central

    Brown, Robert J.; Edmondson, Andrew C.; Griffon, Nathalie; Hill, Theophelus B.; Fuki, Ilia V.; Badellino, Karen O.; Li, Mingyao; Wolfe, Megan L.; Reilly, Muredach P.; Rader, Daniel J.

    2009-01-01

    Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. EL displays a preference to hydrolyze lipids in HDL. We report here that a naturally occurring low frequency coding variant in the EL gene (LIPG), glycine-26 to serine (G26S), is significantly more common in African-American individuals with elevated HDL cholesterol (HDL-C) levels. To test the hypothesis that this variant results in reduced EL function, we extensively characterized and compared the catalytic and noncatalytic functions of the G26S variant and wild-type (WT) EL. While the catalytic-specific activity of G26S EL is similar to WT EL, its secretion is markedly reduced. Consistent with this observation, we found that carriers of the G26S variant had significantly reduced plasma levels of EL protein. Thus, this N-terminal variant results in reduced secretion of EL protein, plausibly leading to increased HDL-C levels. PMID:19411705

  1. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

    PubMed Central

    Groen, Albert K.; Bloks, Vincent W.; Bandsma, Robert H.J.; Ottenhoff, Roelof; Chimini, Giovanna; Kuipers, Folkert

    2001-01-01

    The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1–/–, Abca1+/–, and Abca1+/+ mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1–/– mice were indistinguishable from those in Abca1+/– and Abca1+/+ mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1–/– mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation. PMID:11560953

  2. Role of apolipoprotein A-I in HDL binding to a rat hepatoma cell in culture

    SciTech Connect

    Gottlieb, B.A.

    1985-01-01

    The binding of HDL to rat Fu5AH hepatoma cells at 4/sup 0/, and uptake and degradation at 37/sup 0/, was investigated in monolayer cultures. HDL, free of apo E and apo A-IV, was obtained from the plasma of nephrotic rats (HDLne). /sup 125/I-labeled HDLne bound to the cells in a specific, saturable manner. By Scatchard analysis, two classes of binding sites were obtained: a high affinity binding site (Kd = 1.25 +/- 0.023 ..mu..g/ml, or 5 x 10/sup -9/ M), and a lower affinity site (Kd = 45 +/- 15 ..mu..g/ml, or 1.8 x 10/sup -7/ M). In competitive binding experiments, normal rat HDL was nearly as effective as HDLne, but rat VLDL and human lipoproteins were ineffective. Rat apo A-I/phospholipid complexes also did not complete effectively for HDLne binding, although they were capable of binding to the cells. However, LDL (1.02 < d < 1.063) from nephrotic rat plasma, containing 20% of apo A-I, was as effective as rat HDL in competing for HDLne binding when the competition was expressed as a function of apo A-I content. Control experiments indicated that labeled apo A-I from HDLne did not exchange appreciably with unlabeled apo A-I on the LDLne. When the hepatoma cells were allowed to internalize and degrade HDLne at 37/sup 0/, the acid-soluble products (iodotyrosine and iodide) were derived almost entirely from the breakdown of apo A-I. We conclude that the rat hepatoma cell (Fu5AH) has high affinity HDL binding sites which recognize apo A-I-lipid complexes in which apo A-I an appropriate conformation.

  3. Competitive inhibition of LDL binding and uptake by HDL in aortic endothelial cells

    SciTech Connect

    Alexander, J.J.; Miguel, R.; Graham, D. )

    1990-09-01

    High-density lipoprotein (HDL) may inhibit the binding and cellular uptake of low-density lipoprotein (LDL) as one means of regulating the delivery of exogenous cholesterol to nonhepatic tissues. This may play an important role in atherogenesis, by altering lipid metabolism in cells of the arterial wall. To verify and better characterize this effect, endothelial cells were harvested from bovine aorta and maintained in tissue culture. Following initial preincubation in lipid-deficient culture media, these cells were incubated for 2 hr at 4 degrees C in media containing 125I-LDL (10 micrograms protein/ml) and varying concentrations of either HDL (0-400 micrograms protein/ml) or comparable amounts of Apoprotein A (Apo A), the major protein component of HDL. Intracellular and trypsin-released counts were assayed separately, as a measurement of cellular uptake and membrane bound LDL, respectively. Results of this study indicated an inhibition of LDL binding and uptake by HDL (P less than 0.005, ANOVA). A similar inhibition was found with Apo A alone (P less than 0.005). When identical studies were performed using 125I-Apoprotein B, the protein component of LDL, and Apo A, the latter was found to inhibit the binding of Apo B to the same extent (P less than 0.0006). These results indicate that HDL does inhibit LDL binding and uptake by bovine aortic endothelial cells and that, because this effect is seen equally with only the protein component of these lipoprotein particles, it is most likely due to competitive binding at the receptor level rather than to stearic hindrance or an alteration of the cell membrane.

  4. Higher HDL cholesterol is associated with better cognitive function: the Maine-Syracuse study.

    PubMed

    Crichton, Georgina E; Elias, Merrill F; Davey, Adam; Sullivan, Kevin J; Robbins, Michael A

    2014-11-01

    Few studies have examined associations between different subcategories of cholesterol and cognitive function. We examined relationships between total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride levels and cognitive performance in the Maine-Syracuse Longitudinal Study, a community-based study of cardiovascular risk factors. Cross-sectional analyses were undertaken on data from 540 participants, aged 60 to 98 years, free of dementia and stroke. TC, HDL, LDL, and triglyceride levels were obtained. Cognitive function was assessed using a thorough neuropsychological test battery, including domains of cognitive function indexed by multiple cognitive tests. The cognitive outcomes studied were as follows: Visual-Spatial Memory and Organization, Verbal and Working Memory, Scanning and Tracking, Abstract Reasoning, a Global Composite score, and the Mini-Mental State Examination (MMSE). Significant positive associations were observed between HDL-cholesterol and the Global Composite score, Working Memory, and the MMSE after adjustment for demographic and cardiovascular risk factors. Participants with desirable levels of HDL (≥60 mg/dL) had the highest scores on all cognitive outcomes. There were no significant associations observed between TC, LDL, or triglyceride concentrations and cognition. In older individuals, HDL-cholesterol was related to a composite of Working Memory tests and for general measures of cognitive ability when adjusted for cardiovascular variables. We speculate that persons over 60 are survivors and thus less likely to show cognitive deficit in relation to TC, LDL-cholesterol, and triglycerides. Longitudinal studies are needed to examine relations between specific cognitive abilities and the different subcategories of cholesterol. PMID:25382185

  5. ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet

    PubMed Central

    Terasaka, Naoki; Yu, Shuiqing; Yvan-Charvet, Laurent; Wang, Nan; Mzhavia, Nino; Langlois, Read; Pagler, Tamara; Li, Rong; Welch, Carrie L.; Goldberg, Ira J.; Tall, Alan R.

    2008-01-01

    Plasma HDL levels are inversely related to the incidence of atherosclerotic disease. Some of the atheroprotective effects of HDL are likely mediated via preservation of EC function. Whether the beneficial effects of HDL on ECs depend on its involvement in cholesterol efflux via the ATP-binding cassette transporters ABCA1 and ABCG1, which promote efflux of cholesterol and oxysterols from macrophages, has not been investigated. To address this, we assessed endothelial function in Abca1–/–, Abcg1–/–, and Abca1–/–Abcg1–/– mice fed either a high-cholesterol diet (HCD) or a Western diet (WTD). Non-atherosclerotic arteries from WTD-fed Abcg1–/– and Abca1–/–Abcg1–/– mice exhibited a marked decrease in endothelium-dependent vasorelaxation, while Abca1–/– mice had a milder defect. In addition, eNOS activity was reduced in aortic homogenates generated from Abcg1–/– mice fed either a HCD or a WTD, and this correlated with decreased levels of the active dimeric form of eNOS. More detailed analysis indicated that ABCG1 was expressed primarily in ECs, and that these cells accumulated the oxysterol 7-ketocholesterol (7-KC) when Abcg1–/– mice were fed a WTD. Consistent with these data, ABCG1 had a major role in promoting efflux of cholesterol and 7-KC in cultured human aortic ECs (HAECs). Furthermore, HDL treatment of HAECs prevented 7-KC–induced ROS production and active eNOS dimer disruption in an ABCG1-dependent manner. Our data suggest that ABCG1 and HDL maintain EC function in HCD-fed mice by promoting efflux of cholesterol and 7-oxysterols and preserving active eNOS dimer levels. PMID:18924609

  6. Increased HDL Size and Enhanced Apo A-I Catabolic Rates Are Associated With Doxorubicin-Induced Proteinuria in New Zealand White Rabbits.

    PubMed

    López-Olmos, Victoria; Carreón-Torres, Elizabeth; Luna-Luna, María; Flores-Castillo, Cristobal; Martínez-Ramírez, Miriam; Bautista-Pérez, Rocío; Franco, Martha; Sandoval-Zárate, Julio; Roldán, Francisco-Javier; Aranda-Fraustro, Alberto; Soria-Castro, Elizabeth; Muñoz-Vega, Mónica; Fragoso, José-Manuel; Vargas-Alarcón, Gilberto; Pérez-Méndez, Oscar

    2016-03-01

    The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I. PMID:26781765

  7. Coincubation of PON1, APO A1, and LCAT increases the time HDL is able to prevent LDL oxidation.

    PubMed

    Hine, David; Mackness, Bharti; Mackness, Mike

    2012-02-01

    The inhibition of low-density lipoprotein (LDL) oxidation by high-density lipoprotein (HDL) is a major antiatherogenic property of this lipoprotein. This activity is due, in part, to HDL associated proteins. However, whether these proteins interact in the antioxidant activity of HDL is unknown. LDL was incubated with apolipoprotein A1 (apo A1), lecithin:cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON1) alone or in combination, in the presence or absence of HDL under oxidizing conditions. LDL lipid peroxide concentrations were determined. Apo A1, LCAT, and PON1 all inhibit LDL oxidation in the absence of HDL and enhance the ability of HDL to inhibit LDL oxidation. Their effect was additive rather than synergistic; the combination of these proteins significantly enhanced the length of time LDL was protected from oxidation. This seemed to be due to the ability of PON1 to prevent the oxidative inactivation of LCAT. Apo A1, LCAT, and PON1 can all contribute to the antioxidant activity of HDL in vitro. The combination of apo A1, LCAT, and PON1 prolongs the time that HDL can prevent LDL oxidation, due, at least in part, to the prevention LCAT inactivation. PMID:22184096

  8. Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically defined disease in post-menopausal women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The association of coronary heart disease (CHD) with subpopulations of triglyceride (TG)-rich lipoproteins and high-density lipoproteins (HDL) is established in men, but has not been well characterized in women. Plasma HDL subpopulation concentrations, quantified by 2-dimensional gel electrophoresis...

  9. ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression.

    PubMed

    Burillo, Elena; Lindholt, Jes S; Molina-Sánchez, Pedro; Jorge, Immaculada; Martinez-Pinna, Roxana; Blanco-Colio, Luis Miguel; Tarin, Carlos; Torres-Fonseca, Monica Maria; Esteban, Margarita; Laustsen, Jesper; Ramos-Mozo, Priscilla; Calvo, Enrique; Lopez, Juan Antonio; Vega de Ceniga, Melina; Michel, Jean-Baptiste; Egido, Jesus; Andrés, Vicente; Vazquéz, Jesús; Meilhac, Olivier; Martin-Ventura, Jose Luis

    2015-06-01

    Abdominal aortic aneurysm (AAA) evolution is unpredictable, and there is no therapy except surgery for patients with an aortic size> 5 cm (large AAA). We aimed to identify new potential biomarkers that could facilitate prognosis and treatment of patients with AAA. A differential quantitative proteomic analysis of plasma proteins was performed in AAA patients at different stages of evolution [small AAA (aortic size=3-5 cm) vs large AAA] using iTRAQ labelling, high-throughput nano-LC-MS/MS and a novel multi-layered statistical model. Among the proteins identified, ApoA-I was decreased in patients with large AAA compared to those with small AAA. These results were validated by ELISA on plasma samples from small (n=90) and large AAA (n=26) patients (150± 3 vs 133± 5 mg/dl, respectively, p< 0.001). ApoA-I levels strongly correlated with HDL-Cholesterol (HDL-C) concentration (r=0.9, p< 0.001) and showed a negative correlation with aortic size (r=-0.4, p< 0.01) and thrombus volume (r=-0.3, p< 0.01), which remained significant after adjusting for traditional risk factors. In a prospective study, HDL-C independently predicted aneurysmal growth rate in multiple linear regression analysis (n=122, p=0.008) and was inversely associated with need for surgical repair (Adjusted hazard ratio: 0.18, 95 % confidence interval: 0.04-0.74, p=0.018). In a nation-wide Danish registry, we found lower mean HDL-C concentration in large AAA patients (n=6,560) compared with patients with aorto-iliac occlusive disease (n=23,496) (0.89± 2.99 vs 1.59± 5.74 mmol/l, p< 0.001). Finally, reduced mean aortic AAA diameter was observed in AngII-infused mice treated with ApoA-I mimetic peptide compared with saline-injected controls. In conclusion, ApoA-I/HDL-C systemic levels are negatively associated with AAA evolution. Therapies targeting HDL functionality could halt AAA formation. PMID:25789510

  10. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

    PubMed Central

    Voight, Benjamin F; Peloso, Gina M; Orho-Melander, Marju; Frikke-Schmidt, Ruth; Barbalic, Maja; Jensen, Majken K; Hindy, George; Hólm, Hilma; Ding, Eric L; Johnson, Toby; Schunkert, Heribert; Samani, Nilesh J; Clarke, Robert; Hopewell, Jemma C; Thompson, John F; Li, Mingyao; Thorleifsson, Gudmar; Newton-Cheh, Christopher; Musunuru, Kiran; Pirruccello, James P; Saleheen, Danish; Chen, Li; Stewart, Alexandre FR; Schillert, Arne; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Anand, Sonia; Engert, James C; Morgan, Thomas; Spertus, John; Stoll, Monika; Berger, Klaus; Martinelli, Nicola; Girelli, Domenico; McKeown, Pascal P; Patterson, Christopher C; Epstein, Stephen E; Devaney, Joseph; Burnett, Mary-Susan; Mooser, Vincent; Ripatti, Samuli; Surakka, Ida; Nieminen, Markku S; Sinisalo, Juha; Lokki, Marja-Liisa; Perola, Markus; Havulinna, Aki; de Faire, Ulf; Gigante, Bruna; Ingelsson, Erik; Zeller, Tanja; Wild, Philipp; de Bakker, Paul I W; Klungel, Olaf H; Maitland-van der Zee, Anke-Hilse; Peters, Bas J M; de Boer, Anthonius; Grobbee, Diederick E; Kamphuisen, Pieter W; Deneer, Vera H M; Elbers, Clara C; Onland-Moret, N Charlotte; Hofker, Marten H; Wijmenga, Cisca; Verschuren, WM Monique; Boer, Jolanda MA; van der Schouw, Yvonne T; Rasheed, Asif; Frossard, Philippe; Demissie, Serkalem; Willer, Cristen; Do, Ron; Ordovas, Jose M; Abecasis, Gonçalo R; Boehnke, Michael; Mohlke, Karen L; Daly, Mark J; Guiducci, Candace; Burtt, Noël P; Surti, Aarti; Gonzalez, Elena; Purcell, Shaun; Gabriel, Stacey; Marrugat, Jaume; Peden, John; Erdmann, Jeanette; Diemert, Patrick; Willenborg, Christina; König, Inke R; Fischer, Marcus; Hengstenberg, Christian; Ziegler, Andreas; Buysschaert, Ian; Lambrechts, Diether; Van de Werf, Frans; Fox, Keith A; El Mokhtari, Nour Eddine; Rubin, Diana; Schrezenmeir, Jürgen; Schreiber, Stefan; Schäfer, Arne; Danesh, John; Blankenberg, Stefan; Roberts, Robert; McPherson, Ruth; Watkins, Hugh; Hall, Alistair S; Overvad, Kim; Rimm, Eric; Boerwinkle, Eric; Tybjaerg-Hansen, Anne; Cupples, L Adrienne; Reilly, Muredach P; Melander, Olle; Mannucci, Pier M; Ardissino, Diego; Siscovick, David; Elosua, Roberto; Stefansson, Kari; O'Donnell, Christopher J; Salomaa, Veikko; Rader, Daniel J; Peltonen, Leena; Schwartz, Stephen M; Altshuler, David; Kathiresan, Sekar

    2012-01-01

    Summary Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol

  11. Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

    PubMed

    Samino, Sara; Vinaixa, Maria; Díaz, Marta; Beltran, Antoni; Rodríguez, Miguel A; Mallol, Roger; Heras, Mercedes; Cabre, Anna; Garcia, Lorena; Canela, Nuria; de Zegher, Francis; Correig, Xavier; Ibáñez, Lourdes; Yanes, Oscar

    2015-01-01

    Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide. PMID:26099471

  12. Role of HDL in cholesteryl ester metabolism of lipopolysaccharide-activated P388D1 macrophages[S

    PubMed Central

    Uda, Sabrina; Spolitu, Stefano; Angius, Fabrizio; Collu, Maria; Accossu, Simonetta; Banni, Sebastiano; Murru, Elisabetta; Sanna, Francesca; Batetta, Barbara

    2013-01-01

    Infections share with atherosclerosis similar lipid alterations, with accumulation of cholesteryl esters (CEs) in activated macrophages and concomitant decrease of cholesterol-HDL (C-HDL). Yet the precise role of HDL during microbial infection has not been fully elucidated. Activation of P388D1 by lipopolysaccharide (LPS) triggered an increase of CEs and neutral lipid contents, along with a remarkable enhancement in 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-HDL uptake. Similar results were found in human monocyte-derived macrophages and monocytes cocultured with phytohemagglutinin-activated lymphocytes. Inhibition of cholesterol esterification with Sandoz-58035 resulted in 80% suppression of CE biosynthesis in P388D1. However, only a 35% decrease of CE content, together with increased scavenger receptor class B member 1 (SR-B1) protein expression, was found after 72 h and thereafter up to 16 passages of continuous ACAT suppression. Chronic inhibition blunted the effect of LPS treatment on cholesterol metabolism, increased the ratio of free cholesterol/CE content and enhanced interleukin 6 secretion.These results imply that, besides de novo biosynthesis and acquisition by LDL, HDL contributes probably through SR-B1 to the increased CE content in macrophages, partly explaining the low levels of C-HDL during their activation. Our data suggest that in those conditions where more CEs are required, HDL rather than removing, may supply CEs to the cells. PMID:23956443

  13. Kidney Function as a Determinant of HDL and Triglyceride Concentrations in the Australian Population

    PubMed Central

    Thompson, Michael; Ray, Udayan; Yu, Richard; Hudspeth, Andrew; Smillie, Michael; Jordan, Neville; Bartle, Janet

    2016-01-01

    Background: Chronic kidney disease (CKD) is a potent risk factor for cardiovascular disease (CVD). CVD risk increases in a stepwise manner with increasing kidney impairment and is significantly reduced by kidney transplantation, suggesting a causal relationship. Dyslipidemia, a well recognised CVD risk factor, is highly prevalent in CKD. While dyslipidemia is a risk factor for CKD, kidney impairment can also induce a dyslipidemic state that may contribute to the excess burden of CVD in CKD. We utilised a multipronged approach to determine whether a causal relationship exists. Materials and Methods: Retrospective case-control analysis of 816 patients admitted to the Royal Hobart Hospital in 2008–2009 with different degrees of kidney impairment and retrospective before-after cohort analysis of 60 patients who received a transplanted kidney between 1999 and 2009. Results: Decreased estimated GFR (eGFR) was independently associated with decreased high density lipoprotein (HDL, p < 0.0001) and increased triglyceride concentrations (p < 0.01) in multivariate analysis. There was no significant relationship between eGFR and low density lipoprotein (LDL) or total cholesterol in multivariate analysis. Kidney transplantation increased HDL (p < 0.0001) and decreased triglyceride (p = 0.007) concentration, whereas there was no significant change in LDL and total cholesterol. These effects were dependent on maintenance of graft function, statin therapy (those who were on) if graft failure occurred then HDL again decreased and triglycerides increased. Conclusions: Kidney transplantation ameliorated alterations in plasma lipoprotein profile associated with kidney impairment, an effect that was dependent on the maintenance of graft function. These data suggest that kidney function is a determinant of HDL and triglyceride concentrations in patients with CKD. PMID:27005668

  14. Transient increase in HDL-cholesterol during weight gain by hyperalimentation in healthy subjects.

    PubMed

    Lindström, Torbjörn; Kechagias, Stergios; Carlsson, Martin; Nystrom, Fredrik H

    2011-04-01

    Determination of lipid levels is fundamental in cardiovascular risk assessment. We studied the short-term effects of fast food-based hyperalimentation on lipid levels in healthy subjects. Twelve healthy men and six healthy women with a mean age of 26 ± 6.6 years and an aged-matched control group were recruited for this prospective interventional study. Subjects in the intervention group aimed for a body weight increase of 5-15% by doubling the baseline caloric intake by eating at least two fast food-based meals a day in combination with adoption of a sedentary lifestyle for 4 weeks. This protocol induced a weight gain from 67.6 ± 9.1 kg to 74.0 ± 11 kg (P < 0.001). A numerical increase in the levels of high-density lipoprotein (HDL)-cholesterol occurred in all subjects during the study and this was apparent already at the first week in 16/18 subjects (mean increase at week 1: +22.0 ± 16%, range from -7 to +50%), whereas the highest level of HDL during the study as compared with baseline values varied from +6% to +58% (mean +31.6 ± 15%). The intake of saturated fat in the early phase of the trial related positively with the HDL-cholesterol-increase in the second week (r = 0.53, P = 0.028). Although the levels of insulin doubled at week 2, the increase in low-density lipoprotein (LDL)-cholesterol was only +12 ± 17%, and there was no statistically significant changes in fasting serum triglycerides. We conclude that hyperalimentation can induce a fast but transient increase in HDL-cholesterol that is of clinical interest when estimating cardiovascular risk based on serum lipid levels. PMID:20814413

  15. Unacylated Ghrelin is associated with the isolated low HDL-cholesterol obese phenotype independently of insulin resistance and CRP level

    PubMed Central

    2012-01-01

    Background Low plasma high-density lipoprotein-cholesterol (HDL-c) level is commonly present in obesity and represents an independent cardiovascular risk factor. However, obese patients are a very heterogeneous population and the factors and mechanisms that contribute to low HDL-c remain unclear. The aim of this study was to investigate the association between plasma HDL-c levels and plasma hormonal profiles (insulin, adiponectin, resistin, leptin and ghrelin) in subsets of class II and III obese patients. Methods Fasting plasma levels of glucose, total cholesterol, LDL-c, HDL-c, triglycerides, free fatty acids, apoproteins A-I, B-100, B-48, C-II, C-III, insulin, hs-CRP, adipocytokines (adiponectin, resistin, leptin), unacylated ghrelin, body composition (DXA) and resting energy expenditure were measured in three subsets of obese patients: 17 metabolically abnormal obese (MAO) with metabolic syndrome and the typical metabolic dyslipidaemia, 21 metabolically healthy obese (MHO) without metabolic syndrome and with a normal lipid profile, and 21 isolated low HDL-c obese patients (LHO) without metabolic syndrome, compared to 21 healthy lean control subjects. Results Insulin resistance (HOMA-IR) increased gradually from MHO to LHO and from LHO to MAO patients (p < 0.05 between MHO and MAO and between LHO and MAO). In multiple regression analysis, serum unacylated ghrelin levels were only positively and independently associated with HDL-c levels in the LHO group (p = 0.032). Conclusions These results suggest that, in class II and III obese patients with an isolated low HDL-c phenotype, unacylated ghrelin is positively associated with HDL-c level independently of insulin resistance and CRP levels, and may contribute to the highly prevalent low HDL-c level seen in obesity. PMID:22413940

  16. Apolipoprotein M expression increases the size of nascent pre beta HDL formed by ATP binding cassette transporter A1.

    PubMed

    Mulya, Anny; Seo, Jeongmin; Brown, Amanda L; Gebre, Abraham K; Boudyguina, Elena; Shelness, Gregory S; Parks, John S

    2010-03-01

    Apolipoprotein M (apoM) is a novel apolipoprotein that is reportedly necessary for pre beta HDL formation; however, its detailed function remains unknown. We investigated the biogenesis and properties of apoM and its effects on the initial steps of nascent pre beta HDL assembly by ABCA1 in HEK293 cells. Transiently transfected apoM was localized primarily in the endomembrane compartment. Pulse-chase analyses demonstrated that apoM is inefficiently secreted, relative to human serum albumin, and that approximately 50% remains membrane-associated after extraction with sodium carbonate, pH 11.5. To investigate the role of apoM in nascent pre beta HDL formation, ABCA1-expressing or control cells, transfected with empty vector, apoM, or C-terminal epitope-tagged apoM (apoM-C-FLAG), were incubated with (125)I-apoA-I for 24 h. Conditioned media were harvested and fractionated by fast-protein liquid chromatography (FPLC) to monitor HDL particle size. Pre beta HDL particles were formed effectively in the absence of apoM expression; however, increased apoM expression stimulated the formation of larger-sized nascent pre beta HDLs. Immunoprecipitation with anti-apoA-I antibody followed by apoM Western blot analysis revealed that little secreted apoM was physically associated with pre beta HDL. Our results suggest that apoM is an atypical secretory protein that is not necessary for ABCA1-dependent pre beta HDL formation but does stimulate the formation of larger-sized pre beta HDL. We propose that apoM may function catalytically at an intracellular site to transfer lipid onto pre beta HDL during or after their formation by ABCA1. PMID:19767535

  17. Lipid fluidity at different regions in LDL and HDL of {beta}-thalassemia/Hb E patients

    SciTech Connect

    Morales, Noppawan Phumala . E-mail: scnpm@mahidol.ac.th; Charlermchoung, Chalermkhwan; Luechapudiporn, Rataya; Yamanont, Paveena; Fucharoen, Suthat; Chantharaksri, Udom

    2006-11-24

    Atherosclerosis-related vascular complications in {beta}-thalassemia/hemoglobin E ({beta}-thal/Hb E) patients may result from iron induced oxidation of lipoproteins. To identify the specific site of oxidative damage, changes in lipid fluidity at different regions in LDL and HDL particle were investigated using two fluorescence probes and two ESR spin probes. The magnitude of increased lipid fluidity in thalassemic lipoproteins was dependent on the location of the probes. In hydrophobic region, the rotational correlation times for 16-doxyl stearic acid and DPH anisotropy were markedly changed in LDL and HDL of the patients. In the surface region, there was only a slight change in the order parameter (S) for 5-doxyl stearic acid and TMA-DPH anisotropy. Lipid fluidity at the core of LDL and HDL showed good correlation with oxidative stress markers, the ratio of CL/CO, and the level of {alpha}-tocopherol, suggesting that hydrophobic region of thalassemic lipoprotein was a target site for oxidative damage.

  18. Truncal and abdominal fat as determinants of high triglycerides and low HDL-cholesterol in adolescents.

    PubMed

    Tresaco, Beatriz; Moreno, Luis A; Ruiz, Jonatan R; Ortega, Francisco B; Bueno, Gloria; González-Gross, Marcela; Wärnberg, Julia; Gutiérrez, Angel; García-Fuentes, Miguel; Marcos, Ascensión; Castillo, Manuel J; Bueno, Manuel

    2009-05-01

    We examined whether abdominal and truncal adiposity, assessed with simple anthropometric indices, determines serum triglycerides and high-density lipoprotein (HDL)-cholesterol levels independently of total adiposity amount in adolescents. A total of 547 Spanish adolescents (284 males and 263 females) aged 13-18.5 years were included in this study. Measures of truncal adiposity included subscapular to triceps ratio, and trunk-to-total skinfolds ratio (TTS%). Waist circumference was used as a surrogate of abdominal adiposity, and BMI was used as a measure of total adiposity. The results of the regression models indicated that levels of triglycerides were positively associated with waist circumference and TTS% after controlling for age and Tanner stage in both sexes. Once BMI was entered in the model, these associations remained significant for waist circumference in females. HDL-cholesterol levels were negatively associated with waist circumference in both sexes, and with subscapular to triceps ratio and TTS% in males, after controlling for age and Tanner stage. Once BMI was entered in the model, these associations remained significant for subscapular to triceps ratio and for TTS% in males. The results of this study suggest that in male adolescents, truncal adiposity is negatively associated with levels of HDL-cholesterol, whereas in females, abdominal adiposity is positively associated with levels of triglycerides independently of total adiposity. These findings highlight the deleterious effect of both truncal and abdominal fat depots on the lipid profile already from the first decades of life. PMID:19180070

  19. Secreted Progranulin Is a Homodimer and Is Not a Component of High Density Lipoproteins (HDL)*

    PubMed Central

    Nguyen, Andrew D.; Nguyen, Thi A.; Cenik, Basar; Yu, Gang; Herz, Joachim; Walther, Tobias C.; Davidson, W. Sean; Farese, Robert V.

    2013-01-01

    Progranulin is a secreted glycoprotein, and the GRN gene is mutated in some cases of frontotemporal dementia. Progranulin has also been implicated in cell growth, wound healing, inflammation, and cancer. We investigated the molecular nature of secreted progranulin and provide evidence that progranulin exists as a homodimer. Although recombinant progranulin has a molecular mass of ∼85 kDa by SDS-PAGE, it elutes in fractions corresponding to ∼170–180 kDa by gel-filtration chromatography. Additionally, recombinant progranulin can be intermolecularly cross-linked, yielding a complex corresponding to a dimer (∼180 kDa), and progranulins containing different epitope tags physically interact. In plasma, progranulin similarly forms complexes of ∼180–190 kDa. Although progranulin partially co-fractionated with high density lipoproteins (HDL) by gel-filtration chromatography, we found no evidence that progranulin in mouse or human plasma is a component of HDL either by ultracentrifugation or by lipid binding assays. We conclude that circulating progranulin exists as a dimer and is not likely a component of HDL. PMID:23364791

  20. Effect of the amyloidogenic L75P apolipoprotein A-I variant on HDL subpopulations

    PubMed Central

    Gomaraschi, Monica; Obici, Laura; Simonelli, Sara; Gregorini, Gina; Negrinelli, Alessandro; Merlini, Giampaolo; Franceschini, Guido; Calabresi, Laura

    2011-01-01

    Background Hereditary amyloidosis due to mutations of apolipoprotein A-I (apoA-I) is a rare disease characterized by the deposition of amyloid fibrils constituted by the N-terminal fragment of apoA-I in several organs. L75P is a variant of apoA-I associated with systemic amyloidosis predominantly involving the liver, kidneys, and testis, identified in a large number of unrelated subjects. Objective of the present paper was to evaluate the impact of the L75P apoA-I variant on HDL subpopulations and cholesterol esterification in carriers. Methods and results Plasma samples were collected from 30 carriers of the amyloidogenic L75P apoA-I (Carriers) and from 15 non affected relatives (Controls). Carriers displayed significantly reduced plasma levels of HDL-cholesterol, apoA-I, and apoA-II compared to Controls. Plasma levels of LpA-I, but not LpA-I:A-II, were significantly reduced in Carriers. HDL subclass distribution was not affected by the presence of the variant. The unesterified to total cholesterol ratio was higher, and cholesterol esterification rate and LCAT activity were lower in Carriers than in Controls. Conclusions The L75P apoA-I variant is associated with hypoalphalipoproteinemia, a selective reduction of LpA-I particles, and a partial defect in cholesterol esterification. PMID:21458433

  1. Low HDL cholesterol as a cardiovascular risk factor in rural, urban, and rural-urban migrants: PERU MIGRANT cohort study

    PubMed Central

    Lazo-Porras, María; Bernabe-Ortiz, Antonio; Málaga, Germán; Gilman, Robert H.; Acuña-Villaorduña, Ana; Cardenas-Montero, Deborah; Smeeth, Liam; Miranda, J. Jaime

    2016-01-01

    Introduction Whilst the relationship between lipids and cardiovascular mortality has been well studied and appears to be controversial, very little has been explored in the context of rural-to-urban migration in low-resource settings. Objective Determine the profile and related factors for HDL-c patterns (isolated and non-isolated low HDL-c) in three population-based groups according to their migration status, and determine the effect of HDL-c patterns on the rates of cardiovascular outcomes (i.e. non-fatal stroke and non-fatal myocardial infarction) and mortality. Methods Cross-sectional and 5-year longitudinal data from the PERU MIGRANT study, designed to assess the effect of migration on cardiovascular risk profiles and mortality in Peru. Two different analyses were performed: first, we estimated prevalence and associated factors with isolated and non-isolated low HDL-c at baseline. Second, using longitudinal information, relative risk ratios (RRR) of composite outcomes of mortality, non-fatal stroke and non-fatal myocardial infarction were calculated according to HDL-c levels at baseline. Results Data from 988 participants, rural (n = 201), rural-to-urban migrants (n = 589), and urban (n = 199) groups, was analysed. Low HDL-c was present in 56.5% (95%CI: 53.4%–59.6%) without differences by study groups. Isolated low HDL-c was found in 36.5% (95%CI: 33.5–39.5%), with differences between study groups. In multivariable analysis, urban group (vs. rural), female gender, overweight and obesity were independently associated with isolated low HDL-c. Only female gender, overweight and obesity were associated with non-isolated low HDL-c. Longitudinal analyses showed that non-isolated low HDL-c increased the risk of negative cardiovascular outcomes (RRR = 3.46; 95%CI: 1.23–9.74). Conclusions Isolated low HDL-c was the most common dyslipidaemia in the study population and was more frequent in rural subjects. Non-isolated low HDL-c increased three-to fourfold

  2. Chemical composition and antidiabetic activity of Opuntia Milpa Alta extracts.

    PubMed

    Luo, Chuan; Zhang, Wannian; Sheng, Chunquan; Zheng, Chengjian; Yao, Jianzhong; Miao, Zhenyuan

    2010-12-01

    Three new compounds, 1-3, and 20 known compounds were isolated from the AcOEt and BuOH extract of edible Opuntia Milpa Alta. The petroleum ether extract was examined by GC and MS. A total of 26 compounds were identified, representing 95.6% of the total extract, phytosterol (36.03%) being the most abundant component, and polyunsaturated fatty acids (18.57%) represented the second largest group, followed by phytol (12.28%), palmitic acid, palmitate (13.54%), vitamin E (4.51%), and other compounds (7.47%). The effects of various extracts from edible Opuntia Milpa Alta (petroleum ether extract, AcOEt extract, BuOH extract, aqueous extract, H₂O parts) and the positive control (received dimethylbiguanide) were tested on streptozotocin (STZ)-induced diabetic mice. The results indicated that all the treatment groups could significantly decrease blood glucose levels in STZ-induced diabetic mice compared to the model control group (P<0.01), except the aqueous extract group (P<0.05). Especially, the petroleum ether extract group and the positive control group showed remarkable decrease of blood glucose levels. Taken together, the results indicate that the petroleum ether extract is the major hypoglycemic part in edible Opuntia Milpa Alta, which may be developed to a potential natural hypoglycemic functional ingredient. PMID:21161999

  3. Management of dyslipidemia in the metabolic syndrome: recommendations of the Spanish HDL-Forum.

    PubMed

    Ascaso, Juan; Gonzalez Santos, Pedro; Hernandez Mijares, Antonio; Mangas Rojas, Alipio; Masana, Luis; Millan, Jesus; Pallardo, Luis Felipe; Pedro-Botet, Juan; Perez Jimenez, Francisco; Pintó, Xavier; Plaza, Ignacio; Rubiés, Juan; Zúñiga, Manuel

    2007-01-01

    In order to characterize the metabolic syndrome it becomes necessary to establish a number of diagnostic criteria. Because of its impact on cardiovascular morbidity/mortality, considerable attention has been focussed on the dyslipidemia accompanying the metabolic syndrome. The aim of this review is to highlight the fundamental aspects of the pathophysiology, diagnosis, and the treatment of the metabolic syndrome dyslipidemia with recommendations to clinicians. The clinical expression of the metabolic syndrome dyslipidemia is characterized by hypertriglyceridemia and low levels of high-density lipoprotein-cholesterol (HDL-C). In addition, metabolic syndrome dyslipidemia is associated with high levels of apolipoprotein (apo) B-100-rich particles of a particularly atherogenic phenotype (small dense low-density lipoprotein-cholesterol [LDL-C]. High levels of triglyceride-rich particles (very low-density lipoprotein) are also evident both at baseline and in overload situations (postprandial hyperlipidemia). Overall, the 'quantitative' dyslipidemia characterized by hypertriglyceridemia and low levels of HDL-C and the 'qualitative' dyslipidemia characterized by high levels of apo B-100- and triglyceride-rich particles, together with insulin resistance, constitute an atherogenic triad in patients with the metabolic syndrome. The therapeutic management of the metabolic syndrome, regardless of the control of the bodyweight, BP, hyperglycemia or overt diabetes mellitus, aims at maintaining optimum plasma lipid levels. Therapeutic goals are similar to those for high-risk situations because of the coexistence of multiple risk factors. The primary goal in treatment should be achieving an LDL-C level of <100 mg/dL (or <70 mg/dL in cases with established ischemic heart disease or risk equivalents). A further goal is increasing the HDL-C level to >or=40 mg/dL in men or 50 mg/dL in women. A non-HDL-C goal of 130 mg/dL should also be aimed at in cases of hypertriglyceridemia

  4. Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raising: A systematic review and meta-analysis of relevant preclinical studies and clinical trials.

    PubMed

    Kühnast, Susan; Fiocco, Marta; van der Hoorn, José W A; Princen, Hans M G; Jukema, J Wouter

    2015-09-15

    Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R(2)=0.258, P=0.045; R(2)=0.760, P<0.001), but not for HDL-C (R(2)=0.030, P=0.556). In clinical trials, non-fatal myocardial infarction risk was significantly less in the treatment group with pooled odd ratios of 0.87 [0.81; 0.94] for all trials and 0.85 [0.78; 0.93] after excluding some trials due to off-target adverse events, whereas all-cause mortality was not affected (OR 1.05 [0.99-1.10]). Meta-regression analyses revealed a trend towards an association between between-group differences in absolute change from baseline in LDL-C and non-fatal myocardial infarction (P=0.066), whereas no correlation was found for HDL-C (P=0.955). We conclude that the protective role of lowering LDL-C and non-HDL-C is well-established. The contribution of raising HDL-C on inhibition of atherosclerosis and the prevention of cardiovascular disease remains undefined and may be dependent on the mode of action of HDL-C-modification. Nonetheless, treatment strategies aimed at improving HDL function and raising apolipoprotein A-I may be worth exploring. PMID:25989133

  5. Anthocyanin-rich black elderberry extract improves markers of HDL function and reduces aortic cholesterol in hyperlipidemic mice.

    PubMed

    Farrell, Nicholas; Norris, Gregory; Lee, Sang Gil; Chun, Ock K; Blesso, Christopher N

    2015-04-01

    Serum high-density lipoprotein-cholesterol (HDL-C) is a risk factor considered to be protective of atherosclerosis. However, atherosclerosis is an inflammatory disease and contributes to impairment in high-density lipoprotein (HDL) function, including reductions in HDL-C, HDL antioxidant and anti-inflammatory activities. Anthocyanins are polyphenols that have demonstrated antioxidant and anti-inflammatory properties. The objective of this study was to determine whether an anthocyanin-rich black elderberry extract (Sambucus nigra) (BEE) (13% anthocyanins) would protect against inflammation-related impairments in HDL function and atherosclerosis in apoE(-/-) mice, a mouse model of hyperlipidemia and HDL dysfunction. We fed an AIN-93M diet supplemented with 1.25% (w/w) BEE or control diet to 10 week old male apoE(-/-) mice for 6 weeks. The BEE fed to mice was rich in cyanidin 3-sambubioside (∼ 9.8% w/w) and cyanidin 3-glucoside (∼ 3.8% w/w). After 6 weeks, serum lipids did not differ significantly between groups, while aspartate transaminase (AST) and fasting glucose were reduced in BEE-fed mice. Hepatic and intestinal mRNA changes with BEE-feeding were consistent with an improvement in HDL function (Apoa1, Pon1, Saa1, Lcat, Clu) and a reduction in hepatic cholesterol levels (increased Ldlr and Hmgcr, reduced Cyp7a1). In BEE-fed mice, serum paraoxonase-1 (PON1) arylesterase activity was significantly higher. In addition, mice fed BEE had significantly lower serum chemokine (C-C motif) ligand 2 (CCL2) compared to control-fed mice. Notably, we observed significant reductions in total cholesterol content of the aorta of BEE-fed mice, indicating less atherosclerosis progression. This study suggests that black elderberry may have the potential to influence HDL dysfunction associated with chronic inflammation by impacting hepatic gene expression. PMID:25758596

  6. HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function.

    PubMed

    Berisha, Stela Z; Brubaker, Greg; Kasumov, Takhar; Hung, Kimberly T; DiBello, Patricia M; Huang, Ying; Li, Ling; Willard, Belinda; Pollard, Katherine A; Nagy, Laura E; Hazen, Stanley L; Smith, Jonathan D

    2015-03-01

    HDL functions are impaired by myeloperoxidase (MPO), which selectively targets and oxidizes human apoA1. We previously found that the 4WF isoform of human apoA1, in which the four tryptophan residues are substituted with phenylalanine, is resistant to MPO-mediated loss of function. The purpose of this study was to generate 4WF apoA1 transgenic mice and compare functional properties of the 4WF and wild-type human apoA1 isoforms in vivo. Male mice had significantly higher plasma apoA1 levels than females for both isoforms of human apoA1, attributed to different production rates. With matched plasma apoA1 levels, 4WF transgenics had a trend for slightly less HDL-cholesterol versus human apoA1 transgenics. While 4WF transgenics had 31% less reverse cholesterol transport (RCT) to the plasma compartment, equivalent RCT to the liver and feces was observed. Plasma from both strains had similar ability to accept cholesterol and facilitate ex vivo cholesterol efflux from macrophages. Furthermore, we observed that 4WF transgenic HDL was partially (∼50%) protected from MPO-mediated loss of function while human apoA1 transgenic HDL lost all ABCA1-dependent cholesterol acceptor activity. In conclusion, the structure and function of HDL from 4WF transgenic mice was not different than HDL derived from human apoA1 transgenic mice. PMID:25561462

  7. Targeted Intracellular Delivery of Resveratrol to Glioblastoma Cells Using Apolipoprotein E-Containing Reconstituted HDL as a Nanovehicle

    PubMed Central

    Kim, Sea H.; Adhikari, Birendra Babu; Cruz, Siobanth; Schramm, Michael P.; Vinson, Joe A.; Narayanaswami, Vasanthy

    2015-01-01

    The objective of this study is to transport and deliver resveratrol to intracellular sites using apolipoprotein E3 (apoE3). Reconstituted high-density lipoprotein (rHDL) bearing resveratrol (rHDL/res) was prepared using phospholipids and the low-density lipoprotein receptor (LDLr)-binding domain of apoE3. Biophysical characterization revealed that resveratrol was partitioned into the phospholipid bilayer of discoidal rHDL/res particles (~19 nm diameter). Co-immunoprecipitation studies indicated that the LDLr-binding ability of apoE3 was retained. Cellular uptake of resveratrol to intracellular sites was evaluated in glioblastoma A-172 cells by direct fluorescence using chemically synthesized NBD-labeled resveratrol (res/NBD) embedded in rHDL/res. Competition and inhibition studies indicate that the uptake is by receptor mediated endocytosis via the LDLr, with co-localization of apoE3 and res/NBD in late endosomes/lysosomes. We propose that rHDL provides an ideal hydrophobic milieu to sequester resveratrol and that rHDL containing apoE3 serves as an effective “nanovehicle” to transport and deliver resveratrol to targeted intracellular sites. PMID:26258481

  8. Apolipoprotein A-II is a key regulatory factor of HDL metabolism as appears from studies with transgenic animals and clinical outcomes.

    PubMed

    Maïga, Sira Fatoumata; Kalopissis, Athina-Despina; Chabert, Michèle

    2014-01-01

    The structure and metabolism of HDL are linked to their major apolipoproteins (apo) A-I and A-II. HDL metabolism is very dynamic and depends on the constant remodeling by lipases, lipid transfer proteins and receptors. HDL exert several cardioprotective effects, through their antioxidant and antiinflammatory capacities and through the stimulation of reverse cholesterol transport from extrahepatic tissues to the liver for excretion into bile. HDL also serve as plasma reservoir for C and E apolipoproteins, as transport vehicles for a great variety of proteins, and may have more physiological functions than previously recognized. In this review we will develop several aspects of HDL metabolism with emphasis on the structure/function of apo A-I and apo A-II. An important contribution to our understanding of the respective roles of apo A-I and apo A-II comes from studies using transgenic animal models that highlighted the stabilizatory role of apo A-II on HDL through inhibition of their remodeling by lipases. Clinical studies coupled with proteomic analyses revealed the presence of dysfunctional HDL in patients with cardiovascular disease. Beyond HDL cholesterol, a new notion is the functionality of HDL particles. In spite of abundant literature on HDL metabolic properties, a major question remains unanswered: which HDL particle(s) confer(s) protection against cardiovascular risk? PMID:24012775

  9. A novel role for ABCA1-generated large pre-β migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion[S

    PubMed Central

    Chung, Soonkyu; Gebre, Abraham K.; Seo, Jeongmin; Shelness, Gregory S.; Parks, John S.

    2010-01-01

    In Tangier disease, absence of ATP binding cassette transporter A1 (ABCA1) results in reduced plasma HDL and elevated triglyceride (TG) levels. We hypothesized that hepatocyte ABCA1 regulates VLDL TG secretion through nascent HDL production. Silencing of ABCA1 expression in oleate-stimulated rat hepatoma cells resulted in: 1) decreased large nascent HDL (>10 nm diameter) and increased small nascent HDL (<10 nm) formation, 2) increased large buoyant VLDL1 particle secretion, and 3) decreased phosphatidylinositol-3 (PI3) kinase activation. Nascent HDL-containing conditioned medium from rat hepatoma cells or HEK293 cells transfected with ABCA1 was effective in increasing PI3 kinase activation and reducing VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of isolated large nascent HDL particles to ABCA1-silenced hepatoma cells inhibited VLDL TG secretion to a greater extent than small nascent HDL. Similarly, addition of recombinant HDL, but not human plasma HDL, was effective in attenuating TG secretion and increasing PI3 kinase activation in ABCA1-silenced cells. Collectively, these data suggest that large nascent HDL particles, assembled by hepatic ABCA1, generate a PI3 kinase-mediated autocrine signal that attenuates VLDL maturation and TG secretion. This pathway may explain the elevated plasma TG concentration that occurs in most Tangier subjects and may also account, in part, for the inverse relationship between plasma HDL and TG concentrations in individuals with compromised ABCA1 function. PMID:20215580

  10. Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice

    PubMed Central

    Shih, Diana M.; Shaposhnik, Zory; Meng, Yonghong; Rosales, Melenie; Wang, Xuping; Wu, Judy; Ratiner, Boris; Zadini, Filiberto; Zadini, Giorgio; Lusis, Aldons J.

    2013-01-01

    We examined the effects of a natural secondary bile acid, hyodeoxycholic acid (HDCA), on lipid metabolism and atherosclerosis in LDL receptor-null (LDLRKO) mice. Female LDLRKO mice were maintained on a Western diet for 8 wk and then divided into 2 groups that received chow, or chow + 1.25% HDCA, diets for 15 wk. We observed that mice fed the HDCA diet were leaner and exhibited a 37% (P<0.05) decrease in fasting plasma glucose level. HDCA supplementation significantly decreased atherosclerotic lesion size at the aortic root region, the entire aorta, and the innominate artery by 44% (P<0.0001), 48% (P<0.01), and 94% (P<0.01), respectively, as compared with the chow group. Plasma VLDL/IDL/LDL cholesterol levels were significantly decreased, by 61% (P<0.05), in the HDCA group as compared with the chow diet group. HDCA supplementation decreased intestinal cholesterol absorption by 76% (P<0.0001) as compared with the chow group. Furthermore, HDL isolated from the HDCA group exhibited significantly increased ability to mediate cholesterol efflux ex vivo as compared with HDL of the chow diet group. In addition, HDCA significantly increased the expression of genes involved in cholesterol efflux, such as Abca1, Abcg1, and Apoe, in a macrophage cell line. Thus, HDCA is a candidate for antiatherosclerotic drug therapy.—Shih, D. M., Shaposhnik, Z., Meng, Y., Rosales, M., Wang, X., Wu, J., Ratiner, B., Zadini, F., Zadini, G., Lusis, A. J. Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice. PMID:23752203

  11. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study

    PubMed Central

    Saleheen, Danish; Scott, Robert; Javad, Sundas; Zhao, Wei; Rodrigues, Amrith; Picataggi, Antonino; Lukmanova, Daniya; Mucksavage, Megan L; Luben, Robert; Billheimer, Jeffery; Kastelein, John J P; Boekholdt, S Matthijs; Khaw, Kay-Tee; Wareham, Nick; Rader, Daniel J

    2015-01-01

    Summary Background Although HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity—a prototypical measure of HDL function—has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain. Methods We measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40–79 years, assessed in 1993–97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants. Findings Cholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=–0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51–0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70–0·90) for a per-SD change in cholesterol efflux capacity. Interpretation HDL

  12. Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight and obese postmenopausal women: a MONET study.

    PubMed

    Karelis, Antony D; Pasternyk, Stephanie M; Messier, Lyne; St-Pierre, David H; Lavoie, Jean-Marc; Garrel, Dominique; Rabasa-Lhoret, Rémi

    2007-12-01

    The objective of this cross-sectional study was to examine the relationship between the triglyceride-HDL-cholesterol ratio (TG:HDL-C) and insulin sensitivity in overweight and obese sedentary postmenopausal women. The study population consisted of 131 non-diabetic overweight and obese sedentary postmenopausal women (age; 57.7+/-5.0 y; body mass index (BMI), 32.2+/-4.3 kg/m2). Subjects were characterized by dividing the entire cohort into tertiles based on the TG:HDL-C (T1<0.86 vs. T2=0.86 to 1.35 vs. T3>1.35, respectively). We measured (i) insulin sensitivity (using the hyperinsulinenic-euglycemic clamp and homeostasis model assessment (HOMA)), (ii) body composition (using dual-energy X-ray absorptiometry), (iii) visceral fat (using computed tomography), (iv) plasma lipids, C-reactive protein, 2 h glucose concentration during an oral glucose tolerance test (2 h glucose), as well as fasting glucose and insulin, (v) peak oxygen consumption, and (vi) lower-body muscle strength (using weight training equipment). Significant correlations were observed between the TG:HDL-C and the hyperinsulinemic-euglycemic clamp (r=-0.45; p<0.0001), as well as with HOMA (r=0.42; p<0.0001). Moreover, the TG:HDL-C significantly correlated with lean body mass, visceral fat, 2 h glucose, C-reactive protein, and muscle strength. Stepwise regression analysis showed that the TG:HDL-C explained 16.4% of the variation in glucose disposal in our cohort, which accounted for the greatest source of unique variance. Other independent predictors of glucose disposal were 2 h glucose (10.1%), C-reactive protein (CRP; 7.6%), and peak oxygen consumption (5.8%), collectively (including the TG:HDL-C) explaining 39.9% of the unique variance. In addition, the TG:HDL-C was the second predictor for HOMA, accounting for 11.7% of the variation. High levels of insulin sensitivity were associated with low levels of the TG:HDL-C. In addition, the TG:HDL-C was a predictor for glucose disposal rates and HOMA values

  13. HDL cholesterol: all hope is not lost after the torcetrapib setback--emerging therapeutic strategies on the horizon.

    PubMed

    Verma, Nitin; Figueredo, Vincent M

    2014-01-01

    Lowering low-density lipoprotein cholesterol (LDL) has been definitely shown to reduce cardiovascular events and improve clinical outcomes in the literature. As a result, LDL lowering has become the cornerstone of therapeutic approaches to cardiovascular disease prevention. Recently, there has been a focus on targeting other lipid fractions to improve the clinical risk profile of patients. Raising high-density lipoprotein (HDL) has received considerable attention. Low HDL levels are often seen in combination with elevated triglyceride levels. New therapeutic modalities are being developed to increase HDL levels. Recent failure of agents such as cholesteryl ester transferase protein inhibitor torcetrapib has highlighted the importance of measuring functionality of HDL particles and not just focus quantitatively on HDL-C levels. The heterogeneity of HDL within the systemic circulation results from constant remodeling of particles in response to several factors. Established dyslipidemia therapies such as stains, fibrates, and niacin have already been well known in the literature to have a substantial benefit. Lifestyle changes such as smoking cessation and moderate alcohol consumption have also shown to have some benefit. Several novel HDL therapies are currently being developed, but only the cholesteryl ester transferase protein inhibitors have received considerable attention. Although torcetrapib has received some negative attention due to adverse effects, this overall class of therapeutic agents still holds a lot of promise. Newer agents without the concerned toxicities are currently being developed. ApoA-1-related peptides, peroxisome proliferator-activated receptor agonists, endothelial lipase inhibitors, and liver X receptor agonists are some of the other novel agents currently in various stages of development. PMID:22967983

  14. Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice.

    PubMed

    Petropoulou, Peristera-Ioanna; Berbée, Jimmy F P; Theodoropoulos, Vassilios; Hatziri, Aikaterini; Stamou, Panagiota; Karavia, Eleni A; Spyridonidis, Alexandros; Karagiannides, Iordanes; Kypreos, Kyriakos E

    2015-10-01

    HDL has important immunomodulatory properties, including the attenuation of lipopolysaccharide (LPS)-induced inflammatory response. As lecithin-cholesterol acyltransferase (LCAT) is a critical enzyme in the maturation of HDL we investigated whether LCAT-deficient (Lcat(-/-)) mice present an increased LPS-induced inflammatory response. LPS (100μg/kg body weight)-induced cytokine response in Lcat(-/-) mice was markedly enhanced and prolonged compared to wild-type mice. Importantly, reintroducing LCAT expression using adenovirus-mediated gene transfer reverted their phenotype to that of wild-type mice. Ex vivo stimulation of whole blood with LPS (1-100ng/mL) showed a similar enhanced pro-inflammatory phenotype. Further characterization in RAW 264.7 macrophages in vitro showed that serum and HDL, but not chylomicrons, VLDL or the lipid-free protein fraction of Lcat(-/-) mice, had a reduced capacity to attenuate the LPS-induced TNFα response. Analysis of apolipoprotein composition revealed that LCAT-deficient HDL lacks significant amounts of ApoA-I and ApoA-II and is primarily composed of ApoE, while HDL from Apoa1(-/-) mice is highly enriched in ApoE and ApoA-II. ApoA-I-deficiency did not affect the capacity of HDL to neutralize LPS, though Apoa1(-/-) mice showed a pronounced LPS-induced cytokine response. Additional immunophenotyping showed that Lcat(-/-) , but not Apoa1(-/-) mice, have markedly increased circulating monocyte numbers as a result of increased Cd11b(+)Ly6C(med) monocytes, whereas 'pro-inflammatory' Cd11b(+)Ly6C(hi) monocytes were reduced. In line with this observation, peritoneal macrophages of Lcat(-/-) mice showed a markedly dampened LPS-induced TNFα response. We conclude that LCAT-deficiency increases LPS-induced inflammation in mice due to reduced LPS-neutralizing capacity of immature discoidal HDL and increased monocyte number. PMID:26170061

  15. Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells

    PubMed Central

    Ganesan, Latha P.; Mates, Jessica M.; Cheplowitz, Alana M.; Avila, Christina L.; Zimmerer, Jason M.; Yao, Zhili; Maiseyeu, Andrei; Rajaram, Murugesan V. S.; Robinson, John M.; Anderson, Clark L.

    2016-01-01

    Cholesterol from peripheral tissue, carried by HDL, is metabolized in the liver after uptake by the HDL receptor, SR-B1. Hepatocytes have long been considered the only liver cells expressing SR-B1; however, in this study we describe two disparate immunofluorescence (IF) experiments that suggest otherwise. Using high-resolution confocal microscopy employing ultrathin (120 nm) sections of mouse liver, improving z-axis resolution, we identified the liver sinusoidal endothelial cells (LSEC), marked by FcγRIIb, as the cell within the liver expressing abundant SR-B1. In contrast, the hepatocyte, identified with β-catenin, expressed considerably weaker levels, although optical resolution of SR-B1 was inadequate. Thus, we moved to a different IF strategy, first separating dissociated liver cells by gradient centrifugation into two portions, hepatocytes (parenchymal cells) and LSEC (non-parenchymal cells). Characterizing both portions for the cellular expression of SR-B1 by flow cytometry, we found that LSEC expressed considerable amounts of SR-B1 while in hepatocytes SR-B1 expression was barely perceptible. Assessing mRNA of SR-B1 by real time PCR we found messenger expression in LSEC to be about 5 times higher than in hepatocytes. PMID:26865459

  16. The Orientation and Dynamics of Estradiol and Estradiol Oleate in Lipid Membranes and HDL Disc Models

    PubMed Central

    Vogel, Alexander; Scheidt, Holger A.; Feller, Scott E.; Metso, Jari; Badeau, Robert M.; Tikkanen, Matti J.; Wähälä, Kristiina; Jauhiainen, Matti; Huster, Daniel

    2014-01-01

    Estradiol (E2) and E2 oleate associate with high-density lipoproteins (HDLs). Their orientation in HDLs is unknown. We studied the orientation of E2 and E2 oleate in membranes and reconstituted HDLs, finding that E2 and E2 oleate are membrane-associated and highly mobile. Our combination of NMR measurements, molecular dynamics simulation, and analytic theory identifies three major conformations where the long axis of E2 assumes a parallel, perpendicular, or antiparallel orientation relative to the membrane’s z-direction. The perpendicular orientation is preferred, and furthermore, in this orientation, E2 strongly favors a particular roll angle, facing the membrane with carbons 6, 7, 15, and 16, whereas carbons 1, 2, 11, and 12 point toward the aqueous phase. In contrast, the long axis of E2 oleate is almost exclusively oriented at an angle of ∼60° to the z-direction. In such an orientation, the oleoyl chain is firmly inserted into the membrane. Thus, both E2 and E2 oleate have a preference for interface localization in the membrane. These orientations were also found in HDL discs, suggesting that only lipid-E2 interactions determine the localization of the molecule. The structural mapping of E2 and E2 oleate may provide a design platform for specific E2-HDL-targeted pharmacological therapies. PMID:24988346

  17. Model of an instrumented optoelectronic transmission system in HDL-A and VHDL-AMS

    NASA Astrophysics Data System (ADS)

    Uhring, Wilfried; Herve, Yannick; Pecheux, Francois

    1999-10-01

    The paper presents the model of a complete multidomain system involving two opto-electronic components: the emitter and the receiver. It is written in Anacad Mentor Graphics HDL-A and integrates the propagation environment characteristics and the thermal behavior of each components. First, packages describing electrical, optical, and thermal behavior of each component. First, packages describing electrical, optical, and thermal domains are detailed. Second, the models of the components are explained. They include an electrical, a thermal and an optical part, the latter being particularly developed. Third, the models of the propagation environment, an optical fiber and the related free space, are presented. The components are assembled to build a compete instrumented opto-electronic transmission system. The laser diode emits a digital clock through an optical fiber to a photodiode. The laser diode is thermal controlled through a Peletier module, which can be deactivated as needed. The alignment of the laser diode with the optical fiber can be studied/modified too. The HDL-A resulting models have been simulated in the ELDO environment. Results show that thermal variations influence the quality of the transmission.

  18. Microarray expression profiling identifies genes with altered expression in HDL-deficient mice

    SciTech Connect

    Callow, Matthew J.; Dudoit, Sandrine; Gong, Elaine L.; Speed, Terence P.; Rubin, Edward M.

    2000-05-05

    Based on the assumption that severe alterations in the expression of genes known to be involved in HDL metabolism may affect the expression of other genes we screened an array of over 5000 mouse expressed sequence tags (ESTs) for altered gene expression in the livers of two lines of mice with dramatic decreases in HDL plasma concentrations. Labeled cDNA from livers of apolipoprotein AI (apo AI) knockout mice, Scavenger Receptor BI (SR-BI) transgenic mice and control mice were co-hybridized to microarrays. Two-sample t-statistics were used to identify genes with altered expression levels in the knockout or transgenic mice compared with the control mice. In the SR-BI group we found 9 array elements representing at least 5 genes to be significantly altered on the basis of an adjusted p value of less than 0.05. In the apo AI knockout group 8 array elements representing 4 genes were altered compared with the control group (p < 0.05). Several of the genes identified in the SR-BI transgenic suggest altered sterol metabolism and oxidative processes. These studies illustrate the use of multiple-testing methods for the identification of genes with altered expression in replicated microarray experiments of apo AI knockout and SR-BI transgenic mice.

  19. Acute Decrease in HDL Cholesterol Associated With Exposure to Welding Fumes

    PubMed Central

    Rice, Mary Berlik; Cavallari, Jenn; Fang, Shona; Christiani, David

    2011-01-01

    Objective To investigate acute changes in circulating lipids after exposure to relatively high levels of particulate matter through welding. Methods Using a repeated measures panel study, lipid levels before and after welding and personal exposures to fine particulate matter (PM2.5) were measured in 36 male welders over 63 exposure and/or control days. Results There was a trend toward decrease in HDL (−2.3 mg/dL, P = 0.08) 18 hours after welding. This effect became significant (−2.6 mg/dL, P = 0.05) after adjustment for possible confounders. The effect was strongest (−4.3 mg/dL, P = 0.02) among welders who did not weld the day before the study. There were no significant changes in other lipids associated with welding or PM2.5 exposure. Conclusion Welding exposure was associated with an acute decrease in circulating HDL, which may relate to the inflammatory and proatherosclerotic effects of fine particle exposure. PMID:21187793

  20. Spontaneous remodeling of HDL particles at acidic pH enhances their capacity to induce cholesterol efflux from human macrophage foam cells[S

    PubMed Central

    Nguyen, Su Duy; Öörni, Katariina; Lee-Rueckert, Miriam; Pihlajamaa, Tero; Metso, Jari; Jauhiainen, Matti; Kovanen, Petri T.

    2012-01-01

    HDL particles may enter atherosclerotic lesions having an acidic intimal fluid. Therefore, we investigated whether acidic pH would affect their structural and functional properties. For this purpose, HDL2 and HDL3 subfractions were incubated for various periods of time at different pH values ranging from 5.5 to 7.5, after which their protein and lipid compositions, size, structure, and cholesterol efflux capacity were analyzed. Incubation of either subfraction at acidic pH induced unfolding of apolipoproteins, which was followed by release of lipid-poor apoA-I and ensuing fusion of the HDL particles. The acidic pH-modified HDL particles exhibited an enhanced ability to promote cholesterol efflux from cholesterol-laden primary human macrophages. Importantly, treatment of the acidic pH-modified HDL with the mast cell-derived protease chymase completely depleted the newly generated lipid-poor apoA-I, and prevented the acidic pH-dependent increase in cholesterol efflux. The above-found pH-dependent structural and functional changes were stronger in HDL3 than in HDL2. Spontaneous acidic pH-induced remodeling of mature spherical HDL particles increases HDL-induced cholesterol efflux from macrophage foam cells, and therefore may have atheroprotective effects. PMID:22855736

  1. Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers

    PubMed Central

    Kächele, Martin; Hennige, Anita M.; Machann, Jürgen; Hieronimus, Anja; Lamprinou, Apostolia; Machicao, Fausto; Schick, Fritz; Fritsche, Andreas; Stefan, Norbert; Nürnberg, Bernd; Häring, Hans-Ulrich; Staiger, Harald

    2015-01-01

    Objective Phosphoinositide 3-kinase γ (PI3Kγ) is a G-protein-coupled receptor-activated lipid kinase mainly expressed in leukocytes and cells of the cardiovascular system. PI3Kγ plays an important signaling role in inflammatory processes. Since subclinical inflammation is a hallmark of atherosclerosis, obesity-related insulin resistance, and pancreatic β-cell failure, we asked whether common genetic variation in the PI3Kγ gene (PIK3CG) contributes to body fat content/distribution, serum adipokine/cytokine concentrations, alterations in plasma lipid profiles, insulin sensitivity, insulin release, and glucose homeostasis. Study Design Using a tagging single nucleotide polymorphism (SNP) approach, we analyzed genotype-phenotype associations in 2,068 German subjects genotyped for 10 PIK3CG SNPs and characterized by oral glucose tolerance tests. In subgroups, data from hyperinsulinaemic-euglycaemic clamps, magnetic resonance spectroscopy of the liver, whole-body magnetic resonance imaging, and intravenous glucose tolerance tests were available, and peripheral blood mononuclear cells (PBMCs) were used for gene expression analysis. Results After appropriate adjustment, none of the PIK3CG tagging SNPs was significantly associated with body fat content/distribution, adipokine/cytokine concentrations, insulin sensitivity, insulin secretion, or blood glucose concentrations (p>0.0127, all; Bonferroni-corrected α-level: 0.0051). However, six non-linked SNPs displayed at least nominal associations with plasma HDL-cholesterol concentrations, two of them (rs4288294 and rs116697954) reaching the level of study-wide significance (p = 0.0003 and p = 0.0004, respectively). More precisely, rs4288294 and rs116697954 influenced HDL2-, but not HDL3-, cholesterol. With respect to the SNPs’ in vivo functionality, rs4288294 was significantly associated with PIK3CG mRNA expression in PBMCs. Conclusions We could demonstrate that common genetic variation in the PIK3CG locus, possibly

  2. Evaluation of CETP activity in vivo under non-steady-state conditions: influence of anacetrapib on HDL-TG flux.

    PubMed

    McLaren, David G; Previs, Stephen F; Phair, Robert D; Stout, Steven J; Xie, Dan; Chen, Ying; Salituro, Gino M; Xu, Suoyu S; Castro-Perez, Jose M; Opiteck, Gregory J; Akinsanya, Karen O; Cleary, Michele A; Dansky, Hayes M; Johns, Douglas G; Roddy, Thomas P

    2016-03-01

    Studies in lipoprotein kinetics almost exclusively rely on steady-state approaches to modeling. Herein, we have used a non-steady-state experimental design to examine the role of cholesteryl ester transfer protein (CETP) in mediating HDL-TG flux in vivo in rhesus macaques, and therefore, we developed an alternative strategy to model the data. Two isotopomers ([(2)H11] and [(13)C18]) of oleic acid were administered (orally and intravenously, respectively) to serve as precursors for labeling TGs in apoB-containing lipoproteins. The flux of a specific TG (52:2) from these donor lipoproteins to HDL was used as the measure of CETP activity; calculations are also presented to estimate total HDL-TG flux. Based on our data, we estimate that the peak total postprandial TG flux to HDL via CETP is ∼ 13 mg · h(-1) · kg(-1) and show that this transfer was inhibited by 97% following anacetrapib treatment. Collectively, these data demonstrate that HDL TG flux can be used as a measure of CETP activity in vivo. The fact that the donor lipoproteins can be labeled in situ using well-established stable isotope tracer techniques suggests ways to measure this activity for native lipoproteins in free-living subjects under any physiological conditions. PMID:26658238

  3. Marrubium vulgare extract inhibits human-LDL oxidation and enhances HDL-mediated cholesterol efflux in THP-1 macrophage.

    PubMed

    Berrougui, Hicham; Isabelle, Maxim; Cherki, Mounia; Khalil, Abdelouahed

    2006-12-14

    The objective of the present study was to elucidate the beneficial properties of aqueous extracts of Marrubium vulgare (AEM) towards cardiovascular disease by protecting human-LDL against lipid peroxidation and promoting HDL-mediated cholesterol efflux. Human-LDL were oxidised by incubation with CuSO(4) in the presence of increased concentrations of AEM (0-100 microg/ml). LDL lipid peroxidation was evaluated by conjugated diene formation, vitamin E disappearance as well as LDL-electrophoretic mobility. HDL-mediated cholesterol efflux assay was carried out in human THP-1 macrophages. Incubation of LDL with AEM significantly prolonged the lag phase (P=0.014), lowered the progression rate of lipid peroxidation (P=0.004), reduced the disappearance of vitamin E and the electrophoretic mobility in a dose-dependent manner. Also, incubation of HDL with AEM significantly increased HDL-mediated cholesterol efflux from THP-1 macrophages implicating an independent ATP binding cassette A1 (ABCA1) pathways. Our findings suggest that M. vulgare provides a source of natural antioxidants, which inhibit LDL oxidation and enhance reverse cholesterol transport and thus can prevent cardiovascular diseases development. These antioxidant properties increase the anti-atherogenic potential of HDL. PMID:17045616

  4. Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent.

    PubMed

    Shah, Sunil; Chib, Rahul; Raut, Sangram; Bermudez, Jaclyn; Sabnis, Nirupama; Duggal, Divya; Kimball, Joseph D; Lacko, Andras G; Gryczynski, Zygmunt; Gryczynski, Ignacy

    2016-02-01

    Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy. PMID:26735001

  5. A Retained Secretory Signal Peptide Mediates High Density Lipoprotein (HDL) Assembly and Function of Haptoglobin-related Protein*

    PubMed Central

    Harrington, John M.; Nishanova, Tuiumkan; Pena, Savannah Rose; Hess, Matthew; Scelsi, Chris L.; Widener, Justin; Hajduk, Stephen L.

    2014-01-01

    Haptoglobin-related protein (Hpr) is a component of a minor subspecies of high density lipoproteins (HDL) that function in innate immunity. Here we show that assembly of Hpr into HDL is mediated by its retained N-terminal signal peptide, an unusual feature for a secreted protein and the major difference between Hpr and the soluble acute phase protein haptoglobin (Hp). The 18-amino acid signal peptide is necessary for binding to HDL and interacts directly with the hydrocarbon region of lipids. Utilizing model liposomes, we show that the rate of assembly and steady-state distribution of Hpr in lipid particles is mediated by the physical property of lipid fluidity. Dye release assays reveal that Hpr interacts more rapidly with fluid liposomes. Conversely, steady-state binding assays indicate that more rigid lipid compositions stabilize Hpr association. Lipid association also plays a role in facilitating hemoglobin binding by Hpr. Our data may offer an explanation for the distinct distribution of Hpr among HDL subspecies. Rather than protein-protein interactions mediating localization, direct interaction with phospholipids and sensitivity to lipid fluidity may be sufficient for localization of Hpr and may represent a mechanism of HDL subspeciation. PMID:25037218

  6. Temporal Analysis and Automatic Calibration of the Velodyne HDL-32E LiDAR System

    NASA Astrophysics Data System (ADS)

    Chan, T. O.; Lichti, D. D.; Belton, D.

    2013-10-01

    At the end of the first quarter of 2012, more than 600 Velodyne LiDAR systems had been sold worldwide for various robotic and high-accuracy survey applications. The ultra-compact Velodyne HDL-32E LiDAR has become a predominant sensor for many applications that require lower sensor size/weight and cost. For high accuracy applications, cost-effective calibration methods with minimal manual intervention are always desired by users. However, the calibrations are complicated by the Velodyne LiDAR's narrow vertical field of view and the very highly time-variant nature of its measurements. In the paper, the temporal stability of the HDL-32E is first analysed as the motivation for developing a new, automated calibration method. This is followed by a detailed description of the calibration method that is driven by a novel segmentation method for extracting vertical cylindrical features from the Velodyne point clouds. The proposed segmentation method utilizes the Velodyne point cloud's slice-like nature and first decomposes the point clouds into 2D layers. Then the layers are treated as 2D images and are processed with the Generalized Hough Transform which extracts the points distributed in circular patterns from the point cloud layers. Subsequently, the vertical cylindrical features can be readily extracted from the whole point clouds based on the previously extracted points. The points are passed to the calibration that estimates the cylinder parameters and the LiDAR's additional parameters simultaneously by constraining the segmented points to fit to the cylindrical geometric model in such a way the weighted sum of the adjustment residuals are minimized. The proposed calibration is highly automatic and this allows end users to obtain the time-variant additional parameters instantly and frequently whenever there are vertical cylindrical features presenting in scenes. The methods were verified with two different real datasets, and the results suggest that up to 78

  7. The human HDL proteome displays high inter-individual variability and is altered dynamically in response to angioplasty-induced atheroma plaque rupture.

    PubMed

    Jorge, Inmaculada; Burillo, Elena; Mesa, Raquel; Baila-Rueda, Lucía; Moreno, Margoth; Trevisan-Herraz, Marco; Silla-Castro, Juan Carlos; Camafeita, Emilio; Ortega-Muñoz, Mariano; Bonzon-Kulichenko, Elena; Calvo, Isabel; Cenarro, Ana; Civeira, Fernando; Vázquez, Jesús

    2014-06-25

    Recent findings support potential roles for HDL in cardiovascular pathophysiology not related to lipid metabolism. We address whether HDL proteome is dynamically altered in atheroma plaque rupture. We used immunoaffinity purification of HDL samples from coronary artery disease patients before and after percutaneous transluminal coronary angioplasty (PTCA), a model of atheroma plaque disruption. Samples were analyzed by quantitative proteomics using stable isotope labeling and results were subjected to statistical analysis of protein variance using a novel algorithm. We observed high protein variability in HDL composition between individuals, indicating that HDL protein composition is highly patient-specific. However, intra-individual protein variances remained at low levels, confirming the reproducibility of the method used for HDL isolation and protein quantification. A systems biology analysis of HDL protein alterations induced by PTCA revealed an increase in two protein clusters that included several apolipoproteins, fibrinogen-like protein 1 and other intracellular proteins, and a decrease in antithrombin-III, annexin A1 and several immunoglobulins. Our results support the concept of HDL as dynamic platforms that donate and receive a variety of molecules and provide an improved methodology to use HDL proteome for the systematic analysis of differences among individuals and the search for cardiovascular biomarkers. Biological significance The HDL proteome is an interesting model of clinical relevance and has been previously described to be dynamically altered in response to pathophysiological conditions and cardiovascular diseases. Our study suggests that interindividual variability of HDL proteome is higher than previously thought and provided the detection of a set of proteins that changed their abundance in response to plaque rupture, supporting the concept of HDL as dynamic platforms that donate and receive a variety of molecules. PMID:24747125

  8. A complete backbone spectral assignment of human apolipoprotein AI on a 38 kDa preβHDL (Lp1-AI) particle

    SciTech Connect

    Ren, Xuefeng; Yang, Yunhuang; Neville, T.; Hoyt, David W.; Sparks, Daniel L.; Wang, Jianjun

    2007-06-12

    Apolipoprotein A-I (apoAI, 243-residues) is the major protein component of the high-density lipoprotein (HDL) that has been a hot subject of interests because of its anti-atherogenic properties. This important property of apoAI is related to its roles in reverse cholesterol transport pathway. Upon lipid-binding, apoAI undergoes conformational changes from lipid-free to several different HDL-associated states (1). These different conformational states regulate HDL formation, maturation and transportation. Two initial conformational states of apoAI are lipid-free apoAI and apoAI/preβHDL that recruit phospholipids and cholesterol to form HDL particles. In particular, lipid-free apoAI specifically binds to phospholipids to form lipid-poor apoAI, including apoAI/preβ-HDL (~37 kDa). As a unique class of lipid poor HDL, both in vitro and in vivo evidence demonstrates that apoAI/preβ-HDLs are the most effective acceptors specifically for free cholesterol in human plasma and serves as the precursor of HDL particles (2). Here we report a complete backbone spectral assignment of human apoAI/preβHDL. Secondary structure prediction using backbone NMR parameters indicates that apoAI/preβHDL displays a two-domain structure: the N-terminal four helix-bundle domain (residues 1-186) and the C-terminal flexible domain (residues 187-243). A structure of apoAI/preβ-HDL is the first lipid-associated structure of apoAI and is critical for us to understand how apoAI recruits cholesterol to initialize HDL formation. BMRB deposit with accession number: 15093.

  9. Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol.

    PubMed

    Khetarpal, Sumeet A; Edmondson, Andrew C; Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O; Demissie, Serkalem; Manning, Alisa K; DerOhannessian, Stephanie L; Wolfe, Megan L; Cupples, L Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J

    2011-12-01

    Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. PMID:22174694

  10. Mining the LIPG Allelic Spectrum Reveals the Contribution of Rare and Common Regulatory Variants to HDL Cholesterol

    PubMed Central

    Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O.; Demissie, Serkalem; Manning, Alisa K.; DerOhannessian, Stephanie L.; Wolfe, Megan L.; Cupples, L. Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J.

    2011-01-01

    Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5′ UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5′ UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. PMID:22174694

  11. Anti-ATP synthase autoantibodies from patients with Alzheimer's disease reduce extracellular HDL level.

    PubMed

    Vacirca, Davide; Barbati, Cristiana; Scazzocchio, Beatrice; Masella, Roberta; Rosano, Giuseppe; Malorni, Walter; Ortona, Elena

    2011-01-01

    Aside from being an integral protein involved in the synthesis and hydrolysis of ATP, Ecto-F1-ATPase plays a role in cholesterol homeostasis. We demonstrated the presence of autoantibodies to ecto-F1-ATPase (ASabs) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD). Herein we show that ASabs, unlike irrelevant antibodies, can increase cellular uptake of HDL, a risk factor for the development of AD, via a mechanism involving the prototypical function of ecto-F1-ATPase: the generation of ADP due to the hydrolysis of ATP. Piceatannol, a specific inhibitor ecto-F1-ATPase, completely hindered these effects. We hypothesize that ASabs could exert a pathogenetic role in AD. PMID:21677380

  12. Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.

    PubMed Central

    Cohen, J C; Wang, Z; Grundy, S M; Stoesz, M R; Guerra, R

    1994-01-01

    Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels, but the specific genetic determinants of HDL cholesterol (HDL-C) levels have not been elucidated. In this study, the effects of variation in the genomic regions encoding hepatic lipase, apolipoprotein AI/CIII/AIV, and the cholesteryl ester transfer protein on plasma HDL-C levels were examined in 73 normotriglyceridemic, Caucasian nuclear families. Genetic factors accounted for 56.5 +/- 13% of the interindividual variation in plasma HDL-C levels. For each candidate gene, adjusted plasma HDL-C levels of sibling pairs who shared zero, one, or two parental alleles identical-by-descent were compared using sibling-pair linkage analysis. Allelic variation in the genes encoding hepatic lipase and apolipoprotein AI/CIII/AIV accounted for 25 and 22%, respectively, of the total interindividual variation in plasma HDL-C levels. In contrast, none of the variation in plasma HDL-C levels could be accounted for by allelic variation in the cholesteryl ester transfer protein. These findings indicate that a major fraction of the genetically determined variation in plasma HDL-C levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci. PMID:7989594

  13. Quantitative analysis of intact apolipoproteins in human HDL by top-down differential mass spectrometry

    PubMed Central

    Mazur, Matthew T.; Cardasis, Helene L.; Spellman, Daniel S.; Liaw, Andy; Yates, Nathan A.; Hendrickson, Ronald C.

    2010-01-01

    Top-down mass spectrometry holds tremendous potential for the characterization and quantification of intact proteins, including individual protein isoforms and specific posttranslationally modified forms. This technique does not require antibody reagents and thus offers a rapid path for assay development with increased specificity based on the amino acid sequence. Top-down MS is efficient whereby intact protein mass measurement, purification by mass separation, dissociation, and measurement of product ions with ppm mass accuracy occurs on the seconds to minutes time scale. Moreover, as the analysis is based on the accurate measurement of an intact protein, top-down mass spectrometry opens a research paradigm to perform quantitative analysis of “unknown” proteins that differ in accurate mass. As a proof of concept, we have applied differential mass spectrometry (dMS) to the top-down analysis of apolipoproteins isolated from human HDL3. The protein species at 9415.45 Da demonstrates an average fold change of 4.7 (p-value 0.017) and was identified as an O-glycosylated form of apolipoprotein C-III [NANA-(2 → 3)-Gal-β(1 → 3)-GalNAc, +656.2037 Da], a protein associated with coronary artery disease. This work demonstrates the utility of top-down dMS for quantitative analysis of intact protein mixtures and holds potential for facilitating a better understanding of HDL biology and complex biological systems at the protein level. PMID:20388904

  14. Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein.

    PubMed

    Ochoa, Maria C; Fioravanti, Jessica; Rodriguez, Inmaculada; Hervas-Stubbs, Sandra; Azpilikueta, Arantza; Mazzolini, Guillermo; Gúrpide, Alfonso; Prieto, Jesus; Pardo, Julian; Berraondo, Pedro; Melero, Ignacio

    2013-01-01

    Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα(-/-) mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease. PMID:23149919

  15. β-COP as a Component of Transport Vesicles for HDL Apolipoprotein-Mediated Cholesterol Exocytosis

    PubMed Central

    Ma, Weilie; Lin, Margarita; Ding, Hang; Lin, Guorong; Zhang, Zhizhen

    2016-01-01

    Objective HDL and its apolipoproteins protect against atherosclerotic disease partly by removing excess cholesterol from macrophage foam cells. But the underlying mechanisms of cholesterol clearance are still not well defined. We investigated roles of vesicle trafficking of coatomer β-COP in delivering cholesterol to the cell surface during apoA-1 and apoE-mediated lipid efflux from fibroblasts and THP-1 macrophages. Methods shRNA knockout, confocal and electron microscopy and biochemical analysis were used to investigate the roles of β-COP in apolipoprotein-mediated cholesterol efflux in fibroblasts and THP-1 macrophages. Results We showed that β-COP knockdown by lentiviral shRNA resulted in reduced apoA-1-mediated cholesterol efflux, while increased cholesterol accumulation and formation of larger vesicles were observed in THP-1 macrophages by laser scanning confocal microscopy. Immunogold electron microscopy showed that β-COP appeared on the membrane protrusion complexes and colocalized with apoA-1 or apoE during cholesterol efflux. This was associated with releasing heterogeneous sizes of small particles into the culture media of THP-1 macrophage. Western blotting also showed that apoA-1 promotes β-COP translocation to the cell membrane and secretion into culture media, in which a total of 17 proteins were identified by proteomics. Moreover, β-COP exclusively associated with human plasma HDL fractions. Conclusion ApoA-1 and apoE promoted transport vesicles consisting of β-COP and other candidate proteins to exocytose cholesterol, forming the protrusion complexes on cell surface, which were then released from the cell membrane as small particles to media. PMID:26986486

  16. 9-cis β-Carotene Increased Cholesterol Efflux to HDL in Macrophages.

    PubMed

    Bechor, Sapir; Zolberg Relevy, Noa; Harari, Ayelet; Almog, Tal; Kamari, Yehuda; Ben-Amotz, Ami; Harats, Dror; Shaish, Aviv

    2016-01-01

    Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-βc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages. PMID:27447665

  17. 9-cis β-Carotene Increased Cholesterol Efflux to HDL in Macrophages

    PubMed Central

    Bechor, Sapir; Zolberg Relevy, Noa; Harari, Ayelet; Almog, Tal; Kamari, Yehuda; Ben-Amotz, Ami; Harats, Dror; Shaish, Aviv

    2016-01-01

    Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-βc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages. PMID:27447665

  18. 75 FR 55323 - Alta Wind Holdings, LLC; Notice of Petition for Declaratory Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-10

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind Holdings, LLC; Notice of Petition for Declaratory Order September 2, 2010. Take notice that on August 31, 2010, Alta Wind Holdings, LLC filed a Petition...

  19. 75 FR 76455 - Alta Wind I, LLC; Notice of Petition for Declaratory Order

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-08

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind I, LLC; Notice of Petition for Declaratory Order December 1, 2010. Take notice that on November 19, 2010, Alta Wind I, LLC filed a Petition for Declaratory...

  20. ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT[S

    PubMed Central

    Duka, Adelina; Fotakis, Panagiotis; Georgiadou, Dimitra; Kateifides, Andreas; Tzavlaki, Kalliopi; von Eckardstein, Leonard; Stratikos, Efstratios; Kardassis, Dimitris; Zannis, Vassilis I.

    2013-01-01

    The objective of this study was to establish the role of apoA-IV, ABCA1, and LCAT in the biogenesis of apoA-IV-containing HDL (HDL-A-IV) using different mouse models. Adenovirus-mediated gene transfer of apoA-IV in apoA-I−/− mice did not change plasma lipid levels. ApoA-IV floated in the HDL2/HDL3 region, promoted the formation of spherical HDL particles as determined by electron microscopy, and generated mostly α- and a few pre-β-like HDL subpopulations. Gene transfer of apoA-IV in apoA-I−/− × apoE−/− mice increased plasma cholesterol and triglyceride levels, and 80% of the protein was distributed in the VLDL/IDL/LDL region. This treatment likewise generated α- and pre-β-like HDL subpopulations. Spherical and α-migrating HDL particles were not detectable following gene transfer of apoA-IV in ABCA1−/− or LCAT−/− mice. Coexpression of apoA-IV and LCAT in apoA-I−/− mice restored the formation of HDL-A-IV. Lipid-free apoA-IV and reconstituted HDL-A-IV promoted ABCA1 and scavenger receptor BI (SR-BI)-mediated cholesterol efflux, respectively, as efficiently as apoA-I and apoE. Our findings are consistent with a novel function of apoA-IV in the biogenesis of discrete HDL-A-IV particles with the participation of ABCA1 and LCAT, and may explain previously reported anti-inflammatory and atheroprotective properties of apoA-IV. PMID:23132909

  1. A Single In-Vial Dual Extraction Strategy for the Simultaneous Lipidomics and Proteomics Analysis of HDL and LDL Fractions.

    PubMed

    Godzien, Joanna; Ciborowski, Michal; Armitage, Emily Grace; Jorge, Inmaculada; Camafeita, Emilio; Burillo, Elena; Martín-Ventura, Jose Luis; Rupérez, Francisco J; Vázquez, Jesús; Barbas, Coral

    2016-06-01

    A single in-vial dual extraction (IVDE) procedure for the subsequent analysis of lipids and proteins in the high-density lipoprotein (HDL) and low-density lipoprotein (LDL) fractions derived from the same biological sample is presented. On the basis of methyl-tert-butyl ether (MTBE) extraction, IVDE leads to the formation of three phases: a protein pellet at the bottom, an aqueous phase with polar compounds, and an ether phase with lipophilic compounds. After sample extraction, performed within a high-performance liquid chromatography vial insert, the ether phase was directly injected for lipid fingerprinting, while the protein pellet, after evaporation of the remaining sample, was used for proteomics analysis. Human HDL and LDL isolates were used to test the suitability of the IVDE methodology for lipid and protein analysis from a single sample in terms of data quality and matching composition to that of HDL and LDL. Subsequently, HDL and LDL fractions isolated from ApoE-KO and wild-type mice were used to validate the capacity of IVDE for revealing changes in lipid and protein abundance. Results indicate that IVDE can be successfully used for the subsequent analysis of lipids and proteins with the advantages of time saving, simplicity, and reduced sample amount. PMID:27117984

  2. Lipoprotein lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified gro...

  3. Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice.

    PubMed

    Kareinen, Ilona; Cedó, Lídia; Silvennoinen, Reija; Laurila, Pirkka-Pekka; Jauhiainen, Matti; Julve, Josep; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-02-01

    Reverse cholesterol transport (RCT) pathway from macrophage foam cells initiates when HDL particles cross the endothelium, enter the interstitial fluid, and induce cholesterol efflux from these cells. We injected [(3)H]cholesterol-loaded J774 macrophages into the dorsal skin of mice and measured the transfer of macrophage-derived [(3)H]cholesterol to feces [macrophage-RCT (m-RCT)]. Injection of histamine to the macrophage injection site increased locally vascular permeability, enhanced influx of intravenously administered HDL, and stimulated m-RCT from the histamine-treated site. The stimulatory effect of histamine on m-RCT was abolished by prior administration of histamine H1 receptor (H1R) antagonist pyrilamine, indicating that the histamine effect was H1R-dependent. Subcutaneous administration of two other vasoactive mediators, serotonin or bradykinin, and activation of skin mast cells to secrete histamine and other vasoactive compounds also stimulated m-RCT. None of the studied vasoactive mediators affected serum HDL levels or the cholesterol-releasing ability of J774 macrophages in culture, indicating that acceleration of m-RCT was solely due to increased availability of cholesterol acceptors in skin. We conclude that disruption of the endothelial barrier by vasoactive compounds enhances the passage of HDL into interstitial fluid and increases the rate of RCT from peripheral macrophage foam cells, which reveals a novel tissue cholesterol-regulating function of these compounds. PMID:25473102

  4. Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Tsai, Michael Y.; Johnson, Craig; Kao, W.H. Linda; Sharrett, A. Richey; Arends, Valerie L.; Kronmal, Richard; Jenny, Nancy Swords; Jacobs, David R.; Arnett, Donna; O’Leary, Daniel; Post, Wendy

    2013-01-01

    The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD. PMID:18243217

  5. A Common CNR1 (Cannabinoid Receptor 1) Haplotype Attenuates the Decrease in HDL Cholesterol That Typically Accompanies Weight Gain

    PubMed Central

    Feng, Qiping; Jiang, Lan; Berg, Richard L.; Antonik, Melissa; MacKinney, Erin; Gunnell-Santoro, Jennifer; McCarty, Catherine A.; Wilke, Russell A.

    2010-01-01

    We have previously shown that genetic variability in CNR1 is associated with low HDL dyslipidemia in a multigenerational obesity study cohort of Northern European descent (209 families, median  = 10 individuals per pedigree). In order to assess the impact of CNR1 variability on the development of dyslipidemia in the community, we genotyped this locus in all subjects with class III obesity (body mass index >40 kg/m2) participating in a population-based biobank of similar ancestry. Twenty-two haplotype tagging SNPs, capturing the entire CNR1 gene locus plus 15 kb upstream and 5 kb downstream, were genotyped and tested for association with clinical lipid data. This biobank contains data from 645 morbidly obese study subjects. In these subjects, a common CNR1 haplotype (H3, frequency 21.1%) is associated with fasting TG and HDL cholesterol levels (p = 0.031 for logTG; p = 0.038 for HDL-C; p = 0.00376 for log[TG/HDL-C]). The strength of this relationship increases when the data are adjusted for age, gender, body mass index, diet and physical activity. Mean TG levels were 160±70, 155±70, and 120±60 mg/dL for subjects with 0, 1, and 2 copies of the H3 haplotype. Mean HDL-C levels were 45±10, 47±10, and 48±9 mg/dL, respectively. The H3 CNR1 haplotype appears to exert a protective effect against development of obesity-related dyslipidemia. PMID:21209828

  6. LXR driven induction of HDL-cholesterol is independent of intestinal cholesterol absorption and ABCA1 protein expression.

    PubMed

    Kannisto, Kristina; Gåfvels, Mats; Jiang, Zhao-Yan; Slätis, Katharina; Hu, Xiaoli; Jorns, Carl; Steffensen, Knut R; Eggertsen, Gösta

    2014-01-01

    We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol. PMID:24163219

  7. Isolation and partial characterization of high-density lipoprotein HDL1 from rat plasma by gradient centrifugation.

    PubMed Central

    Lusk, L T; Walker, L F; DuBien, L H; Getz, G S

    1979-01-01

    The lipoproteins isolated from rat plasma by flotation in the density range 1.019-1.063 g/ml were further characterized. Using rate zonal ultracentrifugation, we isolated two lipoproteins in almost equal proportions from this density range. Similar isolations may be accomplished with density gradients in a swinging-bucket rotor. On isopycnic-density-gradient ultracentrifugation one component banded at rho = 1.031 g/ml and the other at rho = 1.054 g/ml. More that 98% of the apoprotein of the lighter component was B protein, and hence this particle is LD (low-density) lipoprotein. Of the apoproteins of the rho = 1.054 g/ml particles, designated lipoprotein HDL1, over 60% was arginine-rich peptide, and the remainder was A-I, A-IV and C peptides. The molecular weight of these lipoproteins determined by agarose column chromatography was 2.36 x 10(6) for LD lipoprotein and 1.30 x 10(6) for lipoprotein HDL1. On electron microscopy the radius of LD lipoprotein was 14.0 nm and that of lipoprotein HDL1 was 10.0 nm, in contrast with molecular radii of 10.4 nm and 8.4 nm respectively determined from the gel-permeation-chromatography data. The lipid and phospholipid composition of both particles was determined. Lipoprotein HDL1 was notable for both the concentration of its esterified cholesterol, which was similar to that of LD lipoprotein, and the low triacylglycerol content, resembling that of HD lipoprotein. The possible origin of lipoprotein HDL1 is discussed. Images Fig. 1. PMID:230819

  8. Impairment of the ABCA1 and SR-BI-mediated cholesterol efflux pathways and HDL anti-inflammatory activity in Alzheimer's disease.

    PubMed

    Khalil, Abdelouahed; Berrougui, Hicham; Pawelec, Graham; Fulop, Tamas

    2012-01-01

    The aim of our study was to investigate the effect of Alzheimer's disease (AD) on the cholesterol efflux capacity and anti-inflammatory activity of HDL. HDL and apoA-I were isolated from 20 healthy subjects and from 39 AD patients. Our results showed that serum- and HDL-mediated cholesterol efflux is significantly impaired in AD patients. This impairment of serum and HDL cholesterol efflux capacity was significantly inversely correlated to the AD severity as evaluated by MMSE scores. Results obtained from SR-BI-enriched Fu5AH and ABCA1-enriched J774 cells revealed that AD impaired the interaction of HDL and apoA-I with both the ABCA1 transporter and SR-BI receptor. Purified apoA-I from AD patients also failed to remove free excess cholesterol from ABCA1-enriched J774 macrophages. Interestingly, the decrease in plasma α-tocopherol content and the increase in MDA formation and HDL relative electrophoretic mobility indicated that AD patients had higher levels of oxidative stress. The anti-inflammatory activity of HDL was also significantly lower in AD patients as measured by the level of ICAM-1 expression. In conclusion, our study provides evidence for the first time that the functionality of HDL is impaired in AD and that this alteration might be caused by AD-associated oxidative stress and inflammation. PMID:22178419

  9. The effects of ABCG5/G8 polymorphisms on HDL-cholesterol concentrations depend on ABCA1 genetic variants in the Boston Puerto Rican health study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background and aims: ATP-binding cassette transporters G5/G8 (ABCG5/G8) are associated with HDL-C concentrations. To assess whether the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ATP-binding cassette transporters A1 (ABCA1), we studied potential interactions between ...

  10. The effect of ABCG5/G8 polymorphisms on plasma HDL cholesterol levels depends on the ABCA1 gene variation in the Boston Puerto Rican Health Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: ATP-binding cassette transporters G5/G8 have shown an association with HDL-C. One of the most likely mechanisms to explain those associations is through ABCA1. Objective: To assess whether the effect of ABCG5/G8 polymorphisms on HDL-C is dependent on ABCA1, we studied potential interacti...

  11. Cholesterol stimulation of HDL binding to human endothelial cells EAhy 926 and skin fibroblasts: evidence for a mechanism independent of cellular metabolism.

    PubMed

    Bernini, F; Bellosta, S; Corsini, A; Maggi, F M; Fumagalli, R; Catapano, A L

    1991-04-24

    The properties of the HDL binding site on the permanent human cell line EAhy 926 were studied. This cell line presents with highly differentiated functions of vascular endothelium. EAhy 926 cells possess HDL3 saturable binding sites with a Kd of about 20 micrograms/ml, which were up-regulated by cholesterol and were pronase- and EDTA-insensitive. Furthermore, HDL3 promoted cholesterol efflux from EAhy 926 cells in a dose-dependent manner. Thus, the HDL-binding site in EAhy 926 cells is similar to that present in fibroblasts, smooth muscle cells and endothelial cells. Up-regulation of HDL binding by cholesterol did not require de novo synthesis of HDL 'receptor' protein, as shown by the lack of effect of cycloheximide and alpha-amanitin and also occurred in fixed, non-living cells. Similar results were obtained using human skin fibroblasts. From these data we conclude that: (a) EAhy 926 cells are a good model for studying the HDL interaction with endothelial cells; (b) a mechanism independent of cellular metabolism is involved in the cholesterol-mediated up-regulation of HDL binding sites in EAhy 926 cells and human skin fibroblasts. PMID:1851638

  12. Three-dimensional models of HDL apoA-I: implications for its assembly and function*

    PubMed Central

    Thomas, Michael J.; Bhat, Shaila; Sorci-Thomas, Mary G.

    2008-01-01

    The purpose of this review is to highlight recent advances toward the refinement of a three-dimensional structure for lipid-bound apolipoprotein A-I (apoA-I) on recombinant HDL. Recently, X-ray crystallography has yielded a new structure for full-length, lipid-free apoA-I. Although this approach has not yet been successful in solving the three-dimensional structure of lipid-bound apoA-I, analysis of the X-ray structures has been of immense help in the interpretation of structural data obtained from other methods that yield structural information. Recent studies emphasize the use of mass spectrometry to unambiguously identify cross-linked peptides or to quantify solvent accessibility using hydrogen-deuterium exchange. The combination of mass spectrometry, molecular modeling, molecular dynamic analysis, and small-angle X-ray diffraction has provided additional structural information on apoA-I folding that complements previous approaches. PMID:18515783

  13. Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans.

    PubMed

    Singaraja, Roshni R; Tietjen, Ian; Hovingh, G Kees; Franchini, Patrick L; Radomski, Chris; Wong, Kenny; vanHeek, Margaret; Stylianou, Ioannis M; Lin, Linus; Wang, Liangsu; Mitnaul, Lyndon; Hubbard, Brian; Winther, Michael; Mattice, Maryanne; Legendre, Annick; Sherrington, Robin; Kastelein, John J; Akinsanya, Karen; Plump, Andrew; Hayden, Michael R

    2014-08-01

    While genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low (≤10th percentile) or high (≥90th percentile) HDLc. Probands were excluded if known mutations existed in the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Family-based association analyses were performed for variants with sufficient power to detect significance at P < 0.05 with a total of 627 family members being assessed. Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. Taken together, we have identified mutations in four novel genes that may play a role in regulating HDLc levels in humans. PMID:24891332

  14. HDL and LDL as therapeutic targets for cardiovascular disease prevention: the possible role of niacin.

    PubMed

    Olsson, A G

    2010-10-01

    Recently two studies on the effect of addition of extended-release niacin to statin treatment on measures of carotid atherosclerosis were estimated in the ARBITER 6-HALTS study (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) study and the Oxford Niacin Study were published. Adding niacin to statin treatment significantly diminished carotid atherosclerosis as measured by ultrasound carotid intima-media thickness or magnetic resonance imaging. An inhibitor of niacin induced flushing, laropiprant has been developed and demonstrated to considerably improve the tolerability of niacin therapy without impeding on its effect on lipoproteins. Still however clear evidence for the clinical benefit of long-term niacin treatment on cardiovascular morbidity and mortality is lacking. The development situation for ezetimibe is similar to that of niacin. Long-term interventional studies with hard endpoints of both therapies are ongoing. Also both drugs, when proven efficient and safe, are eagerly needed in the prevention of cardiovascular disease. PMID:20739153

  15. The effect of quitting smoking on HDL-cholesterol - a review based on within-subject changes

    PubMed Central

    2013-01-01

    A higher concentration of high density lipoprotein cholesterol (HDL-C) in ex-smokers than smokers has consistently been observed. Better evidence of quitting effects comes from within-subject changes. We extend an earlier meta-analysis to quantify the reduction, and investigate variation by time quit and other factors. We conducted Medline and Cochrane searches for studies measuring HDL-C in subjects while still smoking and later having quit. Using unweighted and inverse-variance weighted regression analysis, we related changes (in mmol/l) to intra-measurement period, and estimated time quit, and to study type, location and start year, age, sex, product smoked, validation of quitting, baseline HDL-C, baseline and change in weight/BMI, and any study constraints on diet or exercise. Forty-five studies were identified (17 Europe, 16 North America, 11 Asia, 1 Australia). Thirteen were observational, giving changes over at least 12 months, with most involving >1000 subjects. Others were smoking cessation trials, 12 randomized and 20 non-randomized. These were often small (18 of <100 subjects) and short (14 of <10 weeks, the longest a year). Thirty studies provided results for only one time interval. From 94 estimates of HDL-C change, the unweighted mean was 0.107 (95% CI 0.085-0.128). The weighted mean 0.060 (0.044 to 0.075) was lower, due to smaller estimates in longer term studies. Weighted means varied by time quit (0.083, 0.112, 0.111, 0.072, 0.058 and 0.040 for <3, 3 to <6, 6 to <13, 13 to <27, 27 to <52 and 52+ weeks, p=0.006). After adjustment for time quit, estimates varied by study constraint on diet/exercise (p=0.003), being higher in studies requiring subjects to maintain their pre-quitting habits, but no other clear differences were seen, with significant (p<0.05) increases following quitting being evident in all subgroups studied, except where data were very limited. For both continuing and never smokers, the data are (except for two large studies

  16. Modelo semi-empírico de protuberancia solar a partir del diagnóstico de densidades

    NASA Astrophysics Data System (ADS)

    Cirigliano, D.; Vial, J. C.; Rovira, M.

    A partir de la observación del espectro del quintuplete de C III alrededor de 1175 Å, se ha realizado el diagnóstico de la densidad y presión electrónica, basado en el cálculo del cociente de las intensidades observadas. Una vez establecida la densidad electrónica, y con el cálculo de las velocidades Doppler, hemos investigado el flujo de masa en la protuberancia en función de la temperatura. Estableciendo como hipótesis la conservación del número de partículas que ingresan y salen del cuerpo de la protuberancia, se investiga la variación del área de un tubo de flujo semi-empírico en función de la temperatura. A partir de dicho diagnóstico, se examina el comportamiento del radio del tubo magnético en función de la temperatura, los que dan cuenta de la abertura de las líneas de campo magnético que confinan el plasma y de la divergencia del campo magnético en diferentes alturas de la atmósfera solar.

  17. HDL functionality in reverse cholesterol transport--Challenges in translating data emerging from mouse models to human disease.

    PubMed

    Lee-Rueckert, Miriam; Escola-Gil, Joan Carles; Kovanen, Petri T

    2016-07-01

    Whereas LDL-derived cholesterol accumulates in atherosclerotic lesions, HDL particles are thought to facilitate removal of cholesterol from the lesions back to the liver thereby promoting its fecal excretion from the body. Because generation of cholesterol-loaded macrophages is inherent to atherogenesis, studies on the mechanisms stimulating the release of cholesterol from these cells and its ultimate excretion into feces are crucial to learn how to prevent lesion development or even induce lesion regression. Modulation of this key anti-atherogenic pathway, known as the macrophage-specific reverse cholesterol transport, has been extensively studied in several mouse models with the ultimate aim of applying the emerging knowledge to humans. The present review provides a detailed comparison and critical analysis of the various steps of reverse cholesterol transport in mouse and man. We attempt to translate this in vivo complex scenario into practical concepts, which could serve as valuable tools when developing novel HDL-targeted therapies. PMID:26968096

  18. Dynamic changes in mouse lipoproteins induced by transiently expressed human phospholipid transfer protein (PLTP): importance of PLTP in prebeta-HDL generation.

    PubMed

    Jaari, S; van Dijk, K W; Olkkonen, V M; van der Zee, A; Metso, J; Havekes, L; Jauhiainen, M; Ehnholm, C

    2001-04-01

    The plasma phospholipid transfer protein (PLTP) plays an important role in the regulation of plasma high density lipoprotein (HDL) levels and governs the distribution of HDL sub-populations. In the present study, adenovirus mediated overexpression of human PLTP in mice was employed to investigate the distribution of PLTP in serum and its effect on plasma lipoproteins. Gel filtration experiments showed that the distributions of PLTP activity and mass in serum are different, suggesting that human PLTP circulated in mouse plasma as two distinct forms, one with high and the other with low specific activity. Our study further demonstrates that overexpression of PLTP leads to depletion of HDL and that, as PLTP activity declines, replenishment of the HDL fraction occurs. During this process, the lipoprotein profile displays transient particle populations, including apoA-IV and apoE-rich particles in the LDL size range and small particles containing apoA-II only. The possible role of these particles in HDL reassembly is discussed. The increased PLTP activity enhanced the ability of mouse sera to produce pre(beta)-HDL. The present results provide novel evidence that PLTP is an important regulator of HDL metabolism and plays a central role in the reverse cholesterol transport (RCT) process. PMID:11290460

  19. Thermal transitions in serum amyloid A in solution and on the lipid: implications for structure and stability of acute-phase HDL.

    PubMed

    Jayaraman, Shobini; Haupt, Christian; Gursky, Olga

    2015-08-01

    Serum amyloid A (SAA) is an acute-phase protein that circulates mainly on plasma HDL. SAA interactions with its functional ligands and its pathogenic deposition in reactive amyloidosis depend, in part, on the structural disorder of this protein and its propensity to oligomerize. In vivo, SAA can displace a substantial fraction of the major HDL protein, apoA-I, and thereby influence the structural remodeling and functions of acute-phase HDL in ways that are incompletely understood. We use murine SAA1.1 to report the first structural stability study of human plasma HDL that has been enriched with SAA. Calorimetric and spectroscopic analyses of these and other SAA-lipid systems reveal two surprising findings. First, progressive displacement of the exchangeable fraction of apoA-I by SAA has little effect on the structural stability of HDL and its fusion and release of core lipids. Consequently, the major determinant for HDL stability is the nonexchangeable apoA-I. A structural model explaining this observation is proposed, which is consistent with functional studies in acute-phase HDL. Second, we report an α-helix folding/unfolding transition in SAA in the presence of lipid at near-physiological temperatures. This new transition may have potentially important implications for normal functions of SAA and its pathogenic misfolding. PMID:26022803

  20. HDL Induces the Expression of the M2 Macrophage Markers Arginase 1 and Fizz-1 in a STAT6-Dependent Process

    PubMed Central

    Fisher, Edward A.

    2013-01-01

    Our lab has previously shown in a mouse model that normalization of a low HDL level achieves atherosclerotic plaque regression. This included the shift from a pro (“M1”) to an anti-inflammatory (“M2”) phenotypic state of plaque macrophages. Whether HDL can directly cause this phenotypic change and, if so, what the signaling mechanism is, were explored in the present studies. Murine primary macrophages treated with HDL showed increased gene expression for the M2 markers Arginase-1 (Arg-1) and Fizz-1, which are classically induced by IL-4. HDL was able to potentiate the IL-4-induced changes in Arg-1, and tended to do the same for Fizz-1, while suppressing the expression of inflammatory genes in response to IFNγ. The effects of either IL-4 or HDL were suppressed when macrophages were from STAT6-/- mice, but inhibitor studies suggested differential utilization of JAK isoforms by IL-4 and HDL to activate STAT6 by phosphorylation. Overall, our results describe a new function of HDL, namely its ability to directly enrich macrophages in markers of the M2, anti-inflammatory, state in a process requiring STAT6. PMID:23991225

  1. Low incidence of paradoxical reductions in HDL-C levels in dyslipidemic patients treated with fenofibrate alone or in combination with ezetimibe or ezetimibe/simvastatin

    PubMed Central

    2011-01-01

    Background Fibrates have been reported to cause paradoxical decreases in HDL-C in certain patients. Design and methods This post-hoc analysis explored the frequency/magnitude of HDL-C reductions in a pooled database of mixed dyslipidemic patients (LDL-C:3.4-5.7 mmol/L;TG:1.7-5.7 mmol/L) receiving placebo (PBO), fenofibrate (FENO), ezetimibe plus FENO (EZE+FENO), or EZE/simvastatin plus FENO (EZE/SIMVA+FENO) for 12 weeks. Results PBO-treated patients had the highest incidence of HDL-C reductions from baseline (45%) compared with patients taking FENO (14%), EZE+FENO (9%), or EZE/SIMVA+FENO (9%). Reductions <30% reflected natural variability since the largest reduction in HDL-C approached 30% in the PBO group. Only 3 patients exhibited HDL-C reductions ≥30% (i.e., 2 patients in the FENO group and 1 in the EZE+FENO group). There were no differences in demographic/biochemical characteristics between patients with and without HDL-C reductions. Conclusions The incidence of paradoxical HDL-C reductions was low in mixed dyslipidemic patients receiving FENO alone or combined with EZE or EZE/SIMVA. Trial registrations Clinicaltrials.gov: NCT00092560 and NCT00092573 PMID:22087637

  2. Identification of the Molecular Target of Small Molecule Inhibitors of HDL Receptor SR-BI Activity†,‡,§

    PubMed Central

    Nieland, Thomas J. F.; Shaw, Jared T.; Jaipuri, Firoz A.; Duffner, Jay L.; Koehler, Angela N.; Banakos, Sotirios; Zannis, Vassilis I.; Kirchhausen, Tomas; Krieger, Monty

    2009-01-01

    Scavenger receptor, class B, type I (SR-BI), controls high-density lipoprotein (HDL) metabolism by mediating cellular selective uptake of lipids from HDL without the concomitant degradation of the lipoprotein particle. We previously identified in a high-throughput chemical screen of intact cells five compounds (BLT-1–5) that inhibit SR-BI-dependent lipid transport from HDL, but do not block HDL binding to SR-BI on the cell surface. Although these BLTs are widely used to examine the diverse functions of SR-BI, their direct target(s), SR-BI itself or some other component of the SR-BI pathway, has not been identified. Here we show that SR-BI in the context of a membrane lipid environment is the target of BLT-1, -3, -4, and -5. The analysis using intact cells and an in vitro system of purified SR-BI reconstituted into liposomes was aided by information derived from structure–activity relationship (SAR) analysis of the most potent of these BLTs, the thiosemicarbazone BLT-1. We found that the sulfur atom of BLT-1 was crucially important for its inhibitory activity, because changing it to an oxygen atom resulted in the isostructural, but essentially inactive, semicarbazone derivative BLT-1sc. SAR analysis also established the importance of BLT-1’s hydrophobic tail. BLTs and their corresponding inactive compounds can be used to explore the mechanism and function of SR-BI-mediated selective lipid uptake in diverse mammalian experimental models. Consequently, BLTs may help determine the therapeutic potential of SR-BI-targeted pharmaceutical drugs. PMID:18067275

  3. Discovery of XEN445: a potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice.

    PubMed

    Sun, Shaoyi; Dean, Richard; Jia, Qi; Zenova, Alla; Zhong, Jing; Grayson, Celene; Xie, Clark; Lindgren, Andrea; Samra, Pritpaul; Sojo, Luis; van Heek, Margaret; Lin, Linus; Percival, David; Fu, Jian-Min; Winther, Michael D; Zhang, Zaihui

    2013-12-15

    Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice. PMID:24211162

  4. Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth review

    PubMed Central

    Boes, Eva; Coassin, Stefan; Kollerits, Barbara; Heid, Iris M.; Kronenberg, Florian

    2009-01-01

    High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals. HDLC levels are under considerable genetic control with heritability estimates of up to 80%. The identification and characterization of genetic variants associated with HDLC concentrations can provide new insights into the background of longevity. This review provides an extended overview on the current genetic-epidemiological evidence from association studies on genes involved in HDLC metabolism. It provides a path through the jungle of association studies which are sometimes confusing due to the varying and sometimes erroneous names of genetic variants, positions and directions of associations. Furthermore, it reviews the recent findings from genome-wide association studies which have identified new genes influencing HDLC levels. The yet identified genes together explain only a small amount of less than 10% of the HDLC variance, which leaves an enormous room for further yet to be identified genetic variants. This might be accomplished by large population-based genome-wide meta-analyses and by deep-sequencing approaches on the identified genes. The resulting findings will probably result in a re-drawing and extension of

  5. Apolipoprotein A-I inhibits chemotaxis, adhesion, activation of THP-1 cells and improves the plasma HDL inflammatory index.

    PubMed

    Wang, Li; Chen, Wei-Zhong; Wu, Man-Ping

    2010-02-01

    The anti-inflammatory effects of high density lipoprotein (HDL) are well described, however, such effects of Apolipoprotein A-I (ApoA-I) are less studied. Building on our previous study, we further explored the mechanism of anti-inflammatory effects of ApoA-I, and focused especially on the interaction between monocyte and endothelial cells and plasma HDL inflammatory index in LPS-challenged rabbits. Our results show that ApoA-I significantly decreased LPS-induced MCP-1 release from THP-1 cells and ox-LDL-induced THP-1 migration ratio (P<0.01, respectively). ApoA-I significantly decreased sL-selectin, sICAM-1 and sVCAM-1 release (P<0.01, P<0.01, P<0.05, respectively) from LPS-stimulated THP-1 cells. Furthermore, ApoA-I significantly inhibited LPS-induced CD11b and VCAM-1 expression on THP-1 cells (P<0.01, P<0.05, respectively). ApoA-I diminished LPS-induced mCD14 expression (P<0.01) and NFkappaB nuclear translocation in THP-1 cells. After single dose treatment of ApoA-I, the value of plasma HDL inflammatory index in LPS-challenged rabbits was improved significantly (P<0.05). These results suggest that ApoA-I can inhibit chemotaxis, adhesion and activation of human monocytes and improve plasma HDL inflammatory index with presenting beneficial anti-inflammatory effects. PMID:19819722

  6. Appropriate LDL-C-to-HDL-C Ratio Cutoffs for Categorization of Cardiovascular Disease Risk Factors among Uygur Adults in Xinjiang, China

    PubMed Central

    Chen, Qing-Jie; Lai, Hong-Mei; Chen, Bang-Dang; Li, Xiao-Mei; Zhai, Hui; He, Chun-Hui; Pan, Shuo; Luo, Jun-Yi; Gao, Jing; Liu, Fen; Ma, Yi-Tong; Yang, Yi-Ning

    2016-01-01

    Elevated LDL-C/HDL-C ratio has been shown to be a marker of lipid metabolism as well as a good predictor of coronary artery disease (CAD). Thus, the aim of this study was to investigate whether the LDL-C/HDL-C ratio is useful for detecting cardiovascular disease (CVD) risk factors in general healthy Uygur adults in Xinjiang. A total of 4047 Uygur subjects aged ≥35 years were selected from the Cardiovascular Risk Survey (CRS) study which was carried out from October 2007 to March 2010. Anthropometric data, blood pressure, lipid profile and fasting glucose were measured in all participants. The prevalence, sensitivity, specificity and distance on the receiver operating characteristic (ROC) curve of each LDL-C/HDL-C ratio were calculated. The prevalence of high LDL-C and low HDL-C cholesterol was high and positively correlated with higher LDL-C/HDL-C ratio in the Uygur population. In both men and women, we detected a slight apparent trend of high prevalence of hypertension and hypercholesterolemia with higher LDL-C/HDL-C ratio. Our study also demonstrated that the discriminatory power of the LDL-C/HDL-C ratio for CVD risk factors was slightly stronger in men than in women. Analysis of the shortest distance in the ROC curves for hypertension, dyslipidemia, diabetes, or ≥two of these risk factors suggested a LDL-C/HDL-C ratio cutoff of 2.5 for both men and women. The results of this study showed that a LDL-C/HDL-C ratio cut-off of 2.5 might be used as the predictive marker to detect CVD risk factors among Uygur adults in Xinjiang. PMID:26907312

  7. Longitudinal study of circulating oxidized LDL and HDL and fatty liver: the Cardiovascular Risk in Young Finns Study.

    PubMed

    Kaikkonen, Jari E; Kresanov, Petri; Ahotupa, Markku; Jula, Antti; Mikkilä, Vera; Viikari, Jorma S A; Juonala, Markus; Hutri-Kähönen, Nina; Kähönen, Mika; Lehtimäki, Terho; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Raitakari, Olli T

    2016-04-01

    Oxidative reactions are thought to play a role in the inflammatory condition called fatty liver. It is unclear whether oxidized lipoprotein lipids or proteins are associated with future fatty liver. In the Cardiovascular Risk in Young Finns Study, we determined the circulating levels of LDL and HDL oxidized lipids and studied their associations with fatty liver assessed by ultrasonography. There were 1286 middle-aged subjects with normal liver and 288 subjects with fatty liver. Analysis of oxidized lipids consisted of conjugated dienes in isolated HDL (oxHDLlipids) and LDL (oxLDLlipids). Oxidized LDL was also measured with a method based on antibodies against oxidized apolipoprotein B (oxLDLprot). After adjustment for age, sex, leisure-time physical activity, body mass index, alcohol intake, smoking, serum LDL and HDL cholesterol as well as particle concentrations, participants with elevated oxLDLlipids (odds ratio for 1-SD change in oxLDLlipids = 1.27, p = 0.011) had an increased risk for fatty liver. Similarly, a high oxidation score (oxLDLlipids + oxLDLprot) was directly associated with fatty liver (odds ratio=1.34, p = 0.012). The strongest direct association was seen with a high oxLDLlipids/oxHDLlipids ratio (odds ratio=1.49, p = 0.001). These data suggest that oxidized lipoprotein lipids are linked with the risk of fatty liver in middle-aged adults. PMID:26695550

  8. The importance of low serum levels of high-density lipoprotein cholesterol (HDL-C) as a cardiovascular risk factor.

    PubMed

    Espinosa-Larrañaga, Francisco; Vejar-Jalaf, Margarita; Medina-Santillán, Roberto

    2005-10-01

    In order to discuss and establish a joint position on the treatment of low serum levels of high-density lipoprotein cholesterol (HDL-C), a group of experts involved in the care of people with dyslipidaemia and at risk of cardiovascular disease met in Miami, Florida, U.S., on 5th and 6th March 2005. The experts came from the Latin American countries Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico and Venezuela and had at least five years of experience in the care of patients with dyslipidaemia and low HDL-C. The main objective of the meeting was to discuss and propose a treatment for low serum HDL-C levels as a cardiovascular risk factor in patients and to create a group of useful recommendations in this regard, applicable to the daily clinical practice of physicians dealing with patients with dyslipidaemia and cardiovascular disease. This document describes the methodology developed to obtain these recommendations and presents the results of this academic meeting. PMID:16342610

  9. LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

    PubMed Central

    Michel, C. Charles; Nanjee, M. Nazeem; Olszewski, Waldemar L.; Miller, Norman E.

    2015-01-01

    The mechanisms by which LDLs and HDLs cross the vascular endothelium from plasma into interstitial fluid are not understood, and have never been studied in humans in vivo. We determined whether the plasma-to-lymph clearance rates of LDL and HDL conform with those predicted by passive ultrafiltration through intercellular pores, or if it is necessary to invoke an active process such as receptor-mediated transcytosis. Plasma and afferent peripheral lymph were collected under steady-state conditions from 30 healthy men, and assayed for seven globular proteins of molecular radii 2.89–8.95 nm, complement C3, and apo AI, apo AII, and apo B. Plasma-to-lymph clearance rates of the seven proteins fitted the relation expected for molecules of their size when transported through two populations of pores of radius 4.95 and 20.1 nm. The same model parameters were then found to accurately predict the clearance rates of both HDL and LDL. The apparent clearance of complement C3, previously shown to be secreted by cultured endothelium, exceeded that predicted by the model. We conclude that the transport of HDL and LDL from plasma into interstitial fluid across the peripheral vascular endothelium in healthy humans can be explained by ultrafiltration without invoking an additional active process such as transcytosis. PMID:25398615

  10. The binding capability of plasma phospholipid transfer protein, but not HDL pool size, is critical to repress LPS induced inflammation

    PubMed Central

    Yu, Yang; Cui, Yingjie; Zhao, Yanan; Liu, Shuai; Song, Guohua; Jiao, Peng; Li, Bin; Luo, Tian; Guo, Shoudong; Zhang, Xiangjian; Wang, Hao; Jiang, Xian-Cheng; Qin, Shucun

    2016-01-01

    Phospholipid transfer protein (PLTP) participates in high density lipoprotein (HDL) metabolism. Increased plasma PLTP activity was observed in lipopolysaccharide (LPS) triggered acute inflammatory diseases. This study aimed to determine the exact role of PLTP in LPS induced inflammation. HDL pool size was shrunk both in PLTP deficient mice (PLTP−/−) and PLTP transgenic mice (PLTP-Tg). PLTP displayed a strong protective effect on lethal endotoxemia in mice survival study. Furthermore, after LPS stimulation, the expression of pro-inflammatory cytokines were increased in bone marrow derived macrophage (BMDM) from PLTP−/−, while decreased in BMDM from PLTP-Tg compared with BMDM from wild-type mice (WT). Moreover, LPS induced nuclear factor kappa-B (NFκB) activation was enhanced in PLTP−/− BMDM or PLTP knockdown RAW264.7. Conversely, PLTP overexpression countered the NFκB activation in LPS challenged BMDM. Additionally, the activation of toll like receptor 4 (TLR4) induced by LPS showed no alteration in PLTP−/− BMDM. Finally, PLTP could bind to LPS, attenuate the pro-inflammatory effects of LPS, and improve the cell viability in vitro. To sum up, these findings elucidated that PLTP repressed LPS induced inflammation due to extracellular LPS binding capability, and the protective effects were not related to HDL pool size in mice. PMID:26857615

  11. In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I.

    PubMed

    Zhao, Yannan; Black, Audrey S; Bonnet, David J; Maryanoff, Bruce E; Curtiss, Linda K; Leman, Luke J; Ghadiri, M Reza

    2014-10-01

    We have observed that molecular constructs based on multiple apoA-I mimetic peptides attached to a branched scaffold display promising anti-atherosclerosis functions in vitro. Building on these promising results, we now describe chronic in vivo studies to assess anti-atherosclerotic efficacy of HDL-like nanoparticles assembled from a trimeric construct, administered over 10 weeks either ip or orally to LDL receptor-null mice. When dosed ip, the trimer-based nanolipids markedly reduced plasma LDL-cholesterol levels by 40%, unlike many other apoA-I mimetic peptides, and were substantially atheroprotective. Surprisingly, these nanoparticles were also effective when administered orally at a dose of 75 mg/kg, despite the peptide construct being composed of l-amino acids and being undetectable in the plasma. The orally administered nanoparticles reduced whole aorta lesion areas by 55% and aortic sinus lesion volumes by 71%. Reductions in plasma cholesterol were due to the loss of non-HDL lipoproteins, while plasma HDL-cholesterol levels were increased. At a 10-fold lower oral dose, the nanoparticles were marginally effective in reducing atherosclerotic lesions. Intriguingly, analogous results were obtained with nanolipids of the corresponding monomeric peptide. These nanolipid formulations provide an avenue for developing orally efficacious therapeutic agents to manage atherosclerosis. PMID:24975585

  12. Vitamin E supplementation increases the resistance of both LDL and HDL to oxidation and increases cholesteryl ester transfer activity.

    PubMed

    Arrol, S; Mackness, M I; Durrington, P N

    2000-05-01

    There is increasing evidence that lipid peroxidation and oxidative modification of low density lipoprotein (LDL) is important in atherogenesis. Evidence that antioxidant therapy decreases mortality is, however, inconclusive. We have examined the effects of vitamin E on the susceptibility of LDL and high density lipoprotein (HDL) to oxidation, and on cholesteryl ester heteroexchange in an in vitro system using autologous serum lipoproteins. Vitamin E in doses of 200 and 400 mg/day were administered orally to 21 healthy volunteers (12 females and nine males) aged between 23 and 50 years, and to 16 healthy volunteers (eight females and eight males) aged between 22 and 51 years for 50 days, respectively. Fasting serum lipoproteins, susceptibility of lipoproteins to oxidation and cholesteryl ester transfer activity (CETA) were measured before and after vitamin E supplementation. Serum lipoprotein and lipid concentrations did not change significantly in either group. The LDL-conjugated diene (CD) lag phase during incubation with Cu(2+) was increased by 157% (110-232%) (median (interquartile range)) (P<0.05) on vitamin E (200 mg/day) and by 235% (185-259%) (P<0.0001) on 400 mg/day. The lag phases for LDL-lipid peroxide (LPO) generation were also significantly increased by 146% (122-192%) (P<0.005) and 177% (101-267%) (P<0.005), respectively. The HDL-CD lag phase also increased on both doses 140% (115-169%) (P<0.005) and 171% (122-192%) (P<0.005), as did the HDL-LPO lag phase by 123% (104-153%) (P<0.05) on 200 mg/day and 240% (97-360%) (P<0.005) on 400 mg daily. Cholesteryl ester transfer activity from HDL to very low and low density lipoproteins significantly increased from 12. 7+/-2.6 (mean+/-SEM) to 16+/-3.4 nmol/ml/h (P<0.05) on 200 mg/daily and 10.4+/-2.0 to 19.2+/-3.3 nmol/ml/h (P<0.005) on vitamin E, 400mg day. Thus, vitamin E (200 and 400mg daily) significantly decreased the susceptibility of LDL and HDL to oxidation in vitro. However, the increase in CETA

  13. Novel Apo E-Derived ABCA1 Agonist Peptide (CS-6253) Promotes Reverse Cholesterol Transport and Induces Formation of preβ-1 HDL In Vitro

    PubMed Central

    Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques

    2015-01-01

    Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are

  14. Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro

    DOE PAGESBeta

    Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques; Zhu, Xuewei

    2015-07-24

    Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from themore » carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are

  15. Medición de densidades medias de meteoritos: test del método de inmersión

    NASA Astrophysics Data System (ADS)

    Steren, G.

    Se evaluó una técnica simple para medir las densidades medias de meteoritos, basada en el Método de Arquímedes y que utiliza cuentas de vidrio de 40μ en lugar de un fluído esto presenta la ventaja de no ser intrusivo ni químicamente reactivo (D.Britt and G.Consolmagno, 1996, B.A.A.S.28,1106). El estudio, realizado en junio de este año por participantes de la VI Escuela de Verano del Observatorio del Vaticano, empleó 37 muestras de la colección del Observatorio del Vaticano, de las cuales 26 eran Condritas, 1 Pallasita y 1 Howardita; algunas de ellas ya habian sido estudiadas por otras técnicas aunque también se incluyeron muestras no estudiadas anteriormente.

  16. An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide.

    PubMed

    Wool, Geoffrey D; Vaisar, Tomas; Reardon, Catherine A; Getz, Godfrey S

    2009-09-01

    Modifying apolipoprotein (apo) A-I mimetic peptides to include a proline-punctuated alpha-helical repeat increases their anti-inflammatory properties as well as allows better mimicry of full-length apoA-I function. This study compares the following mimetics, either acetylated or biotinylated (b): 4F (18mer) and 4F-proline-4F (37mer, Pro). b4F interacts with both mouse HDL (moHDL) and LDL in vitro. b4F in vivo plasma clearance kinetics are not affected by mouse HDL level. Administration of biotinylated peptides to mice demonstrates that b4F does not associate with lipoproteins smaller than LDL in vivo, though it does associate with fractions containing free hemoglobin (Hb). In contrast, bPro specifically interacts with HDL. b4F and bPro show opposite binding responses to HDL by surface plasmon resonance. Administration of acetylated Pro to apoE(-/-) mice significantly decreases plasma serum amyloid A levels, while acetylated 4F does not have this ability. In contrast to previous reports that inferred that 4F associates with HDL in vivo, we systematically examined this potential interaction and demonstrated that b4F does not interact with HDL in vivo but rather elutes with Hb-containing plasma fractions. bPro, however, specifically binds to moHDL in vivo. In addition, the number of amphipathic alpha-helices and their linker influences the anti-inflammatory effects of apoA-I mimetic peptides in vivo. PMID:19433476

  17. An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide

    PubMed Central

    Wool, Geoffrey D.; Vaisar, Tomas; Reardon, Catherine A.; Getz, Godfrey S.

    2009-01-01

    Modifying apolipoprotein (apo) A-I mimetic peptides to include a proline-punctuated α-helical repeat increases their anti-inflammatory properties as well as allows better mimicry of full-length apoA-I function. This study compares the following mimetics, either acetylated or biotinylated (b): 4F (18mer) and 4F-proline-4F (37mer, Pro). b4F interacts with both mouse HDL (moHDL) and LDL in vitro. b4F in vivo plasma clearance kinetics are not affected by mouse HDL level. Administration of biotinylated peptides to mice demonstrates that b4F does not associate with lipoproteins smaller than LDL in vivo, though it does associate with fractions containing free hemoglobin (Hb). In contrast, bPro specifically interacts with HDL. b4F and bPro show opposite binding responses to HDL by surface plasmon resonance. Administration of acetylated Pro to apoE−/− mice significantly decreases plasma serum amyloid A levels, while acetylated 4F does not have this ability. In contrast to previous reports that inferred that 4F associates with HDL in vivo, we systematically examined this potential interaction and demonstrated that b4F does not interact with HDL in vivo but rather elutes with Hb-containing plasma fractions. bPro, however, specifically binds to moHDL in vivo. In addition, the number of amphipathic α-helices and their linker influences the anti-inflammatory effects of apoA-I mimetic peptides in vivo. PMID:19433476

  18. Molecular dynamics simulation of human serum paraoxonase 1 in DPPC bilayer reveals a critical role of transmembrane helix H1 for HDL association.

    PubMed

    Patra, Mahesh Chandra; Rath, Surya Narayan; Pradhan, Sukanta Kumar; Maharana, Jitendra; De, Sachinandan

    2014-01-01

    Serum paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-bound mammalian enzyme exhibiting antiatherosclerotic activity. Despite years of research, an accurate model for the binding interaction between PON1 and HDL has not been established. However, it is reported that anchoring of PON1 to HDL is mainly governed by an N-terminal alpha helix H1 and another short helix H2. Here, we studied the molecular association of full-length human PON1 (huPON1) with a HDL-mimetic dipalmitoylphosphatidylcholine (DPPC) bilayer using homology modeling and molecular dynamics simulations. Our results indicate that H1 is the highly dynamic part of huPON1, showing clockwise rotation of up to 30° within the DPPC bilayer. However, without phospholipid molecules, H1 experiences helical distortions, illustrating an incompatible HDL-anchoring conformation. Snorkeling interactions of K3, R18, and R27 together with aromatic locks formed by Y187, Y190, W194, and W202 are highly essential for anchoring of huPON1 to HDL's surface. Molecular mechanics/Poisson-Boltzmann solvent-accessible surface area (MM/PBSA) binding free energy calculation revealed that H1 displays greater binding affinity towards lipid molecules compared with H2 and H3, suggesting that H1 is the most probable HDL-binding domain of PON1. Binding free energy decomposition showed that K3, R18, and R27 interact with polar headgroups of DPPC membrane through electrostatic interaction. Moreover, Y187, Y190, W194, and W202 interact with DPPC lipids mainly through van der Waals interaction. Taken together, these results show that the transmembrane helix H1 along with the interfacial positively charged and aromatic resides were crucial for PON1's association with HDL particle. The current study will be useful towards understanding the antiatherosclerotic and bioscavenging properties of this promiscuous enzyme. PMID:24297451

  19. Folded Functional Lipid-Poor Apolipoprotein A-I Obtained by Heating of High-Density Lipoproteins: Relevance to HDL Biogenesis

    PubMed Central

    Jayaraman, Shobini; Cavigiolio, Giorgio; Gursky, Olga

    2013-01-01

    Synopsis High-density lipoproteins (HDL) remove cell cholesterol and protect from atherosclerosis. The major HDL protein is apolipoprotein A-I (apoA-I). Most plasma apoA-I circulates in lipoproteins, yet ~5% forms monomeric lipid-poor/free species. This metabolically active species is a primary cholesterol acceptor and is central to HDL biogenesis. Structural properties of lipid-poor apoA-I are unclear due to difficulties in isolating this transient species. We used thermal denaturation of human HDL to produce lipid-poor apoA-I. Analysis of the isolated lipid-poor fraction showed protein:lipid weight ratio 3:1, with apoA-I, phosphatidylcholine and cholesterol ester at approximate molar ratios of 1:8:1. Compared to lipid-free apoA-I, lipid-poor apoA-I showed slightly altered secondary structure and aromatic packing, reduced thermodynamic stability, lower self-associating propensity, increased adsorption to phospholipid surface, and comparable ability to remodel phospholipids and form reconstituted HDL. Lipid-poor apoA-I can be formed by heating of either plasma or reconstituted HDL. We propose the first structural model of lipid-poor apoA-I which corroborates its distinct biophysical properties and postulates the lipid-induced ordering of the labile C-terminal region. In summary, HDL heating produces folded functional monomolecular lipid-poor apoA-I that is distinct from lipid-free apoA-I. Increased adsorption to phospholipid surface and reduced C-terminal disorder may help direct lipid-poor apoA-I towards HDL biogenesis. PMID:22150513

  20. Changes in HDL-cholesterol and lipoprotein Lp(a) after 6-month treatment with finasteride in males affected by benign prostatic hyperplasia (BPH).

    PubMed

    Denti, L; Pasolini, G; Cortellini, P; Sanfelici, L; Benedetti, R; Cecchetti, A; Ferretti, S; Bruschieri, L; Ablondi, F; Valenti, G

    2000-09-01

    Androgen effects on lipoproteins, mainly high density lipoprotein (HDL), could be exerted by a direct interaction of testosterone (T) or dihydrotestosterone (DHT) with liver androgen receptors. To assess if T needs to be converted into DHT to affect lipid metabolism, 13 patients were studied, affected with benign prostatic hyperplasia (BPH) and treated with an inhibitor of 5 alpha-reductase (finasteride). They were compared with 15 untreated controls. At baseline and after 3 and 6 months of therapy, each patient was evaluated as for lipoprotein and hormone concentrations, as well as for nutritional status. Body composition was assessed by anthropometry and bio-impedance analysis (BIA). Treatment was associated with a significant increase of HDL-cholesterol (HDL-C), mainly HDL3 subclass, and lipoprotein(a) (Lp(a)), as well as a decline of DHT, whereas no significant changes were apparent for T, estradiol (E2), sex hormone binding hormone (SHBG) and body composition indexes. However, no significant associations between DHT and lipid relative changes were apparent at bivariate correlation analysis. This finding was confirmed by comparing patient subsets identified by cluster analysis, according to HDL subclass individual responses. Rather, a slight association with E2 for HDL2 (positive) and HDL3 (negative) was found. In conclusion, finasteride can modify HDL and Lp(a) concentrations. However, by the data, these effects cannot be definitively attributed to the changes in DHT synthesis induced by finasteride, since a direct and non-specific interference of the drug on liver metabolism cannot be excluded. PMID:10996351

  1. Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry[S

    PubMed Central

    Cao, Jian; Hsu, Yuan-Hao; Li, Sheng; Woods, Virgil L.; Dennis, Edward A.

    2013-01-01

    Lipoprotein-associated phospholipase A2 (Lp-PLA2), specifically Group VIIA PLA2, is a member of the phospholipase A2 superfamily and is found mainly associated with LDL and HDL in human plasma. Lp-PLA2 is considered as a risk factor, a potential biomarker, a target for therapy in the treatment of cardiovascular disease, and evidence suggests that the level of Lp-PLA2 in plasma is associated with the risk of future cardiovascular and stroke events. The differential location of the enzyme in LDL/HDL lipoproteins has been suggested to affect Lp-PLA2 function and/or its physiological role and an abnormal distribution of the enzyme may correlate with diseases. Although a mutagenesis study suggested that a surface helix (residues 362–369) mediates the association between Lp-PLA2 and HDL, the molecular details and mechanism of association has remained unknown. We have now employed hydrogen deuterium exchange mass spectrometry to characterize the interaction between recombinant human Lp-PLA2 and human HDL. We have found that specific residues 113–120, 192–204, and 360–368 likely mediate HDL binding. In a previous study, we showed that residues 113–120 are important for Lp-PLA2-liposome interactions. We now find that residues 192–204 show a decreased deuteration level when Lp-PLA2 is exposed to apoA-I, but not apoA-II, the most abundant apoproteins in HDL, and additionally, residues 360–368 are only affected by HDL.The results suggest that apoA-I and phospholipid membranes play crucial roles in Lp-PLA2 localization to HDL. PMID:23089916

  2. Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice.

    PubMed

    Pitman, Wendy A; Korstanje, Ron; Churchill, Gary A; Nicodeme, Edwige; Albers, John J; Cheung, Marian C; Staton, Megan A; Sampson, Stephen S; Harris, Stephen; Paigen, Beverly

    2002-01-01

    To investigate the quantitative trait loci (QTL) regulating plasma cholesterol, the female progeny of an (SMxNZB/ B1NJ)xNZB/B1NJ backcross were fed an atherogenic diet. After 18 wk, plasma total cholesterol and high-density lipoprotein cholesterol (HDL-C) was measured. HDL-C concentrations were greater in NZB than in SM mice. For standard chow-fed mice, QTL were found near D5Mit370 and D18Mit34. For mice fed an atherogenic diet, a QTL was found near D5Mit239. The QTL for chow-fed and atherogenic-fed mice on chromosome 5 seem to be two different loci. We used a multitrait analysis to rule out pleiotropy in favor of a two-QTL hypothesis. Furthermore, the HDL-C in these strains was induced by the high-fat diet. For inducible HDL-C, one significant locus was found near D15Mit39. The gene for an HDL receptor, Srb1, maps close to the HDL-C QTL at D5Mit370, but the concentrations of Srb1 mRNA and SR-B1 protein and the gene sequence of NZB/B1NJ and SM/J did not support Srb1 as a candidate gene. With these QTL, we have identified chromosomal regions that affect lipoprotein profiles in these strains. PMID:12006675

  3. Beneficial effects of artichoke leaf extract supplementation on increasing HDL-cholesterol in subjects with primary mild hypercholesterolaemia: a double-blind, randomized, placebo-controlled trial.

    PubMed

    Rondanelli, Mariangela; Giacosa, Attilio; Opizzi, Annalisa; Faliva, Milena Anna; Sala, Patrizio; Perna, Simone; Riva, Antonella; Morazzoni, Paolo; Bombardelli, Ezio

    2013-02-01

    The aim of this study was to evaluate the effects of artichoke leaf extract (ALE) supplementation (250 mg, 2 b.i.d.) on the lipid pattern. A randomized, double-blind, placebo-controlled clinical trial was performed on 92 overweight subjects with primary mild hypercholesterolaemia for 8 weeks. Forty-six subjects were randomized to supplementation (age: 54.2 ± 6.6 years, body mass index (BMI): 25.8 ± 3.9 kg/m(2), male/female: 20/26) and 46 subjects to placebo (age: 53.8 ± 9.0 years, BMI: 24.8 ± 1.6 kg/m(2), male/female: 21/25). Verum supplementation was associated with a significant increase in mean high-density lipoprotein (HDL)-cholesterol (p < 0.001) and in mean change in HDL-cholesterol (HDL-C) (p = 0.004). A significantly decreased difference was also found for the mean change in total cholesterol (p = 0.033), low-density lipoprotein (LDL)-cholesterol (p < 0.001), total cholesterol/HDL ratio (p < 0.001) and LDL/HDL ratio (p < 0.001), when verum and placebo treatment were compared. These results indicate that ALE could play a relevant role in the management of mild hypercholesterolaemia, favouring in particular the increase in HDL-C, besides decreasing total cholesterol and LDL-cholesterol. PMID:22746542

  4. Divergent effects of alpha-tocopherol and vitamin C on the generation of dysfunctional HDL associated with diabetes and the Hp 2-2 genotype.

    PubMed

    Asleh, Rabea; Levy, Andrew P

    2010-02-01

    The haptoglobin (Hp) 2-2 genotype is associated with increased risk of cardiovascular disease (CVD) in diabetes (DM). We recently proposed this increased risk arises from the tethering of redox active hemoglobin (Hb) to high density lipoprotein (HDL), thereby resulting in oxidative modification of HDL. Clinical trials have demonstrated that vitamin E (alpha-tocopherol) decreases while vitamin C increases CVD in Hp 2-2 DM individuals. We sought to test the hypothesis that the interaction of alpha-tocopherol or vitamin C on CVD in Hp 2-2 DM was due to their divergent effects on HDL oxidation and function. Vitamin C significantly increased while alpha-tocopherol completely blocked oxidation mediated by glycosylated Hb-Hp 2-2. Vitamin C had no benefit while alpha-tocopherol completely restored HDL function in Hp 2-2 DM mice. Co-administration of vitamin C mitigated the protective effects of alpha-tocopherol on HDL. There exists a pharmacogenomic interaction between vitamin C and alpha-tocopherol and the Hp 2-2 genotype on HDL function and structure. Choosing the correct antioxidant in the correct subset of patients may be critical in order to demonstrate benefit from antioxidant therapy. PMID:19769483

  5. HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function[S

    PubMed Central

    Berisha, Stela Z.; Brubaker, Greg; Kasumov, Takhar; Hung, Kimberly T.; DiBello, Patricia M.; Huang, Ying; Li, Ling; Willard, Belinda; Pollard, Katherine A.; Nagy, Laura E.; Hazen, Stanley L.; Smith, Jonathan D.

    2015-01-01

    HDL functions are impaired by myeloperoxidase (MPO), which selectively targets and oxidizes human apoA1. We previously found that the 4WF isoform of human apoA1, in which the four tryptophan residues are substituted with phenylalanine, is resistant to MPO-mediated loss of function. The purpose of this study was to generate 4WF apoA1 transgenic mice and compare functional properties of the 4WF and wild-type human apoA1 isoforms in vivo. Male mice had significantly higher plasma apoA1 levels than females for both isoforms of human apoA1, attributed to different production rates. With matched plasma apoA1 levels, 4WF transgenics had a trend for slightly less HDL-cholesterol versus human apoA1 transgenics. While 4WF transgenics had 31% less reverse cholesterol transport (RCT) to the plasma compartment, equivalent RCT to the liver and feces was observed. Plasma from both strains had similar ability to accept cholesterol and facilitate ex vivo cholesterol efflux from macrophages. Furthermore, we observed that 4WF transgenic HDL was partially (∼50%) protected from MPO-mediated loss of function while human apoA1 transgenic HDL lost all ABCA1-dependent cholesterol acceptor activity. In conclusion, the structure and function of HDL from 4WF transgenic mice was not different than HDL derived from human apoA1 transgenic mice. PMID:25561462

  6. Baisse du HDL-cholestérol indicateur du stress oxydatif dans le diabète de type 2

    PubMed Central

    Kabamba, Arsène Tshikongo; Bakari, Salvius Amuri; Longanga, Albert Otshudi; Lukumwena, Zet Kalala

    2014-01-01

    L'hypercholestérolémie est étroitement liée au stress oxydatif. Lorsqu'il y a trop de cholestérol qui circule dans le sang, il n'est pas utilisé en totalité par les cellules et il risque de s'accumuler dans les vaisseaux sanguins. Cela peut entrainer la formation des plaques d'athérosclérose qui gênent la circulation sanguine et provoquent des accidents cardiovasculaires. Le stress oxydatif apparait très tôt dans l'histoire des complications du diabète de type 2, et est lié à l'oxydation du glucose mais aussi à la peroxydation lipidique. Le cholestérol-HDL est un marqueur important du stress oxydatif par sa capacité à faciliter la métabolisation du cholestérol, sa baisse est souvent considérée comme la source de beaucoup d'inquiétudes. L'objectif est l’évaluation de la variation du taux de cholestérol-HDL, marqueur du stress oxydatif, chez les patients diabétiques de type 2 dans la population congolaise. Nous avons inclus dans cette étude prospective des cas témoins des patients diabétiques de type 2 reconnus et diagnostiqués, et des témoins non diabétiques appariés selon l’âge et le sexe. Parallèlement au bilan biologique classique, une analyse d'un des facteurs de risque du stress oxydatif a été réalisée: baisse de HDL-Cholestérol. L’âge moyen des 30 patients diabétiques (47,77±10,78 ans) était comparable à celui des 30 témoins (48,83±10,73 ans). Une baisse significative du cholestérol-HDL dans le sang était observée chez 100% des diabétiques et 50% des témoins (p=0,0000). L'augmentation du HDL cholestérol permet d’éliminer le mauvais cholestérol en excès en nettoyant les tissus et en ramenant le cholestérol vers le foie. Lors du diabète de type 2 on constate une baisse sanguine sensible du taux de HDL-cholestérol, qui est signe indicateur du stress oxydatif. PMID:25767660

  7. Amide-linked Ethanolamine Conjugate of Gemfibrozil as a Profound HDL Enhancer: Design, Synthesis, Pharmacological Screening and Docking Study.

    PubMed

    Rai, Himanshu; Dhaneshwar, Suneela S

    2015-01-01

    Elevated concentration of any or all types of lipids in the plasma including hypertriglyceridemia and hypercholesterolemia leads to atherosclerotic cardiovascular disease. Effective medication needs multiple drug therapy as recommended cholesterol and triglyceride levels are difficult to achieve by monotherapy and frequently require the use of more than one lipid-lowering medication. Gemfibrozil lowers plasma triglyceride-rich lipoproteins mainly VLDL and increases HDL. It is associated with short plasma half-life (1.5h) and GIT distress on long term use. In a study it was found that ethanolamine decreases serum cholesterol, especially VLDL cholesterol and LDL cholesterol in rats fed an HF/HC diet. In the present work, we thought of exploring the effect of co-drug of gemfibrozil with ethanolamine (GE-I) as a potential combination therapy for the management of mixed hyperlipidemia. Synthesis of GE-I was effected by CDI coupling. Structure was confirmed spectrally. Interestingly kinetic studies revealed that GE-I resisted chemical and enzymatic hydrolysis. In tritoninduced hyperlipidemia, significant lowering of serum lipid levels was observed. The hallmark of GEI was its profound effect on HDL level which was raised above the normal level by 15%. Docking study also supported modulatory effect of GE-I (docking score -7.012) on PPAR-α which was comparable to docking score of gemfibrozil (-9.432). These preliminary observations prompt us to consider GE-I as a novel, serendipitous, hybrid anti-hyperlipidemic new chemical entity which needs be studied extensively to prove it as an HDL enhancing anti-hyperlipidemic agent. PMID:26285608

  8. Association of HDL-Related Loci with Age-Related Macular Degeneration and Plasma Lutein and Zeaxanthin: the Alienor Study

    PubMed Central

    Merle, Bénédicte M. J.; Maubaret, Cécilia; Korobelnik, Jean-François; Delyfer, Marie-Noëlle; Rougier, Marie-Bénédicte; Lambert, Jean-Charles; Amouyel, Philippe; Malet, Florence; Le Goff, Mélanie; Dartigues, Jean-François; Barberger-Gateau, Pascale; Delcourt, Cécile

    2013-01-01

    Background Several genes implicated in high-density lipoprotein (HDL) metabolism have been reported to be associated with age-related macular degeneration (AMD). Furthermore, HDL transport the two carotenoids, lutein and zeaxanthin, which are highly suspected to play a key-role in the protection against AMD. The objective is to confirm the associations of HDL-related loci with AMD and to assess their associations with plasma lutein and zeaxanthin concentrations. Methods Alienor study is a prospective population-based study on nutrition and age-related eye diseases performed in 963 elderly residents of Bordeaux, France. AMD was graded according to the international classification, from non-mydriatic colour retinal photographs. Plasma lutein and zeaxanthin were determined by normal-phase high-performance liquid chromatography. The following polymorphisms were studied: rs493258 and rs10468017 (LIPC), rs3764261 (CETP), rs12678919 (LPL) and rs1883025 (ABCA1). Results After multivariate adjustment, the TT genotype of the LIPC rs493258 variant was significantly associated with a reduced risk for early and late AMD (OR=0.64, 95%CI: 0.41-0.99; p=0.049 and OR=0.26, 95%CI: 0.08-0.85; p=0.03, respectively), and with higher plasma zeaxanthin concentrations (p=0.03), while plasma lipids were not significantly different according to this SNP. Besides, the LPL variant was associated with early AMD (OR=0.67, 95%CI: 0.45-1.00; p=0.05) and both with plasma lipids and plasma lutein (p=0.047). Associations of LIPC rs10468017, CETP and ABCA1 polymorphisms with AMD did not reach statistical significance. Conclusion These findings suggest that LIPC and LPL genes could both modify the risk for AMD and the metabolism of lutein and zeaxanthin. PMID:24223199

  9. ATHENA: a tool for meta-dimensional analysis applied to genotypes and gene expression data to predict HDL cholesterol levels.

    PubMed

    Holzinger, Emily R; Dudek, Scott M; Frase, Alex T; Krauss, Ronald M; Medina, Marisa W; Ritchie, Marylyn D

    2013-01-01

    Technology is driving the field of human genetics research with advances in techniques to generate high-throughput data that interrogate various levels of biological regulation. With this massive amount of data comes the important task of using powerful bioinformatics techniques to sift through the noise to find true signals that predict various human traits. A popular analytical method thus far has been the genome-wide association study (GWAS), which assesses the association of single nucleotide polymorphisms (SNPs) with the trait of interest. Unfortunately, GWAS has not been able to explain a substantial proportion of the estimated heritability for most complex traits. Due to the inherently complex nature of biology, this phenomenon could be a factor of the simplistic study design. A more powerful analysis may be a systems biology approach that integrates different types of data, or a meta-dimensional analysis. For this study we used the Analysis Tool for Heritable and Environmental Network Associations (ATHENA) to integrate high-throughput SNPs and gene expression variables (EVs) to predict high-density lipoprotein cholesterol (HDL-C) levels. We generated multivariable models that consisted of SNPs only, EVs only, and SNPs + EVs with testing r-squared values of 0.16, 0.11, and 0.18, respectively. Additionally, using just the SNPs and EVs from the best models, we generated a model with a testing r-squared of 0.32. A linear regression model with the same variables resulted in an adjusted r-squared of 0.23. With this systems biology approach, we were able to integrate different types of high-throughput data to generate meta-dimensional models that are predictive for the HDL-C in our data set. Additionally, our modeling method was able to capture more of the HDL-C variation than a linear regression model that included the same variables. PMID:23424143

  10. Interactions of Apolipoproteins AI, AII, B and HDL, LDL, VLDL with Polyurethane and Polyurethane-PEO Surfaces.

    PubMed

    Cornelius, R M; Macri, J; Cornelius, K M; Brash, J L

    2015-11-10

    The lipoproteins (HDL, LDL, VLDL) are important components of blood present in high concentration. Surprisingly, their role in blood-biomaterial interactions has been largely ignored. In previous work apolipoprotein AI (the main protein component of HDL) was identified as a major constituent of protein layers adsorbed from plasma to biomaterials having a wide range of surface properties, and quantitative data on the adsorption of apo AI to a biomedical grade polyurethane were reported. In the present communication quantitative data on the adsorption of apo AI, apo AII and apoB (the latter being a constituent of LDL and VLDL), as well as the lipoprotein particles themselves (HDL, LDL, VLDL), to a biomedical segmented polyurethane (PU) with and without an additive containing poly(ethylene oxide) (material referred to as PEO) are reported. Using radiolabeled apo AI, apo AII, and apoB, adsorption levels on PU from buffer at a protein concentration of 50 μg/mL were found to be 0.34, 0.40, and 0.14 μg/cm(2) (12, 23, and 0.25 nmol/cm(2)) respectively. Adsorption to the PEO surface was <0.02 μg/cm(2) for all three apolipoproteins demonstrating the strong protein resistance of this material. In contrast to the apolipoproteins, significant amounts of the lipoproteins were found to adsorb to the PEO as well as to the PU surface. X-ray photoelectron spectra, following exposure of the surfaces to the lipoproteins, showed a strong phosphorus signal, confirming that adsorption had occurred. It therefore appears that a PEO-containing surface that is resistant to apolipoproteins may be less resistant to the corresponding lipoproteins. PMID:26513526

  11. Pilot-Scale Demonstration of ALTA for NOx Control in Pulverized Coal-Fired Boilers

    SciTech Connect

    Andrew Fry; Devin Davis; Marc Cremer; Bradley Adams

    2008-04-30

    This report describes computational fluid dynamics (CFD) modeling and pilot-scale testing conducted to demonstrate the ability of the Advanced Layered Technology Approach (ALTA) to reduce NO{sub x} emissions in a pulverized coal (PC) boiler. Testing specifically focused on characterizing NO{sub x} behavior with deep burner staging combined with Rich Reagent Injection (RRI). Tests were performed in a 4 MBtu/hr pilot-scale furnace at the University of Utah. Reaction Engineering International (REI) led the project team which included the University of Utah and Combustion Components Associates (CCA). Deep burner staging and RRI, combined with selective non-catalytic reduction (SNCR), make up the Advanced Layered Technology Approach (ALTA) for NO{sub x} reduction. The application of ALTA in a PC environment requires homogenization and rapid reaction of post-burner combustion gases and has not been successfully demonstrated in the past. Operation of the existing low-NO{sub x} burner and design and operation of an application specific ALTA burner was guided by CFD modeling conducted by REI. Parametric pilot-scale testing proved the chemistry of RRI in a PC environment with a NOx reduction of 79% at long residence times and high baseline NOx rate. At representative particle residence times, typical operation of the dual-register low-NO{sub x} burner provided an environment that was unsuitable for NO{sub x} reduction by RRI, showing no NOx reduction. With RRI, the ALTA burner was able to produce NO{sub x} emissions 20% lower than the low-NO{sub x} burner, 76 ppmv vs. 94 ppmv, at a burner stoichiometric ratio (BSR) of 0.7 and a normalized stoichiometric ratio (NSR) of 2.0. CFD modeling was used to investigate the application of RRI for NO{sub x} control on a 180 MW{sub e} wall-fired, PC boiler. A NO{sub x} reduction of 37% from baseline (normal operation) was predicted using ALTA burners with RRI to produce a NO{sub x} emission rate of 0.185 lb/MBtu at the horizontal nose of

  12. HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

    PubMed Central

    Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

    2015-01-01

    Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that

  13. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.

    PubMed

    Krause, Amanda; Mitchell, Claire; Essop, Fahmida; Tager, Susan; Temlett, James; Stevanin, Giovanni; Ross, Christopher; Rudnicki, Dobrila; Margolis, Russell

    2015-10-01

    Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline, and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations. PMID:26079385

  14. Self-rated health showed a consistent association with serum HDL-cholesterol in the cross-sectional Oslo Health Study

    PubMed Central

    Tomten, Sissel E.; Høstmark, Arne T.

    2007-01-01

    Objective: To examine the association between serum HDL-cholesterol concentration (HDL-C) and self rated health (SRH) in several age groups of men and women. Study design and setting: The study had a cross-sectional design and included 18,770 men and women of the Oslo Health Study aged 30; 40 and 45; 69-60; 75-76 years. Results: In both sexes and all age groups, SRH (3 categories: poor, good, very good) was positively correlated with HDL-C. Logistic regression analysis on dichotomized values of SRH (i.e. poor vs. good health) in each age group of men and women showed that increasing HDL-C values were associated with increasing odds for reporting good health; the odds ratio (OR) was highest in young men, and was generally lower in women than in men. Odds ratios in the 4 age groups of men were 4.94 (2.63-9.29), 2.25 (1.63-3.09), 2.12 (1.58-2.86), 1.87 (1.37-2.54); and in women: 3.58 (2.46-5.21), 2.81 (2.23-3.53), 2.28 (1.84-2.82), 1.61 (1.31-1.99). In the whole material, 1 mmol/L increase in HDL-C increased the odds for reporting good health by 2.27 (2.06-2.50; p<0.001), when adjusting for sex, age group, time since food intake and use of cholesterol lowering drugs. Chronic diseases, pain, psychological distress, smoking, alcohol, length of education, and dietary items did not have any major influence on the pattern of the HDL-C vs. SRH association. Conclusion: There was a consistent positive association between HDL-C and SRH, in both men and women in four different age groups, with the strongest association in young people. PMID:18071582

  15. Comparison of apoA-I helical structure and stability in discoidal and spherical HDL particles by HX and mass spectrometry.

    PubMed

    Chetty, Palaniappan Sevugan; Nguyen, David; Nickel, Margaret; Lund-Katz, Sissel; Mayne, Leland; Englander, S Walter; Phillips, Michael C

    2013-06-01

    Elucidation of apoA-I secondary structure in spherical plasma HDL particles is essential for understanding HDL structure and function at the molecular level. To provide this information, we have applied hydrogen exchange (HX) and mass spectrometry methods to compare apoA-I secondary structure in discoidal (two apoA-I molecules/particle) and spherical (five apoA-I molecules/particle) HDL particles. The HX kinetics indicate that the locations of helical segments within the apoA-I molecules are the same in both discoidal and spherical HDL particles (approximately 10 nm hydrodynamic diameter). Helix stabilities in both types of particles are 3-5 kcal/mol, consistent with the apoA-I molecules being in a highly dynamic state with helical segments unfolding and refolding in seconds. For the spherical HDL, apoA-I fragments corresponding to residues 115-158 exhibit bimodal HX kinetics consistent with this segment adopting an inter-converting (on the timescale of tens of minutes) helix-loop configuration. The segment adopting this configuration in the 10 nm disc is shorter because the surface area available to each apoA-I molecule is apparently larger. Loop formation in the central region of the apoA-I molecule contributes to the ability of the protein to adapt to changes in available space on the HDL particle surface. Overall, apoA-I secondary structure is largely unaffected by a change in HDL particle shape from disc to sphere. PMID:23580759

  16. Comparison of apoA-I helical structure and stability in discoidal and spherical HDL particles by HX and mass spectrometry

    PubMed Central

    Chetty, Palaniappan Sevugan; Nguyen, David; Nickel, Margaret; Lund-Katz, Sissel; Mayne, Leland; Englander, S. Walter; Phillips, Michael C.

    2013-01-01

    Elucidation of apoA-I secondary structure in spherical plasma HDL particles is essential for understanding HDL structure and function at the molecular level. To provide this information, we have applied hydrogen exchange (HX) and mass spectrometry methods to compare apoA-I secondary structure in discoidal (two apoA-I molecules/particle) and spherical (five apoA-I molecules/particle) HDL particles. The HX kinetics indicate that the locations of helical segments within the apoA-I molecules are the same in both discoidal and spherical HDL particles (approximately 10 nm hydrodynamic diameter). Helix stabilities in both types of particles are 3–5 kcal/mol, consistent with the apoA-I molecules being in a highly dynamic state with helical segments unfolding and refolding in seconds. For the spherical HDL, apoA-I fragments corresponding to residues 115–158 exhibit bimodal HX kinetics consistent with this segment adopting an inter-converting (on the timescale of tens of minutes) helix-loop configuration. The segment adopting this configuration in the 10 nm disc is shorter because the surface area available to each apoA-I molecule is apparently larger. Loop formation in the central region of the apoA-I molecule contributes to the ability of the protein to adapt to changes in available space on the HDL particle surface. Overall, apoA-I secondary structure is largely unaffected by a change in HDL particle shape from disc to sphere. PMID:23580759

  17. Uncleaved ApoM Signal Peptide Is Required for Formation of Large ApoM/Sphingosine 1-Phosphate (S1P)-enriched HDL Particles*

    PubMed Central

    Liu, Mingxia; Allegood, Jeremy; Zhu, Xuewei; Seo, Jeongmin; Gebre, Abraham K.; Boudyguina, Elena; Cheng, Dongmei; Chuang, Chia-Chi; Shelness, Gregory S.; Spiegel, Sarah; Parks, John S.

    2015-01-01

    Apolipoprotein M (apoM), a plasma sphingosine 1-phosphate (S1P) carrier, associates with plasma HDL via its uncleaved signal peptide. Hepatocyte-specific apoM overexpression in mice stimulates formation of both larger nascent HDL in hepatocytes and larger mature apoM/S1P-enriched HDL particles in plasma by enhancing hepatic S1P synthesis and secretion. Mutagenesis of apoM glutamine 22 to alanine (apoMQ22A) introduces a functional signal peptidase cleavage site. Expression of apoMQ22A in ABCA1-expressing HEK293 cells resulted in the formation of smaller nascent HDL particles compared with wild type apoM (apoMWT). When apoMQ22A was expressed in vivo, using recombinant adenoviruses, smaller plasma HDL particles and decreased plasma S1P and apoM were observed relative to expression of apoMWT. Hepatocytes isolated from both apoMWT- and apoMQ22A-expressing mice displayed an equivalent increase in cellular levels of S1P, relative to LacZ controls; however, relative to apoMWT, apoMQ22A hepatocytes displayed more rapid apoM and S1P secretion but minimal apoMQ22A bound to nascent lipoproteins. Pharmacologic inhibition of ceramide synthesis increased cellular sphingosine and S1P but not medium S1P in both apoMWT and apoMQ22A hepatocytes. We conclude that apoM secretion is rate-limiting for hepatocyte S1P secretion and that its uncleaved signal peptide delays apoM trafficking out of the cell, promoting formation of larger nascent apoM- and S1P-enriched HDL particles that are probably precursors of larger apoM/S1P-enriched plasma HDL. PMID:25627684

  18. Association between lipids, lipoproteins composition of HDL particles and triglyceride-rich lipoproteins, and LCAT and CETP activity in post-renal transplant patients.

    PubMed

    Kimak, Elżbieta; Bylina, Jerzy; Solski, Janusz; Hałabiś, Magdalena; Baranowicz-Gąszczyk, Iwona; Książek, Andrzej

    2013-11-01

    High-density lipoprotein (HDL) remodeling within the plasma compartment and the association between lecithin-cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activity, and lipid, lipoprotein concentrations and composition were investigated. The aim was to examine the high sensitivity of C-reactive protein (hsCRP), lipid, apolipoprotein B (apoB), apoAI, total apoAII, apoAIInonB, apoB-containing apoAII (apoB:AII), total apoCIII, apoCIIInonB, apoB-containing apoCIII (apoB:CIII) concentration and LCAT and CETP activity to gain an insight into the association between them and LCAT and CETP, 57 post-renal transplant (Tx) patients with and without statin therapy and in 15 healthy subjects. Tx patients had moderate hypertriglyceridemia, hypercholesterolemia, and dyslipoproteinemia, disturbed triglyceride-rich lipoproteins (TRLs) and HDL composition, decreased LCAT, and slightly increased hsCRP but no CETP activity. Spearman's correlation test showed the association between lipids and lipoproteins and LCAT or CETP, and multiple ridge stepwise forward regression showed that immunosuppressive therapy in Tx patients can disturb HDL and TRLs composition. The results suggest that inhibition or activation of LCAT is due, in part, to HDL-associated lipoprotein. Lipoprotein composition of apoAI, apoAIInonB, and apoCIIInonB in HDL particle and apoB:AII TRLs can contribute to decrease LCAT mass in Tx patients. Tx patients without statin and with lower triglycerides but higher HDL cholesterol concentration and disturbed lipoprotein composition of ApoAI and apoAII in HDL particle can decrease LCAT, increase LDL cholesterol, aggravate renal graft, and accelerate atherosclerosis and chronic heart diseases. PMID:23479335

  19. 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.

    PubMed

    Flores-Castillo, Cristobal; Zamora-Pérez, Juan Á; Carreón-Torres, Elizabeth; Arzola-Paniagua, Angélica; Aguilar-Salinas, Carlos; López-Olmos, Victoria; Fragoso, José M; Luna-Luna, María; Rodríguez-Pérez, José M; Franco, Martha; Vargas-Alarcón, Gilberto; Pérez-Méndez, Óscar

    2015-08-01

    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. PMID:25982284

  20. Betatrophin Acts as a Diagnostic Biomarker in Type 2 Diabetes Mellitus and Is Negatively Associated with HDL-Cholesterol

    PubMed Central

    Yi, Min; Chen, Rong-ping; Yang, Rui; Guo, Xian-feng; Zhang, Jia-chun; Chen, Hong

    2015-01-01

    Objective. By assessing its circulating concentrations in type 2 diabetes mellitus (T2DM) patients, we aimed to explore the associations of betatrophin with various metabolic parameters and evaluate its diagnostic value in T2DM. Methods. A total of 58 non-diabetes-mellitus (NDM) subjects and 73 age- and sex-matched newly diagnosed T2DM patients were enrolled. Correlation analyses between circulating betatrophin levels and multiple metabolic parameters were performed. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value of betatrophin concentration in T2DM. Results. Circulating betatrophin levels were approximately 1.8 times higher in T2DM patients than in NDM individuals (median 747.12 versus 407.41 pg/mL, P < 0.001). Correlation analysis showed that betatrophin was negatively associated with high-density lipoprotein cholesterol (HDL-C) levels in all subjects. ROC curve analysis identified betatrophin as a potent diagnostic biomarker for T2DM. The optimal cut-off point of betatrophin concentration for predicting T2DM was 501.23 pg/mL. Conclusions. Serum betatrophin levels were markedly increased in newly diagnosed T2DM patients and further elevated in obese T2DM subjects. Betatrophin was negatively correlated with HDL-C levels. Our findings indicate that betatrophin could be a potent diagnostic biomarker for T2DM. PMID:26819617

  1. 78 FR 18972 - Alta Wind X, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-28

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind X, LLC; Supplemental Notice That Initial Market-Based Rate Filing...-referenced proceeding, of Alta Wind X, LLC's application for market-based rate authority, with...

  2. 78 FR 18973 - Alta Wind XI, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-28

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind XI, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for Blanket Section 204 Authorization This is a supplemental notice in the above-referenced proceeding, of Alta Wind XI,...

  3. 77 FR 23712 - Alta Wind VII, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind VII, LLC; Supplemental Notice That Initial Market-Based Rate...-referenced proceeding of Alta Wind VII, LLC's application for market-based rate authority, with...

  4. 76 FR 23806 - Alta Wind VI, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-28

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind VI, LLC; Supplemental Notice That Initial Market-Based Rate Filing...-referenced proceeding of Alta Wind VI, LLC's application for market-based rate authority, with...

  5. 77 FR 35669 - AltaGas Renewable Energy Colorado LLC; Supplemental Notice That Initial Market-Based Rate Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-14

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission AltaGas Renewable Energy Colorado LLC; Supplemental Notice That Initial... notice in the above-referenced proceeding of AltaGas Renewable Energy Colorado LLC application for...

  6. 75 FR 57014 - Alta Wind II, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind II, LLC; Supplemental Notice That Initial Market-Based Rate Filing... the above-referenced proceeding of Alta Wind II, LLC's application for market-based rate...

  7. 75 FR 57013 - Alta Wind III, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind III, LLC; Supplemental Notice That Initial Market-Based Rate... notice in the above-referenced proceeding of Alta Wind III, LLC's application for market-based...

  8. 75 FR 57015 - Alta Wind V, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind V, LLC; Supplemental Notice That Initial Market-Based Rate Filing... the above-referenced proceeding of Alta Wind V, LLC's application for market-based rate...

  9. 75 FR 57014 - Alta Wind IV, LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Alta Wind IV, LLC; Supplemental Notice That Initial Market-Based Rate Filing... the above-referenced proceeding of Alta Wind IV, LLC's application for market-based rate...

  10. 76 FR 3881 - Application To Export Electric Energy; TransAlta Energy Marketing (U.S.) Inc.

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-21

    ... Application To Export Electric Energy; TransAlta Energy Marketing (U.S.) Inc. AGENCY: Office of Electricity Delivery and Energy Reliability, DOE. ACTION: Notice of application. SUMMARY: TransAlta Energy Marketing (U... be surplus energy purchased from electric utilities, Federal power marketing agencies, and...

  11. Carne cocinada a altas temperaturas y el riesgo de cáncer

    Cancer.gov

    Hoja informativa que explica cómo algunos compuestos químicos se forman en la carne cocinada a alta temperatura y describe los resultados de estudios sobre el consumo de estos compuestos químicos y el riesgo de cáncer.

  12. Patellar maltracking is prevalent among patellofemoral pain subjects with patella alta: an upright, weightbearing MRI study

    PubMed Central

    Pal, Saikat; Besier, Thor F.; Beaupre, Gary S.; Fredericson, Michael; Delp, Scott L.; Gold, Garry E.

    2012-01-01

    The purpose of this study is to determine if patellar maltracking is more prevalent among patellofemoral (PF) pain subjects with patella alta compared to subjects with normal patella height. We imaged 37 PF pain and 15 pain free subjects in an open-configuration magnetic resonance imaging scanner while they stood in a weightbearing posture. We measured patella height using the Caton-Deschamps, Blackburne-Peel, Insall-Salvati, Modified Insall-Salvati, and Patellotrochlear indices, and classified the subjects into patella alta and normal patella height groups. We measured patella tilt and bisect offset from oblique-axial plane images, and classified the subjects into maltracking and normal tracking groups. Patellar maltracking was more prevalent among PF pain subjects with patella alta compared to PF pain subjects with normal patella height (two-tailed Fisher’s exact test, p < 0.050). Using the Caton-Deschamps index, 67% (8/12) of PF pain subjects with patella alta were maltrackers, whereas only 16% (4/25) of PF pain subjects with normal patella height were maltrackers. Patellofemoral pain subjects classified as maltrackers displayed a greater patella height compared to the pain free and PF pain subjects classified as normal trackers (two-tailed unpaired t-tests with Bonferroni correction, p < 0.017). This study adds to our understanding of PF pain in two ways - 1) we demonstrate that patellar maltracking is more prevalent in PF pain subjects with patella alta compared to subjects with normal patella height; and 2) we show greater patella height in PF pain subjects compared to pain free subjects using four indices commonly used in clinics. PMID:23165335

  13. Cholesteryl Ester Transfer Protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk.

    PubMed

    Papp, Audrey C; Pinsonneault, Julia K; Wang, Danxin; Newman, Leslie C; Gong, Yan; Johnson, Julie A; Pepine, Carl J; Kumari, Meena; Hingorani, Aroon D; Talmud, Philippa J; Shah, Sonia; Humphries, Steve E; Sadee, Wolfgang

    2012-01-01

    Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5-7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4 × 10(-5), allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8 × 10(-10)) and intron 8 polymorphism rs9930761-T>C (5.6 × 10(-8)) (in high linkage disequilibrium with allele frequencies 6-7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6 × 10(-28) and rs5883 p = 8.6 × 10(-10), adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29-4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex

  14. 2,4,5,2',4',5'-Hexachlorobiphenyl-lipoprotein (LDL, HDL, VLDL) interaction and induced lipidosis in cultured skin fibroblasts

    SciTech Connect

    Kling, D.; Becker, M.M.; Kruth, H.S.; Gamble, W.

    1984-06-01

    2,4,5,2',4',5'-Hexachlorobiphenyl (HCB) induced cytoplasmic inclusions and lipidosis in normal (AG1437) and hypercholesterolemic (GM488) human skin fibroblasts. Quantitative and qualitative microscopic fluorescence analysis showed that the cytoplasmic inclusions are formed as early as 3 hr after treatment with HCB. The inclusions contain lipids but no detectable nonesterified cholesterol or cholesteryl ester. High density lipoproteins (HDL), low density lipoproteins (LDL), and very low density lipoproteins (VLDL) facilitate the apparent uptake of HCB by skin fibroblasts. HDL and LDL appeared to reverse the induction of cytoplasmic inclusions and lipidosis when cells were pretreated with HCB, the HCB was removed from media, and the cells were incubated with LDL or HDL. The results suggest that lipoproteins participate in the uptake and egress of HCB from skin fibroblasts.

  15. Adverse effect of pregnancy on high density lipoprotein (HDL) cholesterol in young adult women. The CARDIA Study. Coronary Artery Risk Development in Young Adults.

    PubMed

    Lewis, C E; Funkhouser, E; Raczynski, J M; Sidney, S; Bild, D E; Howard, B V

    1996-08-01

    The authors analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study in order to examine associations between parity and lipoproteins. Of 2,787 women recruited in 1985-1986, 2,534 (91%) returned in 1987-1988 and 2,393 (86%) returned in 1990-1991 for repeat evaluations. Two-year change (1987-1988 to 1985-1986) in high density lipoprotein (HDL) cholesterol was significantly different among the parity groups. HDL cholesterol decreased in women who had their first pregnancy of at least 28 weeks duration during follow-up (mean +/- standard error, -3.5 +/- 1.2 mg/dl), and this change was significantly different from the increase in women parous at baseline who had no further pregnancies (2.5 +/- 0.3 mg/dl) and in nullipara (2.4 +/- 0.3 mg/dl). There was a nonsignificant trend for a greater decrease in HDL2 cholesterol fraction in the primipara compared with the other groups. The HDL cholesterol decrease remained significant after controlling for race, age, education, oral contraceptive use, and changes in body mass index, waist-hip ratio, physical activity, smoking status, and alcohol intake. Change in HDL cholesterol was also significantly different among the parity groups in analyses of pregnancies that occurred during the subsequent 3 years of follow-up. There were no differences for change in LDL cholesterol or triglycerides. Potential mechanisms for a detrimental effect of pregnancy on HDL cholesterol include hormonal, body composition, or life-style/behavioral changes. PMID:8686693

  16. A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens.

    PubMed

    Homkham, Nontiya; Cressey, Tim R; Ingsrisawang, Lily; Bouazza, Naïm; Ngampiyaskul, Chaiwat; Hongsiriwon, Suchat; Srirojana, Sakulrat; Kanjanavanit, Suparat; Bhakeecheep, Sorakij; Coeur, Sophie Le; Salvadori, Nicolas; Treluyer, Jean Marc; Jourdain, Gonzague; Urien, Saik

    2016-09-01

    Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment. PMID:26749102

  17. Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages

    PubMed Central

    Carnuta, Mihaela G.; Sanda, Gabriela M.; Stancu, Camelia S.; Popescu, Andreea C.; Popescu, Mihaela R.; Vlad, Adelina; Dimulescu, Doina R.; Simionescu, Maya; Sima, Anca V.

    2016-01-01

    We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera. MiR-223 and miR-486 prevailed in HDL2, while miR-92a predominated in HDL3, all three miRNAs discriminating between ACS and SA patients; their levels were increased in HDL from hyperglycemic ACS patients versus normoglycemic ones. The incubation of human macrophages with sera from ACS and SA patients showed that all patients’ sera induced an increase of Drosha, DGCR8 and Dicer expressions and of selected miRNAs levels compared to control sera, the effect being higher in the case of hyperglycemic versus normoglycemic ACS sera. The addition of glucose to SA and ACS sera increased Drosha, DGCR8 and Dicer expression and miRNAs levels in the exposed macrophages. In conclusion, hyperglycemia is associated with increased miR-223, miR-92a, miR-486 levels in HDL, which discriminate between ACS and SA patients. Exposure of human macrophages to ACS compared to SA sera determines the upregulation of Drosha, DGCR8 and Dicer expression and the increase of selected miRNAs production, the effect being augmented by an increased glucose concentration. PMID:27519051

  18. Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages.

    PubMed

    Simionescu, Natalia; Niculescu, Loredan S; Carnuta, Mihaela G; Sanda, Gabriela M; Stancu, Camelia S; Popescu, Andreea C; Popescu, Mihaela R; Vlad, Adelina; Dimulescu, Doina R; Simionescu, Maya; Sima, Anca V

    2016-01-01

    We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera. MiR-223 and miR-486 prevailed in HDL2, while miR-92a predominated in HDL3, all three miRNAs discriminating between ACS and SA patients; their levels were increased in HDL from hyperglycemic ACS patients versus normoglycemic ones. The incubation of human macrophages with sera from ACS and SA patients showed that all patients' sera induced an increase of Drosha, DGCR8 and Dicer expressions and of selected miRNAs levels compared to control sera, the effect being higher in the case of hyperglycemic versus normoglycemic ACS sera. The addition of glucose to SA and ACS sera increased Drosha, DGCR8 and Dicer expression and miRNAs levels in the exposed macrophages. In conclusion, hyperglycemia is associated with increased miR-223, miR-92a, miR-486 levels in HDL, which discriminate between ACS and SA patients. Exposure of human macrophages to ACS compared to SA sera determines the upregulation of Drosha, DGCR8 and Dicer expression and the increase of selected miRNAs production, the effect being augmented by an increased glucose concentration. PMID:27519051

  19. Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma

    PubMed Central

    Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji

    2016-01-01

    Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664

  20. Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

    PubMed

    Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji

    2016-01-01

    Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664

  1. Serum uric acid is associated with increased risk of idiopathic venous thromboembolism in high HDL-C population: A case-control study

    PubMed Central

    YU, MIAO; LING, KEN; TENG, YUNFEI; LI, QIN; MEI, FEI; LI, YIQING; OUYANG, CHENXI

    2016-01-01

    Many studies have indicated that metabolic disorders are positively correlated with idiopathic venous thromboembolism (VTE), whereas the risk factor serum uric acid (SUA) for idiopathic VTE has yet to be investigated. In this retrospective case-control study, 276 idiopathic VTE patients and 536 gender- and age-matched control subjects were included. The subjects in the case and control groups exhibiting common known VTE risk factors and the patients with a first VTE onset in one month were excluded. For the control group, primary and secondary VTE patients were excluded. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and current smoking were significantly associated with idiopathic VTE in the univariate analysis. Hyperuricemia was detected in 56/276 (20.29%) idiopathic patients compared with 71/536 (13.25%) in the control group. HDL-C was considered the most prominent interactive factor for SUA in idiopathic VTE by the interaction analysis. After testing for the interaction terms, SUA was closely associated with idiopathic VTE in the high HDL-C population (P=0.0026 for interaction), while there was no such correlation in the low HDL-C group. The results indicated no obvious correlation between triglyceride and hypertension to idiopathic VTE. In conclusion, SUA is closely associated with an increased risk of idiopathic VTE in the high HDL-C population. The abnormality of SUA may act as an important linkage between atherosclerosis and idiopathic VTE through HDL-C. PMID:27284315

  2. Effects of extended-release niacin/laropiprant, simvastatin, and the combination on correlations between apolipoprotein B, LDL cholesterol, and non-HDL cholesterol in patients with dyslipidemia

    PubMed Central

    Farnier, Michel; Chen, Erluo; Johnson-Levonas, Amy O; McCrary Sisk, Christine; Mitchel, Yale B

    2014-01-01

    Background Statins modify correlations between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) and apoB and non-high-density lipoprotein cholesterol (non-HDL-C); however, it is not known whether niacin-based therapies have similar effects. Objective To evaluate the effects of extended-release niacin (ERN)/laropiprant (LRPT), simvastatin (SIMVA), and ERN/LRPT + SIMVA (pooled ERN/LRPT + SIMVA) on apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients. Methods This post-hoc analysis of a 12-week study evaluated the apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients randomized equally to double-blind ERN/LRPT 1 g/20 mg, SIMVA 10, 20, or 40 mg, or ERN/LRPT 1 g/20 mg + SIMVA (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled in all groups except SIMVA 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIMVA 40 mg (switched to ERN/LRPT 2 g/40 mg + SIMVA 40 mg). Simple linear regression analyses were used to calculate LDL-C and non-HDL-C levels corresponding to known apoB baseline values (ie, in untreated patients) and following treatment. Results The apoB:LDL-C and apoB:non-HDL-C correlations were higher and the predicted LDL-C and non-HDL-C levels for a known apoB value were considerably lower following treatment with ERN/LRPT, SIMVA and ERN/LRPT + SIMVA compared with untreated patients at baseline. Conclusion Greater dissociation of apoB, LDL-C, and non-HDL-C targets occur following treatment with ERN/LRPT, SIMVA, and ERN/LRPT + SIMVA in patients with dyslipidemia. The achievement of more aggressive LDL-C and non-HDL-C goals in patients receiving lipid-modifying therapy may further reduce coronary risk by normalizing apoB-containing atherogenic lipoproteins. PMID:24855368

  3. Effect of Extended-Release Niacin on High-Density Lipoprotein (HDL) Functionality, Lipoprotein Metabolism, and Mediators of Vascular Inflammation in Statin-Treated Patients

    PubMed Central

    Yadav, Rahul; Liu, Yifen; Kwok, See; Hama, Salam; France, Michael; Eatough, Ruth; Pemberton, Phil; Schofield, Jonathan; Siahmansur, Tarza J; Malik, Rayaz; Ammori, Basil A; Issa, Basil; Younis, Naveed; Donn, Rachelle; Stevens, Adam; Durrington, Paul; Soran, Handrean

    2015-01-01

    Background The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment. Methods and Results In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity. Conclusions ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL

  4. Plasma lipoprotein composition in alcoholic hepatitis: accumulation of apolipoprotein E-rich high density lipoprotein and preferential reappearance of "light'-HDL during partial recovery.

    PubMed

    Weidman, S W; Ragland, J B; Sabesin, S M

    1982-05-01

    Abnormal lipoproteins accumulate in the plasma of alcoholic hepatitis patients in association with a deficiency of the cholesterol esterifying enzyme, lecithin:cholesterol acyl-transferase. Most of these abnormal lipoproteins are found in the d > 1.006 g/ml density fraction. To investigate the composition and morphology of the lipoproteins at various times during the illness in four patients, we have employed density gradient ultracentrifugation combined with analyses of gradient fractions by polyacrylamide gel electrophoresis, electroimmunoassay, and electron microscopy. At the onset of the illness, plasma cholesteryl esters ranged from 19-34% of total cholesterol; high density lipoprotein (HDL) cholesterol and apoA-I, the major HDL apoprotein, were <10% of normal; and most of the d > 1.006 g/ml triglycerides and phospholipids were found in the LDL density region. A linear correlation (r = 0.964, P < 0.001) was found between the d > 1.006 g/ml apoB concentration and the summation of the triglyceride and esterified cholesterol for that fraction, indicating a constant ratio of apoB to the summation of these two "core lipids". ApoA-I was primarily found in the fraction d > 1.18 g/ml (HDL(3) and VHDL) but not at all in the HDL(2) density range of the gradient. No cholesteryl esters were present in the apoA-I containing fractions. In contrast to normal, large amounts of apoE accumulated in lipoproteins isolated at d 1.055-1.114 g/ml. The apoE-rich fractions contained primarily phospholipids and unesterified cholesterol; they appeared by electron microscopy to be mixtures of spherical particles, vesicular particles, and chains of bilamellar discs. Analyses of the density gradient fractions by SDS polyacrylamide gel electrophoresis under reducing conditions indicated that apoA-II levels and distribution paralleled apoA-I, not apoE, providing evidence against appreciable concentrations of apoE-apoA-II complexes. During partial recovery from alcoholic hepatitis in three

  5. [A case of laparoscopic surgery for a rectal carcinoid after ALTA therapy for an internal hemorrhoid].

    PubMed

    Aomatsu, Naoki; Nakamura, Masanori; Hasegawa, Tsuyoshi; Nakao, Shigetomi; Uchima, Yasutake; Aomatsu, Keiho

    2014-11-01

    We report a case of laparoscopic surgery for a rectal carcinoid after aluminum potassium and tannic acid (ALTA) therapy for an internal hemorrhoid. A 66-year-old man was admitted to our hospital because of bleeding during defecation. He was diagnosed via anoscopy with Goligher grade II internal hemorrhoids. Examination via colonoscopy revealed 2 yellowish submucosal tumors in the lower rectum that were 5mm and 10mm in diameter. A rectal carcinoid tumor was diagnosed based on histopathology. Abdominal computed tomography demonstrated no metastases to the liver or lymph nodes. First, we performed ALTA therapy for the internal hemorrhoids. Two weeks later, we performed laparoscopic-assisted low anterior resection (D2) for the rectal carcinoid. The patient was discharged without complications and has not experienced recurrence during the 2 years of follow-up care. PMID:25731340

  6. Semitendinosus Tendon Transfer Associated With Distal Alignment for Patella Alta in a Patient With Recurrent Dislocations

    PubMed Central

    Calderazzi, Filippo; Pellegrini, Andrea; Coviello, Gianluca; Groppi, Giulia; Ceccarelli, Francesco

    2015-01-01

    Patellofemoral instability is characterized by pain during normal daily activities and frequent dislocation events. In the reported case, an adolescent girl, aged 15 years, affected by left patellofemoral instability, underwent surgery with a double technique comprising tibial tubercle distalization and medial patellofemoral ligament reconstruction. In case of patella alta associated with patellofemoral instability, surgical treatment should focus on medial patellofemoral ligament repair and on recurrent instability prevention. PMID:26900548

  7. Interaction Between Peroxisome Proliferator Activated Receptor δ and Epithelial Membrane Protein 2 Polymorphisms Influences HDL-C Levels in the Chinese Population.

    PubMed

    Ke, Tingjing; Dorajoo, Rajkumar; Han, Yi; Khor, Chiea-Chuen; van Dam, Rob M; Yuan, Jian-Min; Koh, Woon-Puay; Liu, Jianjun; Teo, Yik Ying; Goh, Daniel Y T; Tai, E Shyong; Wong, Tien Yin; Cheng, Ching-Yu; Friedlander, Yechiel; Heng, Chew-Kiat

    2016-09-01

    Peroxisome proliferator activated receptors (PPARs) are transcription factors involved in the regulation of key metabolic pathways. Numerous in vivo and in vitro studies have established their important roles in lipid metabolism. A few SNPs in PPAR genes have been reported to be associated with lipid levels. In this study, we aimed to investigate the interactive effects between single nucleotide polymorphisms (SNPs) in three PPAR isoforms α/δ/γ and other genetic variants across the genome on plasma high-density lipoprotein-cholesterol (HDL-C) levels. Study subjects (N = 2003) were genotyped using Illumina HumanOmniZhongHua-8 Beadchip. Fifty-three tag SNPs ± 100 kb of PPAR α, δ, and γ (r(2) < 0.2) were selected. The effect of interactions between PPAR SNPs and those across the genome on HDL-C was tested using linear regression models. One statistically significant interaction influencing HDL-C was detected between PPARδ SNP rs2267668 and epithelial membrane protein 2 (EMP2) downstream SNP rs7191411 (N = 1993, β = 0.74, adjusted P = 0.022). This interaction was successfully replicated in the meta-analysis of two additional Chinese cohorts (N = 3948, P = 0.01). The present study showed a novel SNP × SNP interaction between rs2267668 in PPARδ and rs7191411 in EMP2 that has significant impact on circulating HDL-C levels in the Singaporean Chinese population. PMID:27530449

  8. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs...

  9. Gender and age specific differences in the kinetic behavior of TRL, IDL and LDL apolipoprotein B-100 and HDL apolipoprotein A-I

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gender specific differences in lipid and lipoprotein profile, predominantly higher LDL-C, VLDL-C and TG, and lower HDL-C levels have been observed in males compared to females. These differences are influenced by menopausal status and age. To investigate mechanism(s) involved, apolipoprotein (apo) B...

  10. Female attempted suicide patients with low HDL levels are at higher risk of suicide re-attempt within the subsequent year: a clinical cohort study.

    PubMed

    Emet, Mucahit; Yucel, Atakan; Ozcan, Halil; Akgol Gur, Sultan Tuna; Saritemur, Murat; Bulut, Nevzat; Gumusdere, Musa

    2015-01-30

    Our aims were, to clarify the blood lipid differences [Total serum cholesterol (TC), High-density lipoprotein (HDL), Low density lipoprotein (LDL), Triglyceride (TG)] between female patients who had attempted suicide and controls and to determine whether we could use the patients׳ initial lipid profiles to predict suicide re-attempt within the subsequent year. A total of 284 participants (110 cases and 174 controls) were recruited, with no differences in body mass index, age, blood sampling time and gender. Blood samples were collected from all participants for serum lipid profiles and assayed in an auto-analyzer. We divided the suicide re-attempter group into suicide attempters in the subsequent year (SSY) and suicide attempters after the subsequent year (SASY). The TC, LDL, and TG levels were significantly lower in the suicidal group than in the control group. HDL was significantly higher in the suicidal group than in the control group. Low TG (<70mg/dL) (OR (odds ratio)=12.8; 95% CI (confidence interval)=5.4-30.5; p<0.0001)and low LDL/HDL (<1.8) (OR=4.1; 95% CI=1.8-9.3; p=0.001) were significantly associated with a current suicide attempt. HDL levels in the SSY (41.5±4.5mg/dL) were lower than in the non-suicide attempters group (NSA) (50.9±10.3mg/dL) and SASY (58.7±12.8mg/dL)(d.f.=2, F=5.2, p=0.007). Serum HDL level may be a potential candidate predictor for the future risk of suicidality. PMID:25482392

  11. Beneficial effects of selective HDL-raising gene transfer on survival, cardiac remodelling and cardiac function after myocardial infarction in mice.

    PubMed

    Gordts, S C; Muthuramu, I; Nefyodova, E; Jacobs, F; Van Craeyveld, E; De Geest, B

    2013-11-01

    Post-myocardial infarction (MI) ejection fraction is decreased in patients with low high-density lipoprotein (HDL) cholesterol levels, independent of the degree of coronary atherosclerosis. The objective of this study is to evaluate whether selective HDL-raising gene transfer exerts cardioprotective effects post MI. Gene transfer in C57BL/6 low-density lipoprotein receptor (LDLr)(-/-) mice was performed with the E1E3E4-deleted adenoviral vector AdA-I, inducing hepatocyte-specific expression of human apo A-I, or with the control vector Adnull. A ligation of the left anterior descending coronary artery was performed 2 weeks after transfer or saline injection. HDL cholesterol levels were persistently 1.5-times (P<0.0001) higher in AdA-I mice compared with controls. Survival was increased (P<0.01) in AdA-I MI mice compared with control MI mice during the 28-day follow-up period (hazard ratio for mortality 0.42; 95% confidence interval 0.24-0.76). Longitudinal morphometric analysis demonstrated attenuated infarct expansion and inhibition of left ventricular (LV) dilatation in AdA-I MI mice compared with controls. AdA-I transfer exerted immunomodulatory effects and increased neovascularisation in the infarct zone. Increased HDL after AdA-I transfer significantly improved systolic and diastolic cardiac function post MI, and led to a preservation of peripheral blood pressure. In conclusion, selective HDL-raising gene transfer may impede the development of heart failure. PMID:23759702

  12. Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure☆

    PubMed Central

    Asselin, Caroline; Ducharme, Anique; Ntimbane, Thierry; Ruiz, Matthieu; Fortier, Annik; Guertin, Marie-Claude; Lavoie, Joël; Diaz, Ariel; Levy, Émile; Tardif, Jean-Claude; Des Rosiers, Christine

    2013-01-01

    Objective Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA). Methods and results Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R2=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only. Conclusion Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts. PMID:24494189

  13. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation

    PubMed Central

    Galvani, Sylvain; Sanson, Marie; Blaho, Victoria A.; Swendeman, Steven L.; Obinata, Hideru; Conger, Heather; Dahlbäck, Björn; Kono, Mari; Proia, Richard L.; Smith, Jonathan D.; Hla, Timothy

    2016-01-01

    The sphingosine 1-phosphate receptor 1 (S1P1) is abundant in endothelial cells, where it regulates vascular development and microvascular barrier function. In investigating the role of endothelial cell S1P1 in adult mice, we found that the endothelial S1P1 signal was enhanced in regions of the arterial vasculature experiencing inflammation. The abundance of proinflammatory adhesion proteins, such as ICAM-1, was enhanced in mice with endothelial cell–specific deletion of S1pr1 and suppressed in mice with endothelial cell–specific overexpression of S1pr1, suggesting a protective function of S1P1 in vascular disease. The chaperones ApoM+HDL (HDL) or albumin bind to sphingosine 1-phosphate (S1P) in the circulation; therefore, we tested the effects of S1P bound to each chaperone on S1P1 signaling in cultured human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs to ApoM+HDL-S1P, but not to albumin-S1P, promoted the formation of a cell surface S1P1–β-arrestin 2 complex and attenuated the ability of the proinflammatory cytokine TNFα to activate NF-κB and increase ICAM-1 abundance. Although S1P bound to either chaperone induced MAPK activation, albumin-S1P triggered greater Gi activation and receptor endocytosis. Endothelial cell–specific deletion of S1pr1 in the hypercholesterolemic Apoe−/− mouse model of atherosclerosis enhanced atherosclerotic lesion formation in the descending aorta. We propose that the ability of ApoM+HDL to act as a biased agonist on S1P1 inhibits vascular inflammation, which may partially explain the cardiovascular protective functions of HDL. PMID:26268607

  14. VNN1 Gene Expression Levels and the G-137T Polymorphism Are Associated with HDL-C Levels in Mexican Prepubertal Children

    PubMed Central

    Jacobo-Albavera, Leonor; Aguayo-de la Rosa, Pablo I.; Villarreal-Molina, Teresa; Villamil-Ramírez, Hugo; León-Mimila, Paola; Romero-Hidalgo, Sandra; López-Contreras, Blanca E.; Sánchez-Muñoz, Fausto; Bojalil, Rafael; González-Barrios, Juan Antonio; Aguilar-Salinas, Carlos A.; Canizales-Quinteros, Samuel

    2012-01-01

    Background VNN1 gene expression levels and the G-137T polymorphism have been associated with high density lipoprotein cholesterol (HDL-C) levels in Mexican American adults. We aim to evaluate the contribution of VNN1 gene expression and the G-137T variant to HDL-C levels and other metabolic traits in Mexican prepubertal children. Methodology/Principal Findings VNN1 mRNA expression levels were quantified in peripheral blood leukocytes from 224 unrelated Mexican-Mestizo children aged 6–8 years (107 boys and 117 girls) and were genotyped for the G-137T variant (rs4897612). To account for population stratification, a panel of 10 ancestry informative markers was analyzed. After adjustment for admixture, the TT genotype was significantly associated with lower VNN1 mRNA expression levels (P = 2.9 × 10−5), decreased HDL-C levels (β = −6.19, P = 0.028) and with higher body mass index (BMI) z-score (β = 0.48, P = 0.024) in the total sample. In addition, VNN1 expression showed a positive correlation with HDL-C levels (r = 0.220; P = 0.017) and a negative correlation with BMI z-score (r = −0.225; P = 0.015) only in girls. Conclusion/Significance Our data suggest that VNN1 gene expression and the G-137T variant are associated with HDL-C levels in Mexican children, particularly in prepubertal girls. PMID:23185446

  15. Correlation between high density lipoprotein-cholesterol and remodeling index in patients with coronary artery disease: IDEAS (IVUS diagnostic evaluation of atherosclerosis in Singapore)-HDL study.

    PubMed

    Lee, Chi-Hang; Tai, Bee-Choo; Lim, Gek-Hsiang; Chan, Mark Y; Low, Adrian F; Tan, Kathryn C; Chia, Boon-Lock; Tan, Huay-Cheem

    2012-01-01

    Serum level of high density lipoprotein (HDL)-cholesterol is associated with risk of coronary artery disease. We correlated the serum level of cholesterol with coronary artery remodeling index of patients with coronary artery disease. A total of 120 patients with de novo lesions located in native coronary artery were studied. Remodeling index was based on intravascular ultrasound (IVUS) interrogation of the lesions using the static approach, and was defined as external elastic membrane (EEM) area at lesion/average EEM area at proximal and distal reference segments. The average remodeling index was 0.9 (SD: 0.2). The remodeling index was not associated with any of the demographic and coronary risk factors. Stable angina was associated with a low remodeling index. Remodeling index correlated with white blood cell count and HDL-cholesterol, but not with total cholesterol, LDL-cholesterol and triglyceride. In the multiple linear regression analysis, HDL-cholesterol and procedure indication were the only 2 significant predictors of remodeling index. An increase of 1 mg/dL of HDL-cholesterol resulted in a decrease of 0.003 (95% CI: 0.0001, 0.007; P = 0.046) in remodeling index, after adjusting for procedural indications. When stratified according to diabetic status, the negative correlation persisted in non-diabetic (P = 0.023), but not in diabetic, patients (P = 0.707). We found a negative correlation between HDL-cholesterol level and remodeling index. Diabetic status may have an influence on the observed relationship. PMID:21197580

  16. Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCOM1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body we...

  17. Novel variants at KCTD10 and MVK/MMAB genes interact with dietary carbohydrates to modulate HDL-C concentrations in the genetics of lipid lowering drugs and diet network study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background - Several recent genome wide association studies have identified novel loci (KCTD10, MVK and MMAB) associated with HDL-C concentrations. Among environmental factors that influence HDL-C concentrations, high-carbohydrate diets have been associated with low concentrations. Objective - To ev...

  18. Composition, structure and substrate properties of reconstituted discoidal HDL with apolipoprotein A-I and cholesteryl ester

    NASA Astrophysics Data System (ADS)

    Dergunov, Alexander D.; Shabrova, Elena V.; Dobretsov, Gennady E.

    2010-03-01

    To investigate the influence of lipid unsaturation and neutral lipid on the maturation of high density lipoproteins, the discoidal complexes of apoA-I, phosphatidylcholine and cholesteryl ester (CE) were prepared. Saturated dipalmitoylphosphatidylcholine (DPPC) and unsaturated palmitoyllinoleoylphosphatidylcholine (PLPC), palmitoyloleoylphosphatidylcholine (POPC), and fluorescent probe cholesteryl 1-pyrenedecanoate (CPD) that forms in a diffusion- and concentration-dependent manner short-lived dimer of unexcited and excited molecules (excimer) were used. The apoA-I/DPPC/CPD complexes were heterogeneous by size, composition and probe location. CPD molecules incorporated more efficiently into larger complexes and accumulated in a central part of the discs. The apoA-I/POPC(PLPC)/CPD were also heterogeneous, however, probe molecules distributed preferentially into smaller complexes and accumulated at disc periphery. The kinetics of CPD transfer by recombinant cholesteryl ester transfer protein (CETP) to human plasma LDL is well described by two-exponential decay, the fast component with a shorter transfer time being more populated in PLPC compared to DPPC complexes. The presence of CE molecules in discoidal HDL results in particle heterogeneity. ApoA-I influences the CETP activity modulating the properties of apolipoprotein-phospholipid interface. This may include CE molecules accumulation in the boundary lipid in unsaturated phosphatidylcholine and cluster formation in the bulk bilayer in saturated phosphatidylcholine.

  19. Synbiotic food consumption reduces levels of triacylglycerols and VLDL, but not cholesterol, LDL, or HDL in plasma from pregnant women.

    PubMed

    Taghizadeh, Mohsen; Hashemi, Teibeh; Shakeri, Hossein; Abedi, Fatemeh; Sabihi, Sima-Sadat; Alizadeh, Sabihe-Alsadat; Asemi, Zatolla

    2014-02-01

    To our knowledge, no reports are available indicating the effects of synbiotic food consumption on blood lipid profiles and biomarkers of oxidative stress among pregnant women. This study was conducted to evaluate the effects of daily consumption of a synbiotic food on blood lipid profiles and biomarkers of oxidative stress in pregnant women. This randomized, double-blind, controlled clinical trial was performed among 52 primigravida pregnant women, aged 18 to 35-year-old at their third trimester. After a 2-week run-in period, subjects were randomly assigned to consume either a synbiotic (n = 26) or control food (n = 26) for 9 weeks. The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes (1 × 10⁷ CFU) and 0.04 g inulin (HPX)/g as the prebiotic. Patients were asked to consume the synbiotic and control foods two times a day. Biochemical measurements including blood lipid profiles, plasma total antioxidant capacity (TAC) and total glutathione (GSH) were conducted before and after 9 weeks of intervention. Consumption of a synbiotic food for 9 weeks resulted in a significant reduction in serum TAG (P = 0.04), VLDL (P = 0.04) and a significant rise in plasma GSH levels (P = 0.004) compared to the control food. No significant effects of the synbiotic food consumption on serum TC, LDL, HDL and plasma TAC levels (P > 0.05) were observed. Trial registry code: http://www.irct.ir . IRCT201212105623N3. PMID:24271261

  20. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients; a meta-analysis

    PubMed Central

    Boekholdt, S. Matthijs; Arsenault, Benoit J.; Hovingh, G. Kees; Mora, Samia; Pedersen, Terje R.; LaRosa, John C.; Welch, K.M.A.; Amarenco, Pierre; DeMicco, David A.; Tonkin, Andrew M.; Sullivan, David R.; Kirby, Adrienne; Colhoun, Helen M.; Hitman, Graham A.; Betteridge, D. John; Durrington, Paul N.; Clearfield, Michael B.; Downs, John R.; Gotto, Antonio M.; Ridker, Paul M.; Kastelein, John J.P.

    2013-01-01

    Background It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol (LDL-C) on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. Methods and results We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio 0.83, 95%CI 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR 0.79, 95%CI 0.72–0.82). This association was also observed among patients achieving on-statin LDL-C levels < 50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR 0.98, 95%CI 0.94–1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR 0.93, 95%CI 0.90–0.97). Conclusions Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low LDL-C. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction. PMID:23965489

  1. The Alta Stock, Utah: An Exemplar Rock Suite for Learning Metamorphic Concepts

    NASA Astrophysics Data System (ADS)

    Davidson, C.; Haileab, B.

    2003-12-01

    Using rock suites in a discovery-based setting is a terrific way to learn important petrologic processes and concepts such as the role of fluids during metamorphism, phase equilibrium, and metastability to name just a few. A particularly effective rock suite we use in our petrology course is from the contact aureole of the Tertiary Alta stock in Utah. The intrusion of the Alta stock into Paleozoic dolostone containing chert nodules produced a well-defined contact metamorphic aureole that includes talc-, tremolite-, forsterite-, and periclase-in field isograds (Cook and Bowman, 2000). Students work in free-form groups with collaboration between groups to define the mineral assemblages using hand samples and thin sections from throughout the areole and then work out what they think are the important petrologic processes that worked together to form what they see. The main goals of the exercise include: 1) learning to identify mineral assemblages common to metamorphosed siliceous dolostones; 2) learning to infer metamorphic reactions from progressive changes in mineral assemblages; 3) being able to identify balanced metamorphic reactions responsible for isograds mapped in the field; 4) begin to develop an understanding of how bulk composition and fluid composition controls mineral assemblages; and 5) learning how to infer the temperature and fluid composition evolution of the Alta stock aureole based on published T-X(CO2)diagrams. This suite is particularly effective because all the important minerals the students observe in thin section can be defined by the easy to plot and understand CaO-MgO-SiO2 system. This offers the opportunity to introduce (or reinforce) the concept of plotting minerals in composition space, using the phase rule to define the variance of your system, using tie lines to define stable mineral assemblages, and the flipping of tie lines to produce univariant reactions. In addition, the students work out the topology of these reactions in P-T space

  2. Resultados del relevamiento de HI en el Cielo Austral: 3. Relevamiento de Nubes de Alta Velocidad

    NASA Astrophysics Data System (ADS)

    Morras, R.; Bajaja, E.; Arnal, E. M.; Pöppel, W. G. L.

    Los resultados del relevamiento de HI del Hemisferio Austral fueron reprocesados con el fin de incrementar su sensibilidad. Así, se utilizó esta nueva base de datos con el fin de obtener un nuevo relevamiento de Nubes de Alta Velocidad en el cielo austral. El ruido r.m.s. alcanzado es de 0.015-0.020 K, con una resolución espectral de 8 km/seg. El cubrimiento espacial del relevamiento mejora en un factor 16 al realizado por Bajaja et al (1985).

  3. Impact of Rosuvastatin Treatment on HDL-Induced PKC-βII and eNOS Phosphorylation in Endothelial Cells and Its Relation to Flow-Mediated Dilatation in Patients with Chronic Heart Failure.

    PubMed

    Winzer, Ephraim B; Gaida, Pauline; Höllriegel, Robert; Fischer, Tina; Linke, Axel; Schuler, Gerhard; Adams, Volker; Erbs, Sandra

    2016-01-01

    Background. Endothelial function is impaired in chronic heart failure (CHF). Statins upregulate endothelial NO synthase (eNOS) and improve endothelial function. Recent studies demonstrated that HDL stimulates NO production due to eNOS phosphorylation at Ser(1177), dephosphorylation at Thr(495), and diminished phosphorylation of PKC-βII at Ser(660). The aim of this study was to elucidate the impact of rosuvastatin on HDL mediated eNOS and PKC-βII phosphorylation and its relation to endothelial function. Methods. 18 CHF patients were randomized to 12 weeks of rosuvastatin or placebo. At baseline, 12 weeks, and 4 weeks after treatment cessation we determined lipid levels and isolated HDL. Human aortic endothelial cells (HAEC) were incubated with isolated HDL and phosphorylation of eNOS and PKC-βII was evaluated. Flow-mediated dilatation (FMD) was measured at the radial artery. Results. Rosuvastatin improved FMD significantly. This effect was blunted after treatment cessation. LDL plasma levels were reduced after rosuvastatin treatment whereas drug withdrawal resulted in significant increase. HDL levels remained unaffected. Incubation of HAEC with HDL had no impact on phosphorylation of eNOS or PKC-βII. Conclusion. HDL mediated eNOS and PKC-βII phosphorylation levels in endothelial cells do not change with rosuvastatin in CHF patients and do not mediate the marked improvement in endothelial function. PMID:27563480

  4. Impact of Rosuvastatin Treatment on HDL-Induced PKC-βII and eNOS Phosphorylation in Endothelial Cells and Its Relation to Flow-Mediated Dilatation in Patients with Chronic Heart Failure

    PubMed Central

    Gaida, Pauline; Höllriegel, Robert; Fischer, Tina; Linke, Axel; Schuler, Gerhard; Adams, Volker; Erbs, Sandra

    2016-01-01

    Background. Endothelial function is impaired in chronic heart failure (CHF). Statins upregulate endothelial NO synthase (eNOS) and improve endothelial function. Recent studies demonstrated that HDL stimulates NO production due to eNOS phosphorylation at Ser1177, dephosphorylation at Thr495, and diminished phosphorylation of PKC-βII at Ser660. The aim of this study was to elucidate the impact of rosuvastatin on HDL mediated eNOS and PKC-βII phosphorylation and its relation to endothelial function. Methods. 18 CHF patients were randomized to 12 weeks of rosuvastatin or placebo. At baseline, 12 weeks, and 4 weeks after treatment cessation we determined lipid levels and isolated HDL. Human aortic endothelial cells (HAEC) were incubated with isolated HDL and phosphorylation of eNOS and PKC-βII was evaluated. Flow-mediated dilatation (FMD) was measured at the radial artery. Results. Rosuvastatin improved FMD significantly. This effect was blunted after treatment cessation. LDL plasma levels were reduced after rosuvastatin treatment whereas drug withdrawal resulted in significant increase. HDL levels remained unaffected. Incubation of HAEC with HDL had no impact on phosphorylation of eNOS or PKC-βII. Conclusion. HDL mediated eNOS and PKC-βII phosphorylation levels in endothelial cells do not change with rosuvastatin in CHF patients and do not mediate the marked improvement in endothelial function. PMID:27563480

  5. HDL Cholesterol Test

    MedlinePlus

    Advertisement Proceeds from website advertising help sustain Lab Tests Online. AACC is a not-for-profit organization ... for trustworthy health information. Verify Compliance . Produced by Advertisement

  6. Apolipoprotein A-I helical structure and stability in discoidal high-density lipoprotein (HDL) particles by hydrogen exchange and mass spectrometry.

    PubMed

    Sevugan Chetty, Palaniappan; Mayne, Leland; Kan, Zhong-Yuan; Lund-Katz, Sissel; Englander, S Walter; Phillips, Michael C

    2012-07-17

    To understand high-density lipoprotein (HDL) structure at the molecular level, the location and stability of α-helical segments in human apolipoprotein (apo) A-I in large (9.6 nm) and small (7.8 nm) discoidal HDL particles were determined by hydrogen-deuterium exchange (HX) and mass spectrometry methods. The measured HX kinetics of some 100 apoA-I peptides specify, at close to amino acid resolution, the structural condition of segments throughout the protein sequence and changes in structure and stability that occur on incorporation into lipoprotein particles. When incorporated into the large HDL particle, the nonhelical regions in lipid-free apoA-I (residues 45-53, 66-69, 116-146, and 179-236) change conformation from random coil to α-helix so that nearly the entire apoA-I molecule adopts helical structure (except for the terminal residues 1-6 and 237-243). The amphipathic α-helices have relatively low stability, in the range 3-5 kcal/mol, indicating high flexibility and dynamic unfolding and refolding in seconds or less. A segment encompassed by residues 125-158 exhibits bimodal HX labeling indicating co-existing helical and disordered loop conformations that interchange on a time scale of minutes. When incorporated around the edge of the smaller HDL particle, the increase in packing density of the two apoA-I molecules forces about 20% more residues out of direct contact with the phospholipid molecules to form disordered loops, and these are the same segments that form loops in the lipid-free state. The region of disc-associated apoA-I that binds the lecithin-cholesterol acyltransferase enzyme is well structured and not a protruding unstructured loop as reported by others. PMID:22745166

  7. MiR-486 and miR-92a Identified in Circulating HDL Discriminate between Stable and Vulnerable Coronary Artery Disease Patients

    PubMed Central

    Sanda, Gabriela M.; Carnuta, Mihaela G.; Stancu, Camelia S.; Popescu, Andreea C.; Popescu, Mihaela R.; Vlad, Adelina; Dimulescu, Doina R.; Simionescu, Maya; Sima, Anca V.

    2015-01-01

    Small non-coding microRNAs (miRNAs) are implicated in gene regulation, including those involved in coronary artery disease (CAD). Our aim was to identify whether specific serum miRNAs present in the circulating lipoproteins (Lp) are associated with stable or vulnerable CAD patients. A cardiovascular disease-focused screening array was used to assess miRNAs distribution in sera collected from 95 CAD patients: 30 with stable angina (SA), 39 with unstable angina (UA), 26 at one month after myocardial infarction (MI) and 16 healthy control subjects. We found that miR-486, miR-92a and miR-122 presented the highest expression in CAD sera. These miRNA together with miR-125a, miR-146a and miR-33a were further individually analyzed by TaqMan assays. The results were consistent with PCR-array screening data that all of these miRNAs were significantly increased in CAD patients compared to controls. Using a binary logistic regression model, we established that miR-486 and miR-92a in association with some high-density lipoprotein (HDL) components can designate vulnerable CAD patients. Further, all classes of Lp were isolated from sera by density gradient ultracentrifugation. Analysis of the selected miRNAs in each Lp class showed that they were associated mainly with HDL, miR-486 and miR-92a having the highest levels. In UA and MI patients, miR-486 prevailed in HDL2, while miR-92a prevailed in HDL3, and their levels discriminate between stable and vulnerable CAD patients. We identified two circulating miRNAs that in association with some lipid metabolism biomarkers can be used as an additional tool to designate vulnerable CAD patients. PMID:26485305

  8. Case-control study on peroxisome proliferator-activated receptor gamma polymorphism and interaction with HDL on essential hypertension in Chinese Han

    PubMed Central

    Wang, Gang; Xu, Ping; Feng, Wei; Jiang, Xianyan; Zhang, Tao; Li, Jian

    2015-01-01

    Objective(s): To investigate the association of single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors gamma (PPARG) with essential hypertension (EH) and additional role of gene– high-density lipoprotein cholesterol (HDL) interaction. Materials and Methods: A total of 1640 patients with EH (806 males, 834 females), with a mean age of 52.5±12.6 years, were selected, including 816 EH patients and 824 controls, who were enrolled from the community. Three SNPs were selected for genotyping in the case–control study: rs10865710, rs709158, rs1805192. Logistic regression model was used to examine the interaction between SNP and HDL on EH, odds ratio (OR) and 95% confidence interval (95% CI) were also calculated. Results: All genotypes were distributed according to Hardy–Weinberg equilibrium in controls. Logistic regression analysis showed an association between genotypes of variants in rs1805192 and decreased EH risk, EH risk was significantly lower in carriers of Ala allele of the rs1805192 polymorphism than those with Pro/Pro (Pro/Ala+ Ala/Ala versus Pro/Pro, adjusted OR (95% CI) =0.65 (0.53–0.83), after covariate adjustment. In addition, the Ala allele of the rs1805192 polymorphism was also associated with diastolic blood pressure (DBP), but not systolic blood pressure (SBP), we also found, by interaction analysis, combined effect of rs1805192 and HDL on EH risk after covariate adjustment. Conclusion: Our results support an important association between rs1805192 minor allele (Ala allele) of PPARG and lower EH risk, the interaction analysis showed a combined effect of Ala- HDL on lower EH risk. PMID:26877853

  9. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

    PubMed

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D; Granados-Silvestre, Ma de Angeles; Montufar-Robles, Isela; Tito-Alvarez, Ana M; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Lisker, Ruben; Moises, Regina S; Menjivar, Marta; Salzano, Francisco M; Knowler, William C; Bortolini, M Cátira; Hayden, Michael R; Baier, Leslie J; Canizales-Quinteros, Samuel

    2010-07-15

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations. PMID:20418488

  10. The Ala54Thr Polymorphism of the Fatty Acid Binding Protein 2 Gene Modulates HDL Cholesterol in Mexican-Americans with Type 2 Diabetes

    PubMed Central

    Salto, Lorena M.; Bu, Liming; Beeson, W. Lawrence; Firek, Anthony; Cordero-MacIntyre, Zaida; De Leon, Marino

    2015-01-01

    The alanine to threonine amino acid substitution at codon 54 (Ala54Thr) of the intestinal fatty acid binding protein (FABP2) has been associated with elevated levels of insulin and blood glucose as well as with dyslipidemia. The aim of this study was to characterize the effect of this FABP2 polymorphism in Mexican-Americans with type 2 diabetes (T2D) in the context of a three-month intervention to determine if the polymorphism differentially modulates selected clinical outcomes. For this study, we genotyped 43 participant samples and performed post-hoc outcome analysis of the profile changes in fasting blood glucose, HbA1c, insulin, lipid panel and body composition, stratified by the Ala54Thr polymorphism. Our results show that the Thr54 allele carriers (those who were heterozygous or homozygous for the threonine-encoding allele) had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes (those who were homozygous for the alanine-encoding allele). Both groups made clinically important improvements in lipid profiles and glycemic control as a response to the intervention. Whereas the Ala54 homozygotes decreased HDL cholesterol in the context of an overall total cholesterol decrease, Thr54 allele carriers increased HDL cholesterol as part of an overall total cholesterol decrease. We conclude that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes. PMID:26703680

  11. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

    PubMed Central

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K.; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D.; de Ángeles Granados-Silvestre, Ma; Montufar-Robles, Isela; Tito-Alvarez, Ana M.; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P.; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L.; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Lisker, Ruben; Moises, Regina S.; Menjivar, Marta; Salzano, Francisco M.; Knowler, William C.; Bortolini, M. Cátira; Hayden, Michael R.; Baier, Leslie J.; Canizales-Quinteros, Samuel

    2010-01-01

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 × 10−11) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations. PMID:20418488

  12. Gene Therapy Targeting LDL Cholesterol but not HDL Cholesterol Induces Regression of Advanced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia

    PubMed Central

    Li, Rongying; Chao, Hsu; Ko, Kerry W.S.; Cormier, Shelley; Dieker, Carrie; Nour, Elie A.; Wang, Shining; Chan, Lawrence; Oka, Kazuhiro

    2012-01-01

    A reduction in low density lipoprotein (LDL) cholesterol or an increase in high density lipoprotein (HDL) cholesterol can reduce the risk of development of atherosclerosis through overlapping or independent mechanisms. However, the clinical outcome of combined therapy remains in debate. In this study, we first characterized effects of various constructs of helper-dependent adenoviral vector (HDAd) expressing apolipoprotein E3 or LDL receptor (LDLR) in vivo on plasma cholesterol levels. Using this information, we designed experiments and compared the effects of long-term (28 weeks) LDL cholesterol lowering or raising HDL cholesterol, or a combination of both on advanced atherosclerosis in Ldlr−/− mice, a mouse model of familial hypercholesterolemia. Our major findings are: (i) various factors influence in vivo functional activity, which appear to be context dependent; (ii) apolipoprotein AI (APOAI) gene transfer, which raises HDL cholesterol, retards progression of atherosclerosis but does not induce regression; (iii) LDLR or LDLR and APOAI combination gene therapy induces lesion regression; however, LDLR gene transfer accounts for the majority of the effects of combined gene therapy; (iv) LDLR gene therapy reduces interleukin-7, which is a master regulator of T-cell homeostasis, but APOAI gene therapy does not. These results indicate that LDL cholesterol lowering is effective and sufficient in protection against atherosclerosis and induction of regression of pre-existing atherosclerosis. PMID:23106034

  13. The Type 2 Diabetes and Insulin-Resistance Locus Near IRS1 Is A Determinant of HDL Cholesterol and Triglycerides Levels Among Diabetic Subjects

    PubMed Central

    Sharma, Rajani; Prudente, Sabrina; Andreozzi, Francesco; Powers, Christine; Mannino, Gaia; Bacci, Simonetta; Gervino, Ernest V.; Hauser, Thomas H.; Succurro, Elena; Mercuri, Luana; Goheen, Elizabeth H.; Shah, Hetal; Trischitta, Vincenzo; Sesti, Giorgio; Doria, Alessandro

    2011-01-01

    OBJECTIVE SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. METHODS SNP rs2943641 was typed in 2,133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. RESULTS HDL cholesterol decreased by 1 mg/dl (p=0.0045) and serum triglycerides increased by 6 mg/dl (p=0.018) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR=1.00, 95% CI 0.88–1.13). CONCLUSIONS The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population. PMID:21353221

  14. ABCB1, ABCC1, and LRP gene expressions are altered by LDL, HDL, and serum deprivation in a human doxorubicin-resistant uterine sarcoma cell line.

    PubMed

    Celestino, Andréa Turbuck; Levy, Débora; Maria Ruiz, Jorge Luis; Bydlowski, Sérgio Paulo

    2015-02-20

    Multidrug resistance (MDR) is the major cause of cancer treatment failure. The ATP-binding cassette-B1 (ABCB1) transporter, also known as MDR1 or P-glycoprotein, is thought to promote the efflux of drugs from cells. MDR is also associated with the multidrug resistance-associated protein 1 (ABCC1) and the lung resistance-related protein (LRP), a human major vault protein. Moreover, MDR has a complex relationship with lipids. The ABCB1 has been reported to modulate cellular cholesterol homeostasis. Conversely, cholesterol has been reported to modulate multidrug transporters. However, results reported to date are contradictory and confusing. The aim of this study was to investigate whether LDL, HDL, and serum deprivation could influence ABCB1, ABCC1, and LRP expression in a human doxorubicin-resistant uterine sarcoma cell line. ABCB1 and ABCC1 expression increased after 24 h of serum deprivation, and expression returned to basal levels after 72 h. LDL, depending on concentration, increased ABCB1, ABCC1, and LRP expression. ABCB1 expression increased at low HDL, and decreased at high HDL concentrations. We demonstrated that serum deprivation and lipoproteins, particularly LDL, modulated ABCB1 expression and, to a lesser extent, ABCC1 expression. This finding may link the phenomena of drug transport, cholesterol metabolism and cancer. PMID:25603048

  15. Relationship of Lifestyle Medical Advice and Non-HDL Cholesterol Control of a Nationally Representative US Sample with Hypercholesterolemia by Race/Ethnicity

    PubMed Central

    Vaccaro, Joan Anne; Huffman, Fatma G.

    2012-01-01

    Objective. The main purpose of this study was to evaluate the associations of lifestyle medical advice and non-HDL cholesterol control of a nationally representative US sample of adults with hypercholesterolemia by race/ethnicity. Methods. Data were collected by appending sociodemographic, anthropometric, and laboratory data from two cycles of the National Health and Nutrition Survey (2007-2008 and 2009-2010). This study acquired data from male and female adults aged ≥ 20 years (N = 11,577), classified as either Mexican American (MA), (n = 2173), other Hispanic (OH) (n = 1298), Black non-Hispanic (BNH) (n = 2349), or White non-Hispanic (WNH) (n = 5737). Results. Minorities were more likely to report having received dietary, weight management, and exercise recommendations by healthcare professionals than WNH, adjusting for confounders. Approximately 80% of those receiving medical advice followed the recommendation, regardless of race/ethnicity. Of those who received medical advice, reporting “currently controlling or losing weight” was associated with lower non-HDL cholesterol. BNH who reported “currently controlling or losing weight” had higher non-HDL cholesterol than WNH who reported following the advice. Conclusion. The results suggest that current methods of communicating lifestyle advice may not be adequate across race/ethnicity and that a change in perspective and delivery of medical recommendations for persons with hypercholesterolemia is needed. PMID:23119150

  16. Presence of unsedimented precipitate in visually non-turbid supernates in the heparin-manganese method for HDL-cholesterol quantitation.

    PubMed

    Kiss, Z; Simo, I E; Ooi, T C; Meuffels, M; Hindmarsh, J T

    1986-08-01

    An inherent problem with the heparin-manganese precipitation procedure for high density lipoprotein-cholesterol (HDL-C) quantitation is the inability to sediment all the precipitated lipoproteins, especially in hypertriglyceridemic samples. This results in overestimation of HDL-C. Thus ultrafiltration has been recommended for turbid supernates. We have investigated 47 non-turbid supernates for possible presence of unsedimented precipitate. Optical turbidity in these samples was found to correlate with the serum triglyceride level. With ultrafiltration of the supernates, there was a significant decrease in cholesterol, optical turbidity and apoprotein A-I. The percent change in turbidity correlated with the percent change in cholesterol. There was also correlation between percent change in cholesterol and the prefiltration supernate turbidity. These results indicate that visually clear supernates may show optical turbidity; the turbidity is likely due to triglyceride-rich particles, which contain cholesterol; the fall in cholesterol with ultrafiltration is due to removal of these floating particles and some adsorbance of HDL particles to the filters. PMID:3093118

  17. HDL cholesterol levels and weight are the main determinants of subclinical atherosclerosis in the young with type 1 diabetes and suitable glycaemic control.

    PubMed

    Pinto, Camila S; Lana, Janaina M; Gabbay, Monica A L; de Sa, Joao R; Dib, Sergio A

    2014-03-01

    The aim of this study was to evaluate subclinical atherosclerosis and related factors in young type 1 diabetes (T1D) patients and healthy peers. Carotid intima-media thickness (cIMT) and anthropometric/laboratorial data were obtained for 83 T1D patients (mean age 19.5 ± 4.0 years, disease duration 9.8 ± 4.8 years) and for 36 matched healthy subjects. Considering all the participants as one group, male sex (p = 0.008), weight (p = 0.016) and T1D (p < 0.001) were positively associated with a higher cIMT. High-density lipoprotein (HDL) (p = 0.036) was negatively associated with cIMT in T1D. In the male T1D patients, HDL ≤47.5 mg/dL had a sensitivity of 87.5% and specificity of 57% (p = 0.035) in detecting those belonging to a higher cIMT tercile. In conclusion, weight and T1D were associated with increased cIMT. HDL levels ≤47.5 mg/dL were related to a higher cIMT in male T1D patients. PMID:24553254

  18. Crystal Structure of C-terminal Truncated Apolipoprotein A-I Reveals the Assembly of High Density Lipoprotein (HDL) by Dimerization*

    PubMed Central

    Mei, Xiaohu; Atkinson, David

    2011-01-01

    Apolipoprotein A-I (apoA-I) plays important structural and functional roles in plasma high density lipoprotein (HDL) that is responsible for reverse cholesterol transport. However, a molecular understanding of HDL assembly and function remains enigmatic. The 2.2-Å crystal structure of Δ(185–243)apoA-I reported here shows that it forms a half-circle dimer. The backbone of the dimer consists of two elongated antiparallel proline-kinked helices (five AB tandem repeats). The N-terminal domain of each molecule forms a four-helix bundle with the helical C-terminal region of the symmetry-related partner. The central region forms a flexible domain with two antiparallel helices connecting the bundles at each end. The two-domain dimer structure based on helical repeats suggests the role of apoA-I in the formation of discoidal HDL particles. Furthermore, the structure suggests the possible interaction with lecithin-cholesterol acyltransferase and may shed light on the molecular details of the effect of the Milano, Paris, and Fin mutations. PMID:21914797

  19. Cardiovascular protection by apoE and apoE-HDL linked to suppression of ECM gene expression and arterial stiffening

    PubMed Central

    Kothapalli, Devashish; Liu, Shu-Lin; Bae, Yong Ho; Monslow, James; Xu, Tina; Hawthorne, Elizabeth A.; Byfield, Fitzroy J.; Castagnino, Paola; Rao, Shilpa; Rader, Daniel J.; Puré, Ellen; Phillips, Michael C.; Lund-Katz, Sissel; Janmey, Paul A.; Assoian, Richard K.

    2012-01-01

    Summary Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE-containing HDL maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop which increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE-null mice, this stiffening can be reduced by administration of the lysyl oxidase inhibitor, BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics, and this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol. PMID:23103162

  20. THE CONSUMPTION OF RED PUPUNHA (BACTRIS GASIPAES KUNTH) INCREASES HDL CHOLESTEROL AND REDUCES WEIGHT GAIN OF LACTATING AND POST-LACTATING WISTAR RATS

    PubMed Central

    Carvalho, R. Piccolotto; Lemos, J.R. Gonzaga; de Aquino Sales, R. Souza; Martins, M. Gassen; Nascimento, C.H.; Bayona, M.; Marcon, J.L.; Monteiro, J. Barros

    2014-01-01

    Introduction The lactating and post-lactating periods are marked by large metabolic change. Production of milk is 60% lipid dependent. We reported in a recent scientific meeting that Red pupunha palm tree fruit increases HDL cholesterol in lactating rats. This study evaluated if consumption of Red Pupunha by adult female rats has a beneficial impact on the lipid metabolism of lacting and post-lacting adult rats. Objective Evaluate if consumption of red pupunha has a beneficial effect in the lipid metabolism of lacting and post-lacting adult Wistar rats. Research Methods Four groups including two for control; (1) control adult lactating rats, (2) control adults post-lactating rats; and two experimental groups; (3) pupunha adults lactating rats and (4) pupunha adult post-lactating rats were evaluated and compared regarding: weight gain, food consumption, plasma total protein, glucose, total lipid, triglycerides, total cholesterol and HDL-cholesterol levels. The mean difference and its 95% confidence intervals were used for group comparisons. Group comparisons were evaluated by using analysis of variance (one-way ANOVA). The statistical significance of the pairwise differences among groups was assessed by using the two-sided Tukey test. Results There were no important differences in food consumption, plasma glucose, total lipids and triglycerides among groups. The red pupunha lactating group gain less weight showing lower body mass index (BMI) than controls (p < 0.05). Total cholesterol was lower in red pupunha lactating than in controls but not in the red pupunha post-lactating group as compared to controls. Triglycerides were lower in the post-lactating red pupunha group as compared to the control group (p = 0.039) but not for the lactating groups. Red pupunha lactating and post-lactating groups had higher HDL-cholesterol than their corresponding control groups (p ≤ 0.01). Conclusion Original findings include the beneficial effect of red pupunha in post

  1. Loading anticancer drugs into HDL as well as LDL has little affect on properties of complexes and enhances cytotoxicity to human carcinoma cells.

    PubMed

    Kader, Abdul; Pater, Alan

    2002-04-23

    Low density lipoprotein (LDL) has been found to represent a suitable carrier for cytotoxic drugs that may target them to cancer. This study investigated whether very low density lipoprotein (VLDL), LDL and high density lipoprotein (HDL) can be used to effectively incorporate four cytotoxic drugs, 5-fluorouracil (5-FU), 5-iododeoxyuridine (IUdR), doxorubicin (Dox) and vindesine; characterized the complexes; and examined the effect of incorporation on drug cytotoxicity against HeLa cervical and MCF-7 breast carcinoma cells. Significant drug loading was achieved into all three classes of lipoproteins, consistent with the sizes and hydrophobicity of the drugs. The relative loading efficiency was found to be vindesine>IUdR>Dox>5-FU for all three classes of lipoproteins. As shown by electron microscopy (EM), drug incorporation did not affect the size or morphology of the lipoproteins. Differential scanning calorimetry (DSC) showed that drug loading did not significantly change the thermal transition temperature of core lipids in the lipoproteins. The transition enthalpy was changed only for LDL-Dox and LDL-vindesine. The drugs remained stable in the lipoproteins as determined by high performance liquid chromatography (HPLC). EM, DSC and HPLC data suggest that drugs were incorporated into lipoproteins without disrupting their integrity and drugs remained in their stable forms inside lipoproteins. Compared with free drugs in cytotoxicity assays, the IC(50) values of LDL- and HDL-drug complexes were significantly lower (2.4- to 8.6-fold for LDL complexes and 2.5- to 23-fold for HDL complexes). All free or lipoprotein-bound drug formulations were comparably more cytotoxic against MCF-7 than HeLa cells. Upregulating the lipoprotein receptors enhanced, and downregulating them inhibited, the cytotoxicity, indicating the mechanistic involvement of lipoprotein receptor pathways. Complexes of all four drugs with VLDL, in contrast to LDL and HDL, had the same cytotoxicity as the

  2. Anticoagulant activity of tissue factor pathway inhibitor in human plasma is preferentially associated with dense subspecies of LDL and HDL and with Lp(a).

    PubMed

    Lesnik, P; Vonica, A; Guérin, M; Moreau, M; Chapman, M J

    1993-07-01

    Human plasma contains a multivalent, Kunitz-type proteinase inhibitor termed tissue factor pathway inhibitor (TFPI), which specifically inhibits the action of the factor VII(a)-tissue factor complex in coagulation. In the present study, we examined the distribution and anticoagulant activity of TFPI among plasma lipoprotein subspecies separated by isopycnic density gradient ultracentrifugation; this procedure permitted the simultaneous fractionation of the major lipoprotein classes (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], high-density lipoprotein [HDL] 2 and 3, and very-high-density lipoprotein [VHDL]). Studies of eight normolipidemic subjects revealed two major lipoprotein carriers of TFPI activity: dense LDL subspecies (d = 1.039 to 1.063 g/mL) and both dense HDL particles and VHDL (d = 1.133 to 1.190 g/mL), representing 33.8% and 35.9%, respectively, of the total lipoprotein-associated TFPI activity in plasma. TFPI activity was also associated with lipoprotein(a) (Lp[a]), whose density distribution (d = 1.044 to 1.100 g/mL) overlapped that of LDL and HDL2; such association was related to Lp(a)'s particle size and phenotype. VLDL, IDL, and LDL1 through LDL3 (d = 1.019 to 1.039 g/mL), HDL2 (d = 1.063 to 1.100 g/mL), and light subfractions of HDL3 (d = 1.100 to 1.167 g/mL) conveyed only 1.8%, 10%, and 18.5%, respectively, of lipoprotein-associated TFPI activity. Such anticoagulant activity was dependent on the presence of TFPI protein. The dense subspecies of HDL3 (d = 1.133 to 1.167 g/mL) with which TFPI was preferentially associated were small, displayed a cholesteryl ester to protein ratio of approximately 0.2, and were deficient in phospholipid (13.6% to 18.3%). HDL subspecies of d = 1.110 to 1.167 g/mL mainly contained the higher relative molecular mass form of TFPI of 41 kD (a form that is known to be covalently associated with apolipoprotein [apo] A-II) and minor bands of the 35- and 52-k

  3. Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of preβ-1 HDL in vitro

    SciTech Connect

    Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques; Zhu, Xuewei

    2015-07-24

    Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These

  4. Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake.

    PubMed

    Pollard, Ricquita D; Blesso, Christopher N; Zabalawi, Manal; Fulp, Brian; Gerelus, Mark; Zhu, Xuewei; Lyons, Erica W; Nuradin, Nebil; Francone, Omar L; Li, Xiang-An; Sahoo, Daisy; Thomas, Michael J; Sorci-Thomas, Mary G

    2015-06-19

    Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr(-/-), PCPE2(-/-) mice, which had elevated HDL levels compared with LDLr(-/-) mice with similar LDL concentrations. We found that LDLr(-/-), PCPE2(-/-) mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr(-/-) mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr(-/-), PCPE2(-/-) mice was similar to that reported for LDLr(-/-), apoA-I(-/-) mice, which lack any apoA-I/HDL. Furthermore, LDLr(-/-), PCPE2(-/-) mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr(-/-) mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system. PMID:25947382

  5. ALTA: An automated lag-time apparatus for studying the nucleation of supercooled liquids

    NASA Astrophysics Data System (ADS)

    Barlow, Thomas W.; Haymet, A. D. J.

    1995-04-01

    An automated apparatus for studying repeatedly the nucleation of a sample of supercooled liquid is designed and constructed. Many of the ideas are developed from an apparatus of M. Baldwin and B. Vonnegut [Rev. Sci. Instrum. 53, 1911 (1982)]. After preparation of a nonequilibrium state, ALTA measures repeatedly the ``lag time'' or ``induction'' time before nucleation and growth of the equilibrium state. A single sample is used in all experiments. The operation of the apparatus is demonstrated by generating a time series of lag times for the nucleation of supercooled water on (insoluble) AgI crystals at the temperature 269.2 K. The same sample is repeatedly frozen and thawed over 350 times. An average lag time τ can be measured precisely and reproducibly. However, nucleation of this sample is shown to be a stochastic process obeying ``first-order'' kinetics. Improved methods for analyzing time series of nucleation data are presented and tested.

  6. Geologic and hydrologic data collected at test hole NC-8, Vega Alta, Puerto Rico

    USGS Publications Warehouse

    Rodríguez-Martínez, Jesús; Scharlach, Richard A.

    1994-01-01

    Test hole NC-8 was drilled in the municipality of Vega Alta as part of a study of the aquifers in the Northern Coastal Province of Puerto Rico. Test hole NC-8 was drilled to a depth of 1,736 feet below land surface. Geologic and hydrologic data collected during drilling included continuous core, water- quality samples, water-level measurements, and estimates of aquifer yields from the water-bearing zones. Test hole NC-8 penetrated five geologic formations of middle Tertiary age: the Aymamon Limestone, the Los Puertos Formation, the Cibao Formation, the Lares Limestone, and the San Sebastian Formation. Test hole NC-8 penetrated a water-table aquifer and seven artesian aquifers.

  7. [The prevention of caries in Alta Val di Cecina--Volterra: a longitudinal study].

    PubMed

    Benetti, G L; Dini, M; Rossetti, L

    1993-01-01

    The authors present the results of three years' activity relating to "caries' prevention" in comparison with data concerning the research of previous five years. The average and standard deviations of DMFT values with regard to the permanent teeth and dmft concerning the deciduous ones, obtained from the dental visit of 222 children attending the 1st and the 3rd class of the primary school and 1st class of the secondary school, has demonstrated a statistically significant reduction of caries, compared with data concerning 749 pupils of the same standards in the period from 1984 to 1988. This fact confirms that the programme defined by U.S.L. n. 15 "Alta Val di Cecina", including sanitary education for children of primary school with their parents and teachers, besides dental examinations to the filter classes, is a valid instrument to obtain the reduction of carious' pathology in evolutive age. PMID:8265461

  8. Performance of the ALTA 4700 with variable print strategy and optimized resist process

    NASA Astrophysics Data System (ADS)

    Allen, Paul C.; Hamaker, H. Christopher; Morgante, Cris; Berwick, Andrew; White, Michael

    2005-11-01

    The ALTA 4700 incorporates new optical subsystems to improve pattern quality performance and has added the capability to do variable multipass printing. The optical system changes are the addition of a 0.9-NA reduction lens and a new AOD subsystem to reduce beam placement and intensity errors. Variable multipass printing allows two-, four- or eight-pass printing, thereby enabling the user to optimize the pattern quality/throughput tradeoff. Local CDU 3σ performance for one pattern is reduced from 8.2 to 5.1 to 3.4 nm as the number of passes is increased from two to four to eight. Reduction of CDU performance is more pattern dependent going from four to eight passes than going from two to four passes. Pattern write times scale roughly linearly with the number of passes. Local pattern loading effects can limit global CDU performance. These effects can be reduced by optimizing resist selection and develop processes.

  9. Alta Scuola Politecnica: An Ongoing Experiment in the Multidisciplinary Education of Top Students towards Innovation in Engineering, Architecture and Design

    ERIC Educational Resources Information Center

    Benedetto, S.; Bernelli Zazzera, F.; Bertola, P.; Cantamessa, M.; Ceri, S.; Ranci, C.; Spaziante, A.; Zanino, R.

    2010-01-01

    Politecnico di Milano and Politecnico di Torino, the top technical universities in Italy, united their efforts in 2004 by launching a unique excellence programme called Alta Scuola Politecnica (ASP). The ASP programme is devoted to 150 students, selected each year from among the top 5-10% of those enrolled in the Engineering, Architecture and…

  10. SLCO1B1 c.388A>G Polymorphism Is Associated with HDL-C Levels in Response to Atorvastatin in Chilean Individuals

    PubMed Central

    Prado, Yalena; Saavedra, Nicolás; Zambrano, Tomás; Lagos, Jenny; Rosales, Alexy; Salazar, Luis A.

    2015-01-01

    The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects. PMID:26334272

  11. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion

    PubMed Central

    Martin, Gregory G.; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Storey, Stephen M.; Howles, Philip N.; Kier, Ann B.

    2014-01-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  12. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion.

    PubMed

    Martin, Gregory G; Atshaves, Barbara P; Landrock, Kerstin K; Landrock, Danilo; Storey, Stephen M; Howles, Philip N; Kier, Ann B; Schroeder, Friedhelm

    2014-12-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  13. High intake of fatty fish, but not of lean fish, affects serum concentrations of TAG and HDL-cholesterol in healthy, normal-weight adults: a randomised trial.

    PubMed

    Hagen, Ingrid V; Helland, Anita; Bratlie, Marianne; Brokstad, Karl A; Rosenlund, Grethe; Sveier, Harald; Mellgren, Gunnar; Gudbrandsen, Oddrun A

    2016-08-01

    The aim of the present study was to examine whether high intake of lean or fatty fish (cod and farmed salmon, respectively) by healthy, normal-weight adults would affect risk factors of type 2 diabetes and CVD when compared with lean meat (chicken). More knowledge is needed concerning the potential health effects of high fish intake (>300 g/week) in normal-weight adults. In this randomised clinical trial, thirty-eight young, healthy, normal-weight participants consumed 750 g/week of lean or fatty fish or lean meat (as control) for 4 weeks at dinner according to provided recipes to ensure similar ways of preparations and choices of side dishes between the groups. Energy and macronutrient intakes at baseline and end point were similar in all groups, and there were no changes in energy and macronutrient intakes within any of the groups during the course of the study. High intake of fatty fish, but not lean fish, significantly reduced TAG and increased HDL-cholesterol concentrations in fasting serum when compared with lean meat intake. When compared with lean fish intake, fatty fish intake increased serum HDL-cholesterol. No differences were observed between lean fish, fatty fish and lean meat groups regarding fasting and postprandial glucose regulation. These findings suggest that high intake of fatty fish, but not of lean fish, could beneficially affect serum concentrations of TAG and HDL-cholesterol, which are CVD risk factors, in healthy, normal-weight adults, when compared with high intake of lean meat. PMID:27363518

  14. SLCO1B1 c.388A>G Polymorphism Is Associated with HDL-C Levels in Response to Atorvastatin in Chilean Individuals.

    PubMed

    Prado, Yalena; Saavedra, Nicolás; Zambrano, Tomás; Lagos, Jenny; Rosales, Alexy; Salazar, Luis A

    2015-01-01

    The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects. PMID:26334272

  15. Contributions of a disulfide bond and a reduced cysteine side chain to the intrinsic activity of the HDL receptor SR-BI

    PubMed Central

    Yu, Miao; Lau, Thomas Y.; Carr, Steven A.; Krieger, Monty

    2013-01-01

    The high density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), binds HDL and mediates selective cholesteryl ester uptake. SR-BI's structure and mechanism are poorly understood. We used mass spectrometry to assign the two disulfide bonds in SR-BI that connect cysteines within the conserved Cys321-Pro322-Cys323 (CPC) motif and connect Cys280 to Cys334. We used site-specific mutagenesis to evaluate the contributions of the CPC motif and the side chain of extracellular Cys384 to HDL binding and lipid uptake. The effects of CPC mutations on activity were context dependent. Full wild-type (WT) activity required Pro322 and Cys323 only when Cys321 was present. Reduced intrinsic activities were observed for CXC and CPX, but not XXC, XPX or XXX mutants (X≠WT residue). Apparently, a free thiol side chain at position 321 that cannot form an intra-CPC disulfide bond with Cys323 is deleterious, perhaps because of aberrant disulfide bond formation. Pro322 may stabilize an otherwise strained CPC disulfide bond, thus supporting WT activity, but this disulfide bond is not absolutely required for activity. C384X (X=S,T,L,Y,G,A) mutants exhibited altered activities that varied with the side chain's size: larger side chains phenocopied WT SR-BI treated with its thiosemicarbazone inhibitor BLT-1 (increased binding, decreased uptake); smaller side chains produced almost inverse effects (increased uptake:binding ratio). C384X mutants were BLT-1 resistant, supporting the proposal that Cys384's thiol interacts with BLT-1. We discuss the implications of our findings on the functions of the extracellular loop cysteines in SR-BI and compare our results to those presented by other laboratories. PMID:23205738

  16. Natural and induced endoreic hydrological conditions in the Alta Murgia karstic region (Apulia, Southern Italy)

    NASA Astrophysics Data System (ADS)

    Canora, F.; Fidelibus, M. D.; Spilotro, G.

    2009-04-01

    A study aimed at understanding the hydrological processes in karst areas related to the presence of natural and artificial endoreic basins and their modification due to land use change, as well as the influence of above factors on the infiltration rate has been carried out in the Alta Murgia region (Apulia, Southern Italy). The region is a Cretaceous limestone plateau of the Apulian platform, characterized by a mature karstic landscape: due to its elevation, climatic conditions and lithology, the plateau constitutes the main recharge area of the Murgia aquifer. The typical karst topography is essentially related to the subterranean drainage (sinkholes, caves, conduit): surface and subsurface karst geomorphology is strictly interrelated with hydrology. The morphological features of the karstic plateau are defined by the high density of surface karstic forms (mainly dolines), the presence of exposed karst and karren fields, as well as by the extensive outcrop of fractured rocks. Karst surface shows, on the bottom of the morpho-structural depressions called "lame", natural distribution of modest deposits of "terra rossa" and regolith. The "lame" work as streams during and after intense rainfall events, often outlining a primordial ephemeral hydrographical network, frequently convergent towards dolines, poljes or endoreic basins. Alta Murgia shows many natural endoreic basin conditions in a quite flat morphology. In this environment, when intense rainfall events cover large areas and rainfall intensity exceeds the infiltration capacity of soils and/or sinkholes, significant runoff amounts are produced and stored in the basins causing floods. Most of the natural endoreic basins are small and independent: while the majority of them continue functioning as endoreic even in presence of extreme events of high return time, others (quasi-endoreic), under the same circumstances can start contributing to other basins, due to exceeding their water storage capability. This way

  17. Different Functional and Structural Characteristics between ApoA-I and ApoA-4 in Lipid-Free and Reconstituted HDL State: ApoA-4 Showed Less Anti-Atherogenic Activity.

    PubMed

    Yoo, Jeong-Ah; Lee, Eun-Young; Park, Ji Yoon; Lee, Seung-Taek; Ham, Sihyun; Cho, Kyung-Hyun

    2015-06-01

    Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To compare anti-atherogenic properties between apoA-I and apoA-4, we characterized both proteins in lipid-free and lipid-bound state. In lipid-free state, apoA4 showed two distinct bands, around 78 and 67 Å on native gel electrophoresis, while apoA-I showed scattered band pattern less than 71 Å. In reconstituted HDL (rHDL) state, apoA-4 showed three major bands around 101 Å and 113 Å, while apoA-I-rHDL showed almost single band around 98 Å size. Lipid-free apoA-I showed 2.9-fold higher phospholipid binding ability than apoA-4. In lipid-free state, BS3-crosslinking revealed that apoA-4 showed less multimerization tendency upto dimer, while apoA-I showed pentamerization. In rHDL state (95:1), apoA-4 was existed as dimer as like as apoA-I. With higher phospholipid content (255:1), five apoA-I and three apoA-4 were required to the bigger rHDL formation. Regardless of particle size, apoA-I-rHDL showed superior LCAT activation ability than apoA-4-rHDL. Uptake of acetylated LDL was inhibited by apoA-I in both lipid-free and lipid-bound state, while apoA-4 inhibited it only lipid-free state. ApoA-4 showed less anti-atherogenic activity with more sensitivity to glycation. In conclusion, apoA-4 showed inferior physiological functions in lipid-bound state, compared with those of apoA-I, to induce more pro-atherosclerotic properties. PMID:25997739

  18. Different Functional and Structural Characteristics between ApoA-I and ApoA-4 in Lipid-Free and Reconstituted HDL State: ApoA-4 Showed Less Anti-Atherogenic Activity

    PubMed Central

    Yoo, Jeong-Ah; Lee, Eun-Young; Park, Ji Yoon; Lee, Seung-Taek; Ham, Sihyun; Cho, Kyung-Hyun

    2015-01-01

    Apolipoprotein A-I and A-IV are protein constituents of high-density lipoproteins although their functional difference in lipoprotein metabolism is still unclear. To compare anti-atherogenic properties between apoA-I and apoA-4, we characterized both proteins in lipid-free and lipid-bound state. In lipid-free state, apoA4 showed two distinct bands, around 78 and 67 Å on native gel electrophoresis, while apoA-I showed scattered band pattern less than 71 Å. In reconstituted HDL (rHDL) state, apoA-4 showed three major bands around 101 Å and 113 Å, while apoA-I-rHDL showed almost single band around 98 Å size. Lipid-free apoA-I showed 2.9-fold higher phospholipid binding ability than apoA-4. In lipid-free state, BS3-crosslinking revealed that apoA-4 showed less multimerization tendency upto dimer, while apoA-I showed pentamerization. In rHDL state (95:1), apoA-4 was existed as dimer as like as apoA-I. With higher phospholipid content (255:1), five apoA-I and three apoA-4 were required to the bigger rHDL formation. Regardless of particle size, apoA-I-rHDL showed superior LCAT activation ability than apoA-4-rHDL. Uptake of acetylated LDL was inhibited by apoA-I in both lipid-free and lipid-bound state, while apoA-4 inhibited it only lipid-free state. ApoA-4 showed less anti-atherogenic activity with more sensitivity to glycation. In conclusion, apoA-4 showed inferior physiological functions in lipid-bound state, compared with those of apoA-I, to induce more pro-atherosclerotic properties. PMID:25997739

  19. Probing the C-terminal domain of lipid-free apoA-I demonstrates the vital role of the H10B sequence repeat in HDL formation.

    PubMed

    Mei, Xiaohu; Liu, Mingjing; Herscovitz, Haya; Atkinson, David

    2016-08-01

    apoA-I plays important structural and functional roles in reverse cholesterol transport. We have described the molecular structure of the N-terminal domain, Δ(185-243) by X-ray crystallography. To understand the role of the C-terminal domain, constructs with sequential elongation of Δ(185-243), by increments of 11-residue sequence repeats were studied and compared with Δ(185-243) and WT apoA-I. Constructs up to residue 230 showed progressively decreased percent α-helix with similar numbers of helical residues, similar detergent and lipid binding affinity, and exposed hydrophobic surface. These observations suggest that the C-terminal domain is unstructured with the exception of the last 11-residue repeat (H10B). Similar monomer-dimer equilibrium suggests that the H10B region is responsible for nonspecific aggregation. Cholesterol efflux progressively increased with elongation up to ∼60% of full-length apoA-I in the absence of the H10B. In summary, the sequential repeats in the C-terminal domain are probably unstructured with the exception of H10B. This segment appears to be responsible for initiation of lipid binding and aggregation, as well as cholesterol efflux, and thus plays a vital role during HDL formation. Based on these observations and the Δ(185-243) crystal structure, we propose a lipid-free apoA-I structural model in solution and update the mechanism of HDL biogenesis. PMID:27317763

  20. [Fenofibrate: hypolipaemic activity and safety in long-term treatment. Effects on HDL, LDL, VLDL and apoprotein B in short-term treatment (author's transl)].

    PubMed

    Rouffy, J; Sauvanet, J P; Chanu, B; Bakir, R; Goy-Loeper, J; Saya, C; Pinaroli, F

    1980-12-22

    In a study started in 1973 and still in progress (1100 patient-years so far) fenofibrate in daily doses of 200-400 mg consistently proved effective, without any loss of activity with time. The drug lowered serum total cholesterol levels by 17-27% in type IIa, IIb and III primary hyperlipoproteinaemia (HLP) and serum triglyceride levels by 35-51% in type IIb and III HLP and by 46-54% in type IV HLP. Clinically and biologically fenofibrate was always well tolerated, even after 5 years' treatment. Side-effects were uncommon (4%) and mild, and they obliged to discontinue treatment in only 1% of the patients. Abnormal manifestations encountered during therapy appeared to be fortuitous. The effects of the drug on cardiovascular morbidity and mortality could not be determined from this trial. In a short-term study involving 21 patients with type IIa and IIb primary HLP, fenofibrate in doses of 200-400 mg/day produced a significant decrease in total cholesterol, LDL-cholesterol and apoprotein B. It is also reduced triglycerides and VLDL-triglycerides in type IIb HLP. The increase in HDL-cholesterol observed under fenofibrate was significant in type IIa HLP but not in type IIb HLP. In both types, there was a significant rise in HDL: LDL + VLDL ratio. PMID:7208341

  1. Low Maternal Vitamin B12 Status Is Associated with Lower Cord Blood HDL Cholesterol in White Caucasians Living in the UK

    PubMed Central

    Adaikalakoteswari, Antonysunil; Vatish, Manu; Lawson, Alexander; Wood, Catherine; Sivakumar, Kavitha; McTernan, Philip G.; Webster, Craig; Anderson, Neil; Yajnik, Chittaranjan S.; Tripathi, Gyanendra; Saravanan, Ponnusamy

    2015-01-01

    Background and Aims: Studies in South Asian population show that low maternal vitamin B12 associates with insulin resistance and small for gestational age in the offspring. Low vitamin B12 status is attributed to vegetarianism in these populations. It is not known whether low B12 status is associated with metabolic risk of the offspring in whites, where the childhood metabolic disorders are increasing rapidly. Here, we studied whether maternal B12 levels associate with metabolic risk of the offspring at birth. Methods: This is a cross-sectional study of 91 mother-infant pairs (n = 182), of white Caucasian origin living in the UK. Blood samples were collected from white pregnant women at delivery and their newborns (cord blood). Serum vitamin B12, folate, homocysteine as well as the relevant metabolic risk factors were measured. Results: The prevalence of low serum vitamin B12 (<191 ng/L) and folate (<4.6 μg/L) were 40% and 11%, respectively. Maternal B12 was inversely associated with offspring’s Homeostasis Model Assessment 2-Insulin Resistance (HOMA-IR), triglycerides, homocysteine and positively with HDL-cholesterol after adjusting for age and BMI. In regression analysis, after adjusting for likely confounders, maternal B12 is independently associated with neonatal HDL-cholesterol and homocysteine but not triglycerides or HOMA-IR. Conclusions: Our study shows that low B12 status is common in white women and is independently associated with adverse cord blood cholesterol. PMID:25849948

  2. Reference Ranges for Serum Total Cholesterol, HDL-Cholesterol, LDL-Cholesterol, and VLDL-Cholesterol and Triglycerides in Healthy Iranian Ahvaz Population.

    PubMed

    Jalali, Mohammad Taha; Honomaror, Abdolhosain Mosavi; Rekabi, Abdolkarim; Latifi, Mahmod

    2013-07-01

    Cardiovascular diseases (CVD) are recognized as major mortality causes and imposes tremendously heavy socio-economic burden worldwide. A vast variety of risk factors have been introduced in the literature known to enhance the incidence of CVD, such as hyperlipidemia. Therefore in order to make an accurate clinical decision it is essential to have appropriate reference ranges for lipids and lipoprotein particles in a particular population. Healthy female (n = 601) and male (n = 617) cases were randomly selected according to certain exclusion criteria from individuals visiting the major University hospital clinics situated in different part of Ahvaz city, Iran, from June 2010 to December 2010. Fasting blood samples (10 ml) were collected and analyzed for total cholesterol, total triglyceride and HDL-C employing enzymatic assays of CHOD-PAP, GPO-PAP and homogenous methods respectively. The samples were obtained such to include the ethnic populations of Persian, Arab. Lore leaving in this city. The data were analyzed statistically by SPSS-18 software. The obtained results were analyzed then age ethnic-wise and reference ranges (mean ± 1SD) were calculated. Remarkable differences between the obtained results for our population with other nations were seen. Also ethnic difference for HDL-C among our cases was noted. The observed significant differences among different nations and ethnicities emphasizes the need for nation-specific, local reference ranges for lipids and lipoproteins particles, to be established. PMID:24426224

  3. Elevated HDL is a risk factor for recurrent coronary events in a subgroup of non-diabetic postinfarction patients with hypercholesterolemia and inflammation.

    PubMed

    Corsetti, James P; Zareba, Wojciech; Moss, Arthur J; Rainwater, David L; Sparks, Charles E

    2006-07-01

    Recent studies demonstrate important roles for inflammation in development of atherosclerosis with current attention focusing on interactions of inflammation with traditional lipoprotein risk factors. Since the nature of such relationships is largely unknown, we sought to investigate interactions of inflammation with hyperlipidemia in generating cardiovascular risk in a way that would allow recognition of such interactions whether anticipated or not. Thus, we searched for subgroups at high risk for recurrent coronary events in 767 non-diabetic postinfarction patients using an exploratory three-dimensional graphical screening technique with previously established factor analysis-derived inflammatory and lipoprotein-related factors. Results indicated a high-risk patient subgroup defined by factor interaction that was best characterized clinically by high levels of C-reactive protein (CRP) and total cholesterol. Kaplan-Meier and Cox multivariate analysis confirmed high-risk. Additionally, within-subgroup risk related to metabolic, inflammatory, and thrombogenic blood markers was assessed using Cox analysis with results showing only elevated HDL as a significant and independent predictor of risk with hazard ratio, 2.24 (95% CI; 1.12, 4.49; p = 0.023). We conclude that in non-diabetic postinfarction patients, elevated HDL is predictive of risk of recurrent coronary events within a subgroup of patients characterized by simultaneous elevations in serum CRP and total cholesterol. PMID:16242700

  4. Variations in HDL-carried miR-223 and miR-135a concentrations after consumption of dietary trans fat are associated with changes in blood lipid and inflammatory markers in healthy men - an exploratory study.

    PubMed

    Desgagné, Véronique; Guay, Simon-Pierre; Guérin, Renée; Corbin, François; Couture, Patrick; Lamarche, Benoit; Bouchard, Luigi

    2016-06-01

    A high consumption of trans fatty acids (TFAs) is associated with an increased risk of cardiovascular diseases (CVDs). High-density lipoproteins (HDLs) have many cardioprotective properties and transport functional microRNAs (miRNAs) to recipient cells. We hypothesized that dietary TFAs modify the HDL-carried miRNA profile, therefore modulating its cardioprotective properties. We assessed whether consumption of dietary TFAs modifies HDL-carried miR-223-3p and miR-135a-3p concentration and the inter-relationship between diet-induced changes in HDL-carried miRNA concentration and CVD risk markers. In a double blind, randomized, crossover, controlled study, 9 men were fed each of 3 experimental isoenergetic diets: 1) High in industrial TFA (iTFA; 3.7% energy); 2) High in TFA from ruminants (rTFA; 3.7% energy); 3) Low in TFA (control; 0.8% energy) for 4 weeks each. HDLs were isolated by ultracentrifugation and miRNAs were quantified by RT-qPCR. Variations in HDL-miR-223-3p concentration were negatively correlated with variations in HDL-cholesterol after the iTFA diet (rs = 0.82; P = 0.007), and positively correlated with variations in C-reactive protein concentration after the rTFA diet (rs = 0.75; P = 0.020). Variations in HDL-miR-135a-3p concentration were positively correlated with variations in total triglyceride (TG) concentration following the iTFA diet (rs = -0.82; P = 0.007), and with variations in low-density lipoprotein (LDL)-TG concentration following the rTFA diet (rs = 0.83; P = 0.005), compared to the control diet. However, the consumption of dietary TFAs has no significant unidirectional impact on HDL-carried miR-223-3p and miR-135a-3p concentrations. Our results suggest that the variability in the HDL-carried miRNAs response to TFA intake, by being associated with variations in CVD risk factors, might reflect physiological changes in HDL functions. PMID:27099924

  5. Purification and neuroprotective effects of polysaccharides from Opuntia Milpa Alta in cultured cortical neurons.

    PubMed

    Chen, Yang; Zhao, Bo; Huang, Xiaolan; Zhan, Jinjin; Zhao, Yan; Zhou, Mei; Guo, Lianjun

    2011-11-01

    Opuntia is a traditional plant from China with medicinal applications. In this experiment, polysaccharides from Opuntia Milpa Alta (MAPs) were analyzed using gas chromatograph-mass spectrometer (GC-MS) method and result showed that MAPs contained mannose (6.37%), rhamnose (14.94%), xylose (1.99%), arabinose (24.07%), galactose (38.25%), ribose (2.63%) and glucose (11.48%). The neuroprotective effects of MAPs were evaluated at the mechanistic level in vitro models of cerebral ischemic injury. In vitro oxygen/glucose deprivation (OGD) model, MAPs (0.5 μg/ml, 5 μg/ml, 50 μg/ml) effectively increased cell viability by methyl thiazolyl tetrazolium (MTT) assay, inhibited cell cytotoxicity by lactate dehydrogenase (LDH) assay, reduced neuronal cell death, suppressed the production of intracellular reactive oxygen species (ROS), decreased of intracellular free Ca(2+) concentrations ([Ca(2+)](i)), and reduced extracellular glutamate level. Therefore, MAPs might prevent intracellular calcium overload and decreased glutamate excitotoxicity, both of which can cause neuronal injury and death in vitro models of cerebral ischemic injury. PMID:21763720

  6. Small mammals from the Chelemhá Cloud Forest Reserve, Alta Verapaz, Guatemala

    USGS Publications Warehouse

    Matson, Jason O.; Ordóñez-Garza, Nicté; Woodman, Neal; Bulmer, Walter; Eckerlin, Ralph P.; Hanson, J. Delton

    2014-01-01

    We surveyed the small mammals of remnant mixed hardwood-coniferous cloud forest at elevations ranging from 2,100–2,300 m in the Chelemhá Cloud Forest Reserve, Alta Verapaz, Guatemala. Removal-trapping using a combination of live traps, snap traps, and pitfall traps for 6 days in January 2007 resulted in 175 captures of 15 species of marsupials, shrews, and rodents. This diversity of small mammals is the highest that we have recorded from a single locality of the 10 visited during eight field seasons in the highlands of Guatemala. Based on captures, the most abundant species in the community of small mammals is Peromyscus grandis (n = 50), followed by Handleyomys rhabdops (n = 27), Heteromys desmarestianus(n = 18), Reithrodontomys mexicanus (n = 17), Handleyomys saturatior (n = 16), Sorex veraepacis (n = 15), and Scotinomys teguina (n = 13). The remaining eight species were represented by one to five individuals.

  7. apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Vezeridis, Alexander; Dafnis, Ioannis; Chroni, Angeliki; Kardassis, Dimitris; Zannis, Vassilis I

    2014-07-01

    The K146N/R147W substitutions in apoE3 were described in patients with a dominant form of type III hyperlipoproteinemia. The effects of these mutations on the in vivo functions of apoE were studied by adenovirus-mediated gene transfer in different mouse models. Expression of the apoE3[K146N/R147W] mutant in apoE-deficient (apoE(-/-)) or apoA-I-deficient (apoA-I(-/-))×apoE(-/-) mice exacerbated the hypercholesterolemia and increased plasma apoE and triglyceride levels. In apoE(-/-) mice, the apoE3[K146N/R147W] mutant displaced apoA-I from the VLDL/LDL/HDL region and caused the accumulation of discoidal apoE-containing HDL. The WT apoE3 cleared the cholesterol of apoE(-/-) mice without induction of hypertriglyceridemia and promoted formation of spherical HDL. A unique property of the truncated apoE3[K146N/R147W]202 mutant, compared with similarly truncated apoE forms, is that it did not correct the hypercholesterolemia. The contribution of LPL and LCAT in the induction of the dyslipidemia was studied. Treatment of apoE(-/-) mice with apoE3[K146N/R147W] and LPL corrected the hypertriglyceridemia, but did not prevent the formation of discoidal HDL. Treatment with LCAT corrected hypertriglyceridemia and generated spherical HDL. The combined data indicate that the K146N/R147W substitutions convert the full-length and the truncated apoE3[K146N/R147W] mutant into a dominant negative ligand that prevents receptor-mediated remnant clearance, exacerbates the dyslipidemia, and inhibits the biogenesis of HDL. PMID:24776540

  8. Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

    PubMed Central

    2013-01-01

    Background In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body weight. We used a linear regression model. Selected genes corresponded to folate metabolism, vitamins B-12, A, and E, and cholesterol pathways or lipid metabolism. Methods Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI-TOF mass spectrometry platform. The adjusted phenotype, y, was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7. Results Statistically significant SNP (where P values were adjusted for false discovery rate) included: CETP (rs7499892 and rs5882); SLC46A1 (rs37514694; rs739439); SLC19A1 (rs3788199); CD36 (rs3211956); BCMO1 (rs6564851), APOA5 (rs662799), and ABCA1 (rs4149267). Many prior association trends of the SNP with HDL were replicated in our cross-validation study. Significantly, the association of SNP in folate transporters (SLC46A1 rs37514694 and rs739439; SLC19A1 rs3788199) with HDL was identified in our study. Conclusions Given recent literature on the role of niacin in the biogenesis of HDL, focus on status and metabolism of B-vitamins and metabolites of eccentric cleavage of β-carotene with lipid metabolism is exciting for future study. PMID:23656756

  9. Environmental exposure to mercury in the urban area of Alta Floresta

    SciTech Connect

    Hacon, S.; Rochedo, E.R.R.; Calysto, R.R.; Lacerda, L.D.

    1994-12-31

    Mercury has been released into the Amazonia ecosystem as a result of gold mining activities over the past 15 years. Metallic mercury is used to amalgamate gold particulate. During the amalgamation process, a significant amount of metallic Hg finds its way into the aquatic and terrestrial systems. About 65 to 83% of the total mercury emission by gold mining activities enters directly into the atmosphere. The inorganic Hg is then methylated by microbiota and the organic Hg is bioaccumulated within the aquatic food chain, from which humans are a top predator. Alta Floresta is the most important gold trading center in Amazonia. The urban population is exposed to a high concentration of Hg in the atmosphere, ranging from 23 to 5,788 ng/m{sup 3}. Also the mercury levels in fishes eaten locally are high, mainly in fish from Teles Pires river. Nine from the eleven species most consumed by the urban population are carnivorous, and constitute about 98% of all fish eaten locally. The highest Hg levels are found in Brachyplastistoma sp. (Piraiba), ranging from 1.7 to 3.0 {mu}g/g (w.w.) and Paulicea Luetkin (Jau), ranging from 0.4 to 2.7 {mu}g/g (w. w.) assuming an average fish consumption rate of 31 grams per day, an weighted average of Hg fish concentration of 1.2 {mu}g/g, an average body weight for adults of 60 kg and an average exposure duration of 8 years, the estimated incorporation 0.63 pg of Hg per kg of body weight would imply that attention should be given to the critical groups such as children and woman in the child-bearing age, since fetus are more sensitive to mercury than adults.

  10. Wet Conditions during the Last Glaciation in the Chihuahuan Desert, Alta Babicora Basin, Mexico

    NASA Astrophysics Data System (ADS)

    Metcalfe, Sarah; Say, Alison; Black, Stuart; McCulloch, Robert; O'Hara, Sarah

    2002-01-01

    A 467-cm core (B94/3) from the Alta Babicora basin in the Chihuahuan Desert, northern Mexico (29°N, 108°W), documents lake-level and climate changes over the past ca. 65,000 yr. Chronological control is provided by four accelerator mass spectrometry 14C dates and five U-series dates on diatom silica. The core has been analyzed for magnetic susceptibility, loss-on-ignition, carbonate content, sediment chemistry and mineralogy, and pollen and diatom composition. The basin was occupied by a deep freshwater lake throughout the late Pleistocene which, based on shoreline evidence, was at least 19 m deeper than today. The lake shallowed after ca. 57,000 yr B.P. High variability typified the period between 54,600 and 38,000 yr B.P., probably with periodic desiccation and deflation. A deep-water lake was reestablished after 38,000 yr B.P. and persisted until ca. 29,000 yr B.P. Shallowing occurred through the last glacial maximum, although the lake was still deeper than at present. The Pleistocene-Holocene transition was marked by a distinctive change in the diatom flora. There is no diatom record for much of the Holocene, but other proxies indicate generally dry, stable catchment conditions. The Babicora record is more akin to those from the southwest United States than it is to Central America and northern South America. Wet conditions in the late Pleistocene are attributed to winter rainfall from midlatitudes in contrast to the modern, tropical, summer rainfall regime.

  11. Adaptation of rainfed agriculture to climatic variability in the Mixteca Alta Region of Oaxaca, Mexico

    NASA Astrophysics Data System (ADS)

    Rogé, P.; Friedman, A. R.; Astier, M.; Altieri, M.

    2015-12-01

    The traditional management systems of the Mixteca Alta Region of Oaxaca, Mexico offer historical lessons about resilience to climatic variability. We interviewed small farmers to inquire about the dynamics of abandonment and persistence of a traditional management systems. We interpret farmers' narratives from a perspective of general agroecological resilience. In addition, we facilitated workshops in small farmers described their adaptation to past climate challenges and identified 14 indicators that they subsequently used to evaluate the condition of their agroecosystems. The most recent years presented increasingly extreme climatic and socioeconomic hardships: increased temperatures, delayed rainy seasons, reduced capacity of soils to retain soil moisture, changing cultural norms, and reduced rural labor. Farmers reported that their cropping systems were changing for multiple reasons: more drought, later rainfall onset, decreased rural labor, and introduced labor-saving technologies. Examination of climate data found that farmers' climate narratives were largely consistent with the observational record. There have been increases in temperature and rainfall intensity, and an increase in rainfall seasonality that may be perceived as later rainfall onset. Farmers ranked landscape-scale indicators as more marginal than farmer management or soil quality indicators. From this analysis, farmers proposed strategies to improve the ability of their agroecosystems to cope with climatic variability. Notably, they recognized that social organizing and education are required for landscape-level indicators to be improved. Transformative change is required to develop novel cropping systems and complementary activities to agriculture that will allow for farming to be sustained in the face of these challenges. Climate change adaptation by small farmers involves much more than just a set of farming practices, but also community action to tackle collective problems.

  12. Extra-hepatic metabolism of 7-ketocholesterol occurs by esterification to fatty acids via cPLA2α and SOAT1 followed by selective efflux to HDL

    PubMed Central

    Lee, Jung Wha; Huang, Jiahn-Dar; Rodriguez, Ignacio R.

    2015-01-01

    Accumulation of 7-ketocholesterol (7KCh) in tissues has been previously associated with various chronic aging diseases. Orally ingested 7KCh is readily metabolized by the liver and does not pose a toxicity threat. However, 7KCh formed in situ, usually associated with lipoprotein deposits, can adversely affect surrounding tissues by causing inflammation and cytotoxicity. In this study we have investigated various mechanisms for extra-hepatic metabolism of 7KCh (e.g. hydroxylation, sulfation) and found only esterification to fatty acids. The esterification of 7KCh to fatty acids involves the combined action of cytosolic phospholipase A2 alpha (cPLA2α) and sterol O-acyltransferase (SOAT1). Inhibition of either one of these enzymes ablates 7KCh-fatty acid ester (7KFAE) formation. The 7KFAEs are not toxic and do not induce inflammatory responses. However, they can be unstable and re-release 7KCh. The higher the degree of unsaturation, the more unstable the 7KFAE (e.g. 18:0>18:1>18:2>18:3>>20:4). Biochemical inhibition and siRNA knockdown of SOAT1 and cPLA2α ablated the 7KFAE synthesis in cultured ARPE19 cells, but had little effect on the 7KCh-induced inflammatory response. Overexpression of SOAT1 reduced the 7KCh-induced inflammatory response and provided some protection from cell death. This effect is likely due to the increased conversion of 7KCh to 7KFAEs, which reduced the intracellular 7KCh levels. Addition of HDL selectively increased the efflux of 7KFAEs and enhanced the effect of SOAT1 overexpression. Our data suggests an additional function for HDL in aiding extra-hepatic tissues to eliminate 7KCh by returning 7KFAEs to the liver for bile acid formation. PMID:25617738

  13. Biotechnical performance of vegetal species in slope conservation in Cruz Alta, RS, Brazil

    NASA Astrophysics Data System (ADS)

    Prates Bisso, Fernando; Durlo, Miguel

    2016-04-01

    The aim of this work was the evaluation of biotechnical performance of different vegetal species growth in the slope soil conservation and reforest (revegetate). The study was performed with oxic soil talus, in Cruz Alta - RS, Brazil (28°23'28.14" S and 53°22'25.61" W) and began in January 2010. The sow treatments employed were: 1) cuttings of Ateleia glazioveana; 2) cuttings of Pyrostegia venusta; 3) seedlings of Baccharis trimera; 4) Seedlings of Cynodom plectostachyus; 5) blank, no sow. The evaluated parameters were: plant survival ratio (%); vegetal covered percentage; natural revegetation (plants/m2); the slope soil level reduction (cm); and water and soil runoff. C. plectostachyus and B. trimera afforded considerable higher survival (92% and 78.5%, respectively) and vegetation cover of the slope (99.6% and 82.9%) than other species. The natural revegetation showed an increase according to the ground above the slope (146.9 plants/m2) compared with the slope ramp (22.1 plants/m2). Moreover, C. plectostachyus, A. glazioveana, P. venusta, B. trimera and C. plectostachyus treatments showed 34.9, 28.6, 23.0 and 21.0 plants/m2, respectively, when compared with the blank (2.5 plants/m2) in the slope ramp region. Furthermore, the sow line regions gave 91.2 plants/m2) whereas the regions among lines afforded 8.6 plants/m2. Additionally, C. plectostachyus showed soil average drawdown profile decrease of 12.8 mm after 360 days after planting, and A. glazioveana reached 16.9 mm after 540 days according to the blank (34.0 mm). Considering the period of 60 to 360 days, it was observed significant differences in the soil loss estimative and reduction percentage compared to blank were: Blank 127.9 ton/ha/year; A. glazioveana, 117.9 ton/ha/year (-8%); P. venusta, 116.3 ton/ha/year (-9%); B. trimera, 106.7 ton/ha/year (-17%); and C. plectostachyus, 73.2 ton/ha/year (-43%). Thus, C. plectostachyus showed the best survival and vegetal coverage producing significant reduction of

  14. Alta FT-150: The Thruster for LISA Pathfinder and LISA/NGO Missions

    NASA Astrophysics Data System (ADS)

    Paita, L.; Cesari, U.; Nania, F.; Priami, L.; Rossodivita, A.; Giusti, N.; Andrenucci, M.; Estublier, D.

    2013-01-01

    FT-150© FEEP thruster has successfully completed an endurance test at Alta's Micropropulsion laboratory. The updated thruster design dramatically enhances performance with respect to previous FEEP devices and marks a major step forward in the LISA Pathfinder and NGO programmes as well as space propulsion capability in general. The test campaign took place in two parts. Firstly, the new design was tested to validate that the new configuration was compliant with the requirements of the Lisa Pathfinder mission with particular emphasis on the achievement of required total impulse and minimum and maximum thrust levels.The second part of the campaign was aimed at testing a worst-case DFACS profile of the LISA Pathfinder mission using the Elegant Breadboard Power Control Unit (EBB PCU) commanding at 10 Hz and acquiring at 50 Hz. Both purposes of the campaign were successfully met. A total impulse of more than 1080 Ns and a firing time of more than 3500 hours were achieved. No degradation of efficiency and performance was recorded over the entire test. During the first part, more then 600 Ns of total impulse and about 2000 hours of firing time were achieved. Different thrust profiles were commanded with an average thrust of about 87 μN. The minimum and maximum thrust were 1 μN and 150 μN respectively. Short periods at zero N (i.e. thruster switched-off) were also commanded. The measured mass efficiency and specific impulse, 60% and 8000 s respectively, demonstrated that the current design of the thruster is fully compatible with the much larger impulse requirement of LISA mission. The simulation of the worst-case DFACS cycles at 10 Hz was also successfully performed. Three different DFACS cycles representative of the worst cases were performed. These cycles highlighted one of the main advantages of this technology: the controllability and response time that can be verified immediately with electrical feedback parameters like total voltage and beam current (data

  15. Three-dimensional modeling of oxidized-LDL accumulation and HDL mass transport in a coronary artery: a proof-of-concept study for predicting the region of atherosclerotic plaque development.

    PubMed

    Sakellarios, Antonis I; Siogkas, Panagiotis K; Athanasiou, Lambros S; Exarchos, Themis P; Papafaklis, Michail I; Bourantas, Christos V; Naka, Katerina K; Michalis, Lampros K; Filipovic, Nenad; Parodi, Oberdan; Fotiadis, Dimitrios I

    2013-01-01

    Low density lipoprotein (LDL) has a significant role on the atherosclerotic plaque development, while the concentration of high density lipoproteins (HDL) is considered to play an atheroprotective role according to several biochemical mechanisms. In this work, it is the first time that both LDL and HDL concentrations are taken into account in order to predict the regions prone for plaque development. Our modeling approach is based on the use of a realistic three-dimensional reconstructed pig coronary artery in two time points. Biochemical data measured in the pig were also included in order to develop a more customized model. We modeled coronary blood flow by solving the Navier-Stokes equations in the arterial lumen and plasma filtration in the arterial wall using Darcy's Law. HDL transport was modeled only in the arterial lumen using the convection-diffusion equation, while LDL transport was modeled both in the lumen and the arterial wall. An additional novelty of this work is that we model the oxidation of LDL taking into account the atheroprotective role of HDL. The results of our model were in good agreement with histological findings demonstrating that increased oxidized LDL is found near regions of advanced plaques, while non-oxidized LDL is found in regions of early plaque types. PMID:24110737

  16. High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN): an interventional study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat ...

  17. Pollination biology of Eulophia alta (Orchidaceae) in Amazonia: effects of pollinator composition on reproductive success in different populations

    PubMed Central

    Jürgens, Andreas; Bosch, Simone R.; Webber, Antonio C.; Witt, Taina; Frame, Dawn; Gottsberger, Gerhard

    2009-01-01

    Background and Aims Spatial variation in pollinator composition and abundance is a well-recognized phenomenon. However, a weakness of many studies claiming specificity of plant–pollinator interactions is that they are often restricted to a single locality. The aim of the present study was to investigate pollinator effectiveness of the different flower visitors to the terrestrial orchid Eulophia alta at three different localities and to analyse whether differences in pollinator abundance and composition effect this plant's reproductive success. Methods Natural pollination was observed in vivo, and manipulative experiments were used to study the pollination biology and breeding system of E. alta at three sites near Manaus, Brazil. To gain a better understanding of the underlying mechanisms of pollinator attraction, nectar composition and secretion patterns were also studied, floral scent composition was analysed and a bioassay was conducted. Key Results Flower visitors, pollinator composition, pollinia transfer efficiency of particular pollinator species and natural fruit set differed among the investigated populations of E. alta. Flowers were self-compatible, partially autogamous and effectively pollinated by five bee species (four Centris species and Xylocopa muscaria). Visiting insects appeared to imbibe small amounts of hexose-rich nectar. Nectar sugar content was highest on the third day after flower opening. Floral fragrance analyses revealed 42 compounds, of which monoterpenes and benzenoids predominated. A bioassay using floral parts revealed that only floral tissue from the labellum chamber and labellum tip was attractive to flower visitors. Conclusions The data suggest that observed differences in reproductive success in the three populations cannot be explained by absolute abundance of pollinators alone. Due to behavioural patterns such as disturbance of effective pollinators on flowers by male Centris varia bees defending territory, pollinia transfer

  18. A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio.

    PubMed

    Guevara-Cruz, Martha; Torres, Nimbe; Tovar, Armando R; Tejero, M Elizabeth; Castellanos-Jankiewicz, Ashley; del Bosque-Plata, Laura

    2014-01-01

    Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention. PMID:25238846

  19. [The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy].

    PubMed

    Dobiásová, M; Frohlich, J

    2000-03-01

    The new atherogenic plasma index (AIP) is a logarithmic transformation of the ratio of the molar triglyceride (TG) concentration and high density lipoprotein cholesterol (HDL-C). AIP correlates closely with the size of LDL particles (r = 0.8) and esterification rate of plasma cholesterol devoid of apo B lipoproteins (FERHDL), r = 0.9 which are considered at present the most sensitive indicators of the atherogenic plasma profile. AIP was recommended by the authors, based on analysis of results of 11 previous studies (1156 subjects) where FERHDL and plasma lipid parameters were investigated in different groups of people who differed as to the atherogenic risk. The AIP index was moreover used for evaluation of a clinical study comprising 609 patients with hyperlipidaemia, who were treated for three months with ciprofibrate (Lipanor). The mean AIP values of non-risk groups (plasma from umbilical blood, children, healthy women etc.) equalled zero or were lower, while with an increasing atherogenic risk (men, women after the menopause) AIP reached positive values, incl. high positive values in risk groups (plasma of diabetic subjects, patients with HLP, patients with positive angiography, myocardial infarction etc.). In all groups women had lower AIP values as compared with males. In patients after Lipanor therapy the AIP declined (from 0.58 +/- 0.17 to 0.33_0.18 in men, from 0.50 +/- 0.18 to 0.21 +/- 0.19 in women). If we consider AIP values from negative ones to 0.15 as "safe" from the aspect of atherogenicity, before Lipanor treatment these "safe" levels were recorded in 1.5% men and in 5.2% women and after treatment in 32% men and 48% women. The results indicate, that AIP which reflects the plasma lipoprotein profile quantifies the relations between TG and HDL-C and thus can be an objective indicator of the atherogenic risk and effectiveness of treatment and it is useful because it can be assessed in any surgery. PMID:11048517

  20. Coffee intake can promote activity of antioxidant enzymes with increasing MDA level and decreasing HDL-cholesterol in physically trained rats

    PubMed Central

    Choi, Eun-Young; Jang, Jin-Young

    2010-01-01

    This study investigated the effect of coffee intake and exercise on the antioxidative activity and plasma cholesterol profile of physically trained rats while they were exercising. Forty eight rats were under either the control diet with water (C) or control diet with coffee (CF) and at the same time they were given physical training for 4 weeks. In terms of physical training, the rats were exercised on a treadmill for 30 minutes everyday. At the end of 4 weeks, animals in each dietary group were subdivided into 3 groups: before-exercise (BE); during-exercise (DE); after-exercise (AE). Animals in the DE group were exercised on a treadmill for one hour, immediately before being sacrificed. Animals in the AE group were allowed to take a rest for one hour after exercise. TG levels were significantly high in coffee intake group than in control group. Also TG level of AE group was significantly higher than that of BE group. Exercise and coffee-exercise interaction effects were significant in total cholesterol (P = 0.0004, 0.0170). The AE of coffee intake group showed highest total cholesterol levels. HDL-cholesterol was significantly lower in coffee intake group than in control group. Coffee, exercise, and coffee-exercise interaction effects were significant in SOD (P = 0.0001, 0.0001, and 0.0001). The AE and BE of coffee intake group showed higher SOD levels than the other four groups. Catalase activities were significantly higher in coffee intake group than control group. No significant main effect was found in GSH/GSSG. Coffee, exercise, and coffee-exercise interaction effects were significant in MDA levels (P = 0.0464, 0.0016, and 0.0353). The DE and AE of coffee intake group and the DE of control group showed higher MDA levels than the BE of control group. Therefore, coffee intake can promote activities of antioxidant enzyme but it also increases MDA and decreases HDL-cholesterol in physically trained rats. PMID:20827343

  1. Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss[S

    PubMed Central

    Kuo, Kung-Kai; Wu, Bin-Nan; Liu, Chung-Pin; Yang, Tzu-Yang; Kao, Li-Pin; Wu, Jiunn-Ren; Lai, Wen-Ter; Chen, Ing-Jun

    2015-01-01

    The phosphodiesterase inhibitor (PDEI)/eNOS enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects with simvastatin and explored hormone-sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, and 5 mg/kg/day) and simvastatin (5 mg/kg/day) were administered in C57BL/6J male mice fed a high-fat diet (HFD) by gavage for 8 weeks. KMUP-1 inhibited HFD-induced plasma/liver TG, total cholesterol, and LDL; increased HDL/3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)/Rho kinase II (ROCK II)/PPARγ/ABCA1; and decreased liver and body weight. KMUP-1 HCl in drinking water (2.5 mg/200 ml tap water) for 1–14 or 8–14 weeks decreased HFD-induced liver and body weight and scavenger receptor class B type I expression and increased protein kinase A (PKA)/PKG/LDLRs/HSL expression and immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10−7∼10−5 M) reversed HMGR expression by feedback regulation, colocalized expression of ABCA1/apolipoprotein A-I/LXRα/PPARγ, and reduced exogenous geranylgeranyl pyrophosphate/farnesyl pyrophosphate (FPP)-induced RhoA/ROCK II expression. A guanosine 3′,5′-cyclic monophosphate (cGMP) antagonist reversed KMUP-1-induced ROCK II reduction, indicating cGMP/eNOS involvement. KMUP-1 inceased PKG and LDLRs surrounded by LDL and restored oxidized LDL-induced PKA expresion. Unlike simvastatin, KMUP-1 could not inhibit 14C mevalonate formation. KMUP-1 could, but simvastatin could not, decrease ROCK II expression by exogenous FPP/CGPP. KMUP-1 improves HDL via PPARγ/LXRα/ABCA1/Apo-I expression and increases LDLRs/PKA/PKG/HSL expression and immunoreactivity, leading to TG hydrolysis to lower hepatic fat and body weight. PMID:26351364

  2. Human influence on late Holocene fluvial landscape and stratigraphy in the Mixteca Alta of Oaxaca, Mexico

    NASA Astrophysics Data System (ADS)

    Leigh, D. S.; Holdridge, G. H.; Kowalewski, S. A.

    2011-12-01

    The Mixteca Alta of south-central Mexico (state of Oaxaca) is a high-elevation plateau where population and agricultural steadily grew over the past 3000 years, but with a few significant episodes of population decline. Currently, the landscape is highly eroded and gullied in response to widespread land abandonment and diminished population attributed to the Spanish conquest during the 1500s and 1600s. Abandonment apparently resulted in neglect of prehistoric cross-drainage retaining walls, known as lama-bordos, which had been constructed throughout agricultural watersheds for millennia to retain runoff and sediment. Our research seeks to establish the earliest ages for construction of lama-bordos, which are buried by more than 10 m of alluvium in some localities; and we hope to determine if the chronology of alluvial sedimentation is related to fluctuations in population density versus climate changes or other drivers. Sampling is focused on relatively small tributary watersheds (<10 km^2) in the valley of Rio Culebra near the town of Coixlahuaca. Our general hypothesis is counter to Malthusian theory in that we posit land degradation and erosion was punctuated by episodes of population decline when there were insufficient people to maintain the lama-bordo infrastructure. Methods involve: (1) detailed stratigraphic and pedogenic description and sampling of several outcrops; (2) radiocarbon and luminescence dating of stratigraphic sections; (3) geochemical and lithological tracing of sedimentary beds to discriminate time periods of gully erosion; (4) relating the alluvial chronology to archaeological surveys that have established the occupation history of the region. Results indicate that upland gully erosion had occurred prior to widespread human occupation of the area, because >4000 cal yr BP cut-and-fill stratigraphic units commonly contain detritus from upland subsoil and underlying bedrock. We provide numerous radiocarbon dates for the oldest lama-bordos, and

  3. Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration.

    PubMed

    Lanktree, Matthew B; Elbers, Clara C; Li, Yun; Zhang, Guosheng; Duan, Qing; Karczewski, Konrad J; Guo, Yiran; Tragante, Vinicius; North, Kari E; Cushman, Mary; Asselbergs, Folkert W; Wilson, James G; Lange, Leslie A; Drenos, Fotios; Reiner, Alex P; Barnes, Michael R; Keating, Brendan J

    2015-09-01

    Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10(-5) in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women's Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10(-4). Replication confirmed rs868213, located in a splice donor region of exocyst complex component 3-like 1 (EXOC3L1) as a novel signal for HDL (additive allelic effect β = 0.02; P = 1.4 × 10(-8); meta-analyses of discovery and replication). EXOC3L1 is strongly expressed in vascular endothelium and forms part of the exocyst complex, a key facilitator of the trafficking of lipid receptors. Increasing sample sizes for genetic studies in nonEuropean populations will continue to improve our understanding of lipid metabolism. PMID:26199122

  4. A high-carbohydrate diet enhances the adverse effect of the S2 allele of APOC3 SstI polymorphism on the TG/HDL-C ratio only in young Chinese females.

    PubMed

    Song, Yong Yan; Gong, Ren Rong; Zhang, Zhen; Li, Yuan Hao; Xiao, Li Ying; Zhou, Xue Dong; Fang, Ding Zhi

    2011-06-01

    Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the SstI polymorphism in the apoCIII gene (APOC3). Fifty-six healthy university students (27 males and 29 females, 22.89 ± 1.80 years) were given a washout diet of 54% carbohydrate for 7 days, followed by a high-CHO diet of 70% carbohydrate for 6 days without total energy restriction. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apoB100, apoAI, and the APOC3 SstI polymorphism were analyzed. The ratios of serum lipids and apoB100/apoAI were calculated. At baseline, the TG/HDL-C ratio was significantly higher in females, but not in males, with the S2 allele. The differences in the TG/HDL-C ratio between genotypes remained the same after the washout and the high-CHO diet in females. When compared with those before the high-CHO diet, the TC/HDL-C (male S2 carriers: 3.13 ± 1.00 vs 2.36 ± 0.65, P = 0.000; male subjects with the S1S1 genotype: 2.97 ± 0.74 vs 2.09 ± 0.55, P = 0.000; female S2 carriers: 2.68 ± 0.36 vs 2.24 ± 0.37, P = 0.004; female subjects with the S1S1 genotype: 2.69 ± 0.41 vs 2.09 ± 0.31, P = 0.000) and LDL-C/HDL-C (male S2 carriers: 1.44 ± 0.71 vs 1.06 ± 0.26, P = 0.012; male subjects with the S1S1 genotype: 1.35 ± 0.61 vs 1.01 ± 0.29, P = 0.005; female S2 carriers: 1.18 ± 0.33 vs 1.00 ± 0.18, P = 0.049; female subjects with the S1S1 genotype: 1.18 ± 0.35 vs 1.04 ± 0.19, P = 0.026) ratios were significantly decreased after the high-CHO diet regardless of gender and of genotype of the APOC3 SstI polymorphism. However, in female S2 carriers, the TG/HDL-C (1.38 ± 0.46 vs 1.63 ± 0.70, P = 0.039) ratio was significantly increased after the high-CHO diet. In conclusion, the high-CHO diet has

  5. Contact metamorphism surrounding the Alta stock: Finite element model simulation of heat- and {sup 18}O/{sup 16}O mass-transport during prograde metamorphism

    SciTech Connect

    Cook, S.J.; Bowman, J.R.; Forster, C.B.

    1997-01-01

    Results of calcite-dolomite geothermometry and oxygen isotope studies of marbles in the southern portion of the contact aureole surrounding the Alta stock (Utah) provide evidence for extensive hydrothermal metamorphism in this part of the aureole. Simulation of these two independent data sets with two-dimensional, finite element fluid flow and heat transport models constrains the pattern of fluid flow, minimum permeability, and the permeability structure in this part of the aureole. Model results demonstrate that intrusion of the stock into a homogeneous, isotropic permeability medium yields peak metamorphic temperatures significantly lower than those measured in the marbles and significant {sup 18}O depletions both above and below the Alta-Grizzly thrust system. The latter contradicts the observations in the south aureole that {sup 18}O depletions in the marbles are restricted to marbles below the Alta-Grizzly thrust; dolomitic marbles above the thrust retain original sedimentary values up to the intrusive contact. Models with horizontal permeability barriers above the Alta-Grizzly thrust and extending over the top of the Alta stock are capable of reproducing the observed thermal and {delta}{sup 18}O profiles in the southern aureole. The presence of such horizontal barriers reduces the predominantly vertical fluid flow and heat transfer that would occur in a homogeneous and isotropic permeability medium, forcing fluid flow and heat transfer laterally away from the upper flanks of the stock. Such horizontal flow patterns are necessary to produce significant {sup 18}O depletion above the thrust, and to provide the necessary lateral heat transfer to duplicate the observed temperature profile. Best fit model results to the observed thermal and {delta}{sup 18}O profiles provide several new insights into the dynamics of fluid circulation and hydrogeologic characteristics of the southern Alta aureole during prograde metamorphism.

  6. Realistic intake of a flavanol-rich soluble cocoa product increases HDL-cholesterol without inducing anthropometric changes in healthy and moderately hypercholesterolemic subjects.

    PubMed

    Martínez-López, Sara; Sarriá, Beatriz; Sierra-Cinos, José Luis; Goya, Luis; Mateos, Raquel; Bravo, Laura

    2014-02-01

    To assess whether antioxidant, anti-inflammatory and other cardio-protective effects attributed to cocoa are achieved when regularly consuming moderate amounts of a flavanol-rich soluble cocoa product, a non-randomized, controlled, crossover, free-living study was carried out in healthy (n = 24; 25.9 ± 5.6 years) and moderately hypercholesterolemic (200-240 mg dL(-1); n = 20; 30.0 ± 10.3 years) volunteers. Participants consumed two servings per day (7.5 g per serving) of a soluble cocoa product (providing 45.3 mg flavanols per day) in milk, which was compared with consuming only milk during a 4 week period. The effects on systolic and diastolic blood pressure and heart rate were determined, as well as on serum lipid and lipoprotein profiles, interleukins (IL)-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), vascular (VCAM-1) and intercellular cell adhesion molecules (ICAM-1), serum malondialdehyde (MDA), carbonyl groups (CG), ferric reducing/antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and free radical scavenging capacity (ABTS). During the study, the volunteers' diets and physical activity were also evaluated, as well as any changes in weight, skin folds, circumferences and related anthropometric parameters. Cocoa and certain polyphenol-rich fruits and vegetables and their derivatives were restricted. After consuming the cocoa product positive effects were observed such as an increase in serum HDL-C (p < 0.001) and dietary fiber intake (p = 0.050), whereas IL-10 decreased (p = 0.022). Other cardiovascular-related biomarkers and anthropometric parameters were unaffected. We have therefore concluded that regular consumption of this cocoa product in a Spanish-Mediterranean diet may protect against cardiovascular disease in healthy and hypercholesterolemic subjects without producing any weight gain or other anthropometric changes. PMID:24394704

  7. Higher breakfast glycaemic load is associated with increased metabolic syndrome risk, including lower HDL-cholesterol concentrations and increased TAG concentrations, in adolescent girls.

    PubMed

    Nicholl, Analise; du Heaume, Mary; Mori, Trevor A; Beilin, Lawrence J; Oddy, Wendy H; Bremner, Alexandra P; O'Sullivan, Therese A

    2014-12-28

    Almost all previous studies examining the associations between glycaemic load (GL) and metabolic syndrome risk have used a daily GL value. The daily value does not distinguish between peaks of GL intake over the day, which may be more closely associated with the risk of the metabolic syndrome. The aim of the present study was to investigate the cross-sectional associations between daily and mealtime measures of GL and metabolic syndrome risk, including metabolic syndrome components, in adolescents. Adolescents participating in the 14-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study completed 3 d food records and metabolic assessments. Breakfast GL, lunch GL, dinner GL and a score representing meal GL peaks over the day were determined in 516 adolescents. Logistic regression models were used to investigate whether GL variables were independent predictors of the metabolic syndrome in this population-based cohort (3.5% prevalence of the metabolic syndrome). Breakfast GL was found to be predictive of the metabolic syndrome in girls (OR 1.15, 95% CI 1.04, 1.27; P <0.01), but not in boys. Other meal GL values and daily GL were found to be not significant predictors of the metabolic syndrome. When breakfast GL was examined in relation to each of the components of the metabolic syndrome in girls, it was found to be negatively associated with fasting HDL-cholesterol concentrations (P= 0.037; β = - 0.004; 95% CI - 0.008, - 0.002) and positively associated with fasting TAG concentrations (P= 0.008; exp(β) = 1.002; 95% CI 1.001, 1.004). he results of the present study suggest that there may be an association between breakfast composition and metabolic syndrome components in adolescent girls. These findings support further investigation into including lower-GL foods as part of a healthy breakfast in adolescence, particularly for girls. PMID:25327283

  8. Oxygen Isotope and Microtextural Evidence for Fluctuations in Fluid Pressure During Contact Metamorphism, Alta Aureole, Utah, USA

    NASA Astrophysics Data System (ADS)

    Bowman, J. R.; Valley, J. W.; Kita, N.

    2006-12-01

    Thin section-scale textures record a detailed history of prograde and retrograde reactions in the periclase (Per) zone of the Alta Stock aureole. New ion microprobe (SIMS) measurements (10 micron spot, ±0.2 permil, 1sd) of the oxygen isotope compositions of the carbonates preserving these textures provide evidence for at least two cycles of oscillation of fluid pressure (Pfl) between lithostatic (PL) and hydrostatic (Phyd) conditions during evolution of the inner aureole. Infiltration of water-rich fluids during prograde metamorphism converted dolomite (Dol) to Per + calcite (Cal) marble and caused significant 18O/16O depletion in the Dol protolith (Initial δ18O (Cal) > +25 permil), producing Cal with δ18O values of +11 permil. The SIMS values approximate oxygen isotope exchange equilibrium with the Alta stock, indicating that infiltrating fluids were likely magmatic. Exsolution of fluid from the crystallizing magma, coupled with geothermometry from the periclase zone marbles, requires Pfl> PL. Horizontally-oriented expansion cracks filled with brucite (Br) extend from Br pseudomorphs after periclase, and cut retrograde Dol that partially to completely rims the Br pseudomorphs. This earlier retrograde Dol is significantly depleted in 18O/16O relative to matrix Cal, with δ18O of +5 to +7.1 permil. These lower δ18O values indicate that meteoric water infiltrated into the Per marbles during cooling and resulting partial back reaction of Per + Cal to Dol, prior to the hydration of the remaining Per to Br. Influx of meteoric water requires sufficient increase in permeability to permit surface- derived meteoric water to penetrate to the estimated 4.5 km depth of this structural level of the Alta aureole, and suggests a resulting decrease in Pfl to hydrostatic pressure conditions. The horizontally-oriented expansion cracks associated with the Br pseudomorphs indicate that sub-vertical expansion accompanied hydration of Per to Br, requiring that Pfl increase again to

  9. An observatory system for physical and biogeochemical parameters in the northern Adriatic Sea: the "Acqua Alta" oceanographic platform

    NASA Astrophysics Data System (ADS)

    Benetazzo, Alvise; Barbariol, Francesco; Bastianini, Mauro; Bergamasco, Andrea; Bergamasco, Filippo; Bernardi Aubry, Fabrizio; Bertotti, Luciana; Bonaldo, Davide; Cavaleri, Luigi; Carniel, Sandro; Falcieri, Francesco M.; Finotto, Stefania; Lester, Graham; Licer, Matjaz; Malacic, Vlado; Minuzzo, Tiziano; Sclavo, Mauro

    2015-04-01

    The history of the "Acqua Alta" oceanographic platform (http://www.ismar.cnr.it/infrastructures/piattaforma-acqua-alta) started more than forty years ago, shortly after the dramatic surge that affected the city of Venice in late 1966. Since then, benefiting also from recent funding acquired within the National Flagship Project RITMARE, great efforts have been devoted to monitor the oceanographic and atmospheric conditions in the Northern Adriatic Sea (NA), in the proximity of the Venice lagoon. Nowadays the "Acqua Alta", located on a 16 m depth area, represents a success story of the Institute of Marine Sciences (ISMAR) of the Italian National Research Council (CNR), that manages the structure and used collected data to improve the knowledge of the fragile sea environment that surrounds the Venetian littoral. The directional wave observations started in 1979, representing one of the world longest continuous series. On the sea surface, waves are now routinely observed by means of a submerged acoustic-Doppler system that provides burst of directional wave data, including significant wave height, mean wave period and direction of propagation. Currently these wave parameters are integrated with the data collected by a stereo-video system (namely Wave Acquisition Stereo System, WASS) that provides the 3-D profile of the wavy sea surface. WASS data are unleashing a "new view" for ocean waves providing the complete space-time dynamics of wave groups. Moreover, a series of multiparameters probes permits to measure the vertical distribution of sea temperature (at nine depths from the surface to the bottom), salinity (three positions), dissolved oxygen (two positions), and turbidity close to the sea bottom. The collected data are continuously used to track the water masses that enter, leave, and are produced within the NA. A striking example is provided by the temperature and salinity data used to follow the exceptional dense water formation that occurred in this basin

  10. An observatory system for physical and biogeochemical parameters in the northern Adriatic Sea: the "Acqua Alta" oceanographic platform

    NASA Astrophysics Data System (ADS)

    Benetazzo, Alvise; Barbariol, Francesco; Bastianini, Mauro; Bergamasco, Andrea; Bergamasco, Filippo; Bernardi Aubry, Fabrizio; Bertotti, Luciana; Bonaldo, Davide; Cavaleri, Luigi; Carniel, Sandro; Falcieri, Francesco M.; Finotto, Stefania; Lester, Graham; Licer, Matjaz; Malacic, Vlado; Minuzzo, Tiziano; Sclavo, Mauro

    2015-04-01

    The history of the "Acqua Alta" oceanographic platform (http://www.ismar.cnr.it/infrastructures/piattaforma-acqua-alta) started more than forty years ago, shortly after the dramatic surge that affected the city of Venice in late 1966. Since then, benefiting also from recent funding acquired within the National Flagship Project RITMARE, great efforts have been devoted to monitor the oceanographic and atmospheric conditions in the Northern Adriatic Sea (NA), in the proximity of the Venice lagoon. Nowadays the "Acqua Alta", located on a 16 m depth area, represents a success story of the Institute of Marine Sciences (ISMAR) of the Italian National Research Council (CNR), that manages the structure and used collected data to improve the knowledge of the fragile sea environment that surrounds the Venetian littoral. The directional wave observations started in 1979, representing one of the world longest continuous series. On the sea surface, waves are now routinely observed by means of a submerged acoustic-Doppler system that provides burst of directional wave data, including significant wave height, mean wave period and direction of propagation. Currently these wave parameters are integrated with the data collected by a stereo-video system (namely Wave Acquisition Stereo System, WASS) that provides the 3-D profile of the wavy sea surface. WASS data are unleashing a "new view" for ocean waves providing the complete space-time dynamics of wave groups. Moreover, a series of multiparameters probes permits to measure the vertical distribution of sea temperature (at nine depths from the surface to the bottom), salinity (three positions), dissolved oxygen (two positions), and turbidity close to the sea bottom. The collected data are continuously used to track the water masses that enter, leave, and are produced within the NA. A striking example is provided by the temperature and salinity data used to follow the exceptional dense water formation that occurred in this basin

  11. Simulation of patella alta and the implications for in vitro patellar tracking in the ovine stifle joint.

    PubMed

    Bertollo, Nicky; Pelletier, Matthew H; Walsh, William R

    2012-11-01

    Patella alta is associated with adverse cartilage adaptations, patellofemoral pain, and instability. It is defined by a relatively long patellar tendon and patella positioned in a more proximal location within the patellar groove of the femur. This study used the ovine stifle joint model to investigate the effect of patellar tendon lengthening on the 3D passive kinematics of the patellofemoral and tibiofemoral joints. Eight patellar tendons were lengthened in 2 mm increments up to a maximum of 12 mm (20%) using a device placed in series with the transected patellar tendon. Three-dimensional kinematics were measured in the intact joint and at each increment of patellar tendon length (L(T)) during passively induced tibiofemoral flexion. Patellar flexion angle was linearly correlated with tibial flexion angle in the intact joint, and this correlation persisted after tendon lengthening (R = 0.897-0.965, p < 0.01). Patellofemoral kinematics expressed as a function of tibial flexion angle were significantly altered by L(T) increases >9%. In contrast, when patellofemoral kinematics were expressed as a function of patellar flexion angle they were not significantly altered by increases in L(T). Tibiofemoral kinematics were not affected by the L(T) increases. These results demonstrate that for a given tibial flexion angle, patellar tendon lengthening alters the patellar flexion angle. However, for a given patellar flexion angle, the orientation of the patella in the remaining five degrees of freedom is unchanged, implying a repeatable path of patellar motion. PMID:22581606

  12. apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

    PubMed Central

    Huang, L S; Voyiaziakis, E; Markenson, D F; Sokol, K A; Hayek, T; Breslow, J L

    1995-01-01

    apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes. Images PMID:7593600

  13. Comparative Study of Glucose Homeostasis, Lipids and Lipoproteins, HDL Functionality, and Cardiometabolic Parameters in Modestly Severely Obese African Americans and White Americans With Prediabetes: Implications for the Metabolic Paradoxes

    PubMed Central

    Healy, Sara J.; Osei, Kwame

    2015-01-01

    OBJECTIVE To determine whether modestly severe obesity modifies glucose homeostasis, levels of cardiometabolic markers, and HDL function in African Americans (AAs) and white Americans (WAs) with prediabetes. RESEARCH DESIGN AND METHODS We studied 145 subjects with prediabetes (N = 61 WAs, N = 84 AAs, mean age 46.5 ± 11.2 years, mean BMI 37.8 ± 6.3 kg/m2). We measured fasting levels of lipids, lipoproteins, and an inflammatory marker (C-reactive protein [CRP]); HDL functionality (i.e., levels of paraoxonase 1 [PON1]); and levels of oxidized LDL, adiponectin, and interleukin-6 (IL-6). We measured serum levels of glucose, insulin, and C-peptide during an oral glucose tolerance test. Values for insulin sensitivity index (Si), glucose effectiveness index (Sg), glucose effectiveness at zero insulin (GEZI), and acute insulin response to glucose (AIRg) were derived using a frequently sampled intravenous glucose tolerance test (using MINMOD software). RESULTS Mean levels of fasting and incremental serum glucose, insulin, and C-peptide tended to be higher in WAs versus AAs. The mean Si was not different in WAs versus AAs (2.6 ± 2.3 vs. 2.9 ± 3.0 × 10−4 × min−1 [μU/mL]−1). Mean values for AIRg and disposition index as well as Sg and GEZI were lower in WAs than AAs. WAs had higher serum triglyceride levels than AAs (116.1 ± 55.5 vs. 82.7 ± 44.2 mg/dL, P = 0.0002). Mean levels of apolipoprotein (apo) A1, HDL cholesterol, PON1, oxidized LDL, CRP, adiponectin, and IL-6 were not significantly different in obese AAs versus WAs with prediabetes. CONCLUSIONS Modestly severe obesity attenuated the ethnic differences in Si, but not in Sg and triglyceride levels in WAs and AAs with prediabetes. Despite the lower Si and PON1 values, AAs preserved paradoxical relationships between the Si and HDL/apoA1/triglyceride ratios. We conclude that modestly severe obesity has differential effects on the pathogenic mechanisms underlying glucose homeostasis and atherogenesis in obese

  14. Descripción de la zona de alta difusión en un modelo bidimensional para hojas de corriente

    NASA Astrophysics Data System (ADS)

    Montero, M. F.; Paola, C. A.; Platzeck, A. M.

    Los modelos bidimensionales para describir hojas de corriente de alta simetría no suministran una descripción detallada de las regiones donde la difusión es considerablemente importante. Tal es el caso de los modelos desarrollados en la década del '60 por Sweet, Parker, Petschek y Sonnerup. En esta comunicación presentamos una solución de las ecuaciones MHD en el entorno del origen, construyendo series bidimensionales para todas las magnitudes físicas involucradas. Valiéndonos de la alta simetría y de las características del problema, logramos reducir el número de coeficientes a calcular. Utilizamos un programa autoconsistente para extender el cálculo a regiones vecinas con difusión moderada o despreciable.

  15. 15,000-yr pollen record of vegetation change in the high altitude tropical Andes at Laguna Verde Alta, Venezuela

    NASA Astrophysics Data System (ADS)

    Rull, Valentí; Abbott, Mark B.; Polissar, Pratigya J.; Wolfe, Alexander P.; Bezada, Maximiliano; Bradley, Raymond S.

    2005-11-01

    Pollen analysis of sediments from a high-altitude (4215 m), Neotropical (9°N) Andean lake was conducted in order to reconstruct local and regional vegetation dynamics since deglaciation. Although deglaciation commenced ˜15,500 cal yr B.P., the area around the Laguna Verde Alta (LVA) remained a periglacial desert, practically unvegetated, until about 11,000 cal yr B.P. At this time, a lycopod assemblage bearing no modern analog colonized the superpáramo. Although this community persisted until ˜6000 cal yr B.P., it began to decline somewhat earlier, in synchrony with cooling following the Holocene thermal maximum of the Northern Hemisphere. At this time, the pioneer assemblage was replaced by a low-diversity superpáramo community that became established ˜9000 cal yr B.P. This replacement coincides with regional declines in temperature and/or available moisture. Modern, more diverse superpáramo assemblages were not established until ˜4600 cal yr B.P., and were accompanied by a dramatic decline in Alnus, probably the result of factors associated with climate, humans, or both. Pollen influx from upper Andean forests is remarkably higher than expected during the Late Glacial and early to middle Holocene, especially between 14,000 and 12,600 cal yr B.P., when unparalleled high values are recorded. We propose that intensification of upslope orographic winds transported lower elevation forest pollen to the superpáramo, causing the apparent increase in tree pollen at high altitude. The association between increased forest pollen and summer insolation at this time suggests a causal link; however, further work is needed to clarify this relationship.

  16. Importance of landscape features and Earth observation derived habitat maps for modelling amphibian distribution in the Alta Murgia National Park

    NASA Astrophysics Data System (ADS)

    Ficetola, Gentile Francesco; Adamo, Maria; Bonardi, Anna; De Pasquale, Vito; Liuzzi, Cristiano; Lovergine, Francesco; Marcone, Francesco; Mastropasqua, Fabio; Tarantino, Cristina; Blonda, Palma; Padoa-Schioppa, Emilio

    2015-05-01

    Traditionally, analyses of relationships between amphibians and habitat focused on breeding environments (i.e., pond features) more than on the features of the surrounding environment. Nevertheless, for most amphibians the terrestrial phase is longer than the aquatic phase, and consequently landscape features (i.e., habitat mosaics) may have an important role for modelling amphibian distribution. There were different aims in this analysis. Firstly, we compared the effectiveness of the information provided by land cover/use (LC/LU) classes and habitat classes defined according to a new habitat taxonomy named General Habitat Category (GHC), which is based on the concept of biological forms of dominant vegetation and class naturalness. The GHC map used was obtained from a pre-existing validated LC/LU map, by integrating spectral and spatial measurements from very high resolution Earth observation data according to ecological expert rules involving concepts related to spatial and temporal relationships among LC/LU and habitat classes. Then, we investigated the importance for amphibians of the landscape surrounding ponds within the Italian Alta Murgia National Park. The work assessed whether LC/LU classes in pond surrounds are important for the presence/absence of amphibians in this area, and identified which classes are more important for amphibians. The results obtained can provide useful indications to management strategies aiming at the conservation of amphibians within the study area. An information-theoretic approach was adopted to assess whether GHC maps allow to improve the performance of species distribution models. We used the Akaike's Information Criterion (AICc) to compare the effectiveness of GHC categories versus LC/LU categories in explaining the presence/absence of pool frogs. AICc weights suggest that GHC categories can better explain the distribution of frogs, compared to LC/LU classes.

  17. Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling.

    PubMed

    Corsetti, James P; Salzman, Peter; Ryan, Dan; Moss, Arthur J; Zareba, Wojciech; Sparks, Charles E

    2016-09-01

    Data is presented that was utilized as the basis for Bayesian network modeling of influence pathways focusing on the central role of a polymorphism of plasminogen activator inhibitor-2 (PAI-2) on recurrent cardiovascular disease risk in patients with high levels of HDL cholesterol and C-reactive protein (CRP) as a marker of inflammation, "Influences on Plasminogen Activator Inhibitor-2 Polymorphism-Associated Recurrent Cardiovascular Disease Risk in Patients with High HDL Cholesterol and Inflammation" (Corsetti et al., 2016; [1]). The data consist of occurrence of recurrent coronary events in 166 post myocardial infarction patients along with 1. clinical data on gender, race, age, and body mass index; 2. blood level data on 17 biomarkers; and 3. genotype data on 53 presumptive CVD-related single nucleotide polymorphisms. Additionally, a flow diagram of the Bayesian modeling procedure is presented along with Bayesian network subgraphs (root nodes to outcome events) utilized as the data from which PAI-2 associated influence pathways were derived (Corsetti et al., 2016; [1]). PMID:27284570

  18. A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease

    PubMed Central

    Kallend, D.G.; Reijers, J.A.A.; Bellibas, S.E.; Bobillier, A.; Kempen, H.; Burggraaf, J.; Moerland, M.; Wijngaard, P.L.J.

    2016-01-01

    Aims Apolipoprotein A-1 (ApoA-1), based on epidemiology, is inversely associated with cardiovascular (CV) events. Human carriers of the ApoA-1 Milano variant have a reduced incidence of CV disease. Regression of atherosclerotic plaque burden was previously observed on intravascular ultrasound (IVUS) with ETC-216, a predecessor of MDCO-216. MDCO-216, a complex of dimeric ApoA-1 Milano and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, is being developed to reduce atherosclerotic plaque burden and CV events. We investigated the efficacy and safety of a single infusion of MDCO-216 in healthy volunteers and in patients with coronary artery disease (CAD). Methods and results Twenty-four healthy volunteers and 24 patients with documented CAD received a 2-h infusion of MDCO-216 in a randomized, placebo controlled, single ascending dose study. Five cohorts of healthy volunteers and four cohorts of CAD patients received ApoA-1 Milano doses ranging from 5 to 40 mg/kg. Subjects were followed for 30 days. Dose-dependent increases in ApoA-1, phospholipid, and pre-beta 1 HDL and decreases in ApoE were observed. Prominent and sustained increases in triglyceride, and decreases in HDL-C, endogenous ApoA-1 and ApoA-II occurred at doses >20 mg/kg and profound increases in ABCA1-mediated cholesterol efflux were observed. Other lipid and lipoprotein parameters were generally unchanged. MDCO-216 was well tolerated. Conclusions MDCO-216-modulated lipid parameters profoundly increased ABCA1-mediated cholesterol efflux and was well tolerated. These single-dose data support further development of this agent for reducing atherosclerotic disease and subsequent CV events. PMID:27418968

  19. Impact of land-cover change in the southern Amazonia climate: a case study for the region of Alta Floresta, Mato Grosso, Brazil.

    PubMed

    Dubreuil, Vincent; Debortoli, Nathan; Funatsu, Beatriz; Nédélec, Vincent; Durieux, Laurent

    2012-01-01

    The transformation of forest into pastures in the Brazilian Amazon leads to significant consequences to climate at local scale. In the region of Alta Floresta (Mato Grosso, Brazil), deforestation has been intense with over half the forests being cut since 1970. This article first examines the evolution of precipitation observed in this region and shows a significant trend in the decrease in total precipitation especially at the end of the dry season and at the beginning of the rainy season. The study then compares the temperatures measured in cleared and forested sectors within a reserve in the area of Alta Floresta (Mato Grosso, Brazil) between 2006 and 2007. The cleared sector was always hotter and drier (from 5% to 10%) than the forested area. This difference was not only especially marked during the day when it reached on average 2°C but also seemed to increase during the night with the onset of the dry season (+0.5°C). The Urban Heat Island effect is also evident especially during the night and in the dry season. PMID:21479561

  20. Genetic diversity of endophytic diazotrophs of the wild rice, Oryza alta and identification of the new diazotroph, Acinetobacter oryzae sp. nov.

    PubMed

    Chaudhary, Hassan Javed; Peng, Guixiang; Hu, Mei; He, Yumei; Yang, Lijuan; Luo, Yan; Tan, Zhiyuan

    2012-05-01

    Thirty-three endophytic diazotrophs were isolated from surface-sterilized leaves, stem, and roots of wild rice Oryza alta. The SDS-PAGE profile of total protein and insertion sequence-based polymerase chain reaction (IS-PCR) fingerprinting grouped the isolates into four clusters (I-IV). The 16S rRNA gene sequence homology of the representative strains B21, B31, B1, and B23 of clusters I, II, III, and IV were assigned to Pseudomonas oleovorans (99.2% similarity), Burkholderia fungorum (99.4% similarity), Enterobacter cloacae (98.9% similarity), and Acinetobacter johnsonii (98.4% similarity), respectively. The results showed wide genetic diversity of the putative diazotrophic strains of the wild rice, O. alta, and the strains of cluster IV are the first report of nitrogen-fixing Acinetobacter species. The cell size, phenotypic characters, total protein profile, genomic DNA fingerprinting, DNA-DNA hybridization, and antibiotic resistance differentiated strain B23(T) from its closest relatives A. johnsonii LMG999(T) and Acinetobacter haemolyticus LMG996(T). The DNA-DNA hybridization also distinguished the strain B23(T) from the closely related Acinetobacter species. Based on these data, a novel species, Acinetobacter oryzae sp. nov., and strain B23(T) (=LMG25575(T) = CGMCC1.10689(T)) as the type strain were proposed. PMID:22105517

  1. Anisometry of Medial Patellofemoral Ligament Reconstruction in the Setting of Patella Alta and Increased Tibial Tubercle-Trochlear Groove (TT-TG) Distance

    PubMed Central

    Redler, Lauren H.; Meyers, Kathleen N.; Munch, Jacqueline; Dennis, Elizabeth R.; Nguyen, Joseph; Stein, Beth E. Shubin

    2016-01-01

    Objectives: Medial patellofemoral ligament (MPFL) reconstruction is a common procedure to treat recurrent patellofemoral instability. However, the effects of an elevated tibial tubercle-trochlear groove (TT-TG) distance and patella alta, as measured by the Caton-Deschamps (C/D) ratio, on MPFL isometry remain unclear. We hypothesized that increased lateralization and proximalization of the tibial tubercle (TT) will have increasingly adverse effects on the isometry of the MPFL. Methods: Ten fresh-frozen cadaveric knees were placed on a custom testing fixture, with a fixed femur and tibia mobile through 120 degrees of flexion. The quadriceps tendon was loaded with 10.8 N in an anatomic direction using a weighted pulley system. A 0.2 N patellar lateral displacement load was used to simulate an intact lateral retinaculum to avoid over-medializing the patella. A tunnel was drilled under fluoroscopic guidance from Schottle’s point on the medial distal femur through the lateral cortex. A suture anchor was placed at the upper 66% of the medial border of the patella and the sutures were shuttled through to the lateral side and attached to a pulley with a 1 N weight. Retroreflective markers were attached to the femur, tibia, patella, and suture. MPFL length change, as measured by suture marker motion, was assessed using a 3D motion capture system through a range of motion between 0 deg and 110 deg with the native TT anatomy. Recordings were repeated after a flat TT osteotomy and transfer to a TT-TG of 20 mm and 25 mm and a C/D ratio of 1.2 and 1.4, including all combinations. Generalized estimating equation (GEE) modeling technique was used to analyze and control for the clustered nature of the data. SAS version 9.3 (SAS Inc., Cary, NC) was used for all data analyses. Results: Analysis was performed on 9 specimens secondary to significant deviations in the baseline normative data. Intact knees showed MPFL isometry through 20-70 degrees range of motion. Tibial tubercle

  2. Slip rates along active faults estimated with cosmic-ray exposure dates: Application to the Bogd fault, Gobi-Altaï, Mongolia

    NASA Astrophysics Data System (ADS)

    Ritz, J. F.; Brown, E. T.; Bourlès, D. L.; Philip, H.; Schlupp, A.; Raisbeck, G. M.; Yiou, F.; Enkhtuvshin, B.

    1995-11-01

    Dating morphological features displaced along active faults presents a major difficulty in evaluation of slip rates. We used in-situ produced 10 Be to calculate minimum ages for alluvial surfaces misaligned by movement along a major active fault in the Gobi-Altaï (western Mongolia). The maximum slip rate of ≈1.2 mm/yr suggested by this method contrasts strongly with rates of ≈20 mm/yr that we estimated by correlation of alluvial deposition with warm humid periods associated with the last glacial termination estimated to have occurred about 12 ka in western Tibet. The 10Be-based slip rate indicates that strong earthquakes can occur along faults with low slip rates and demonstrates the contribution of cosmic-ray exposure dating in Quaternary tectonic analyses.

  3. The environmental balance of the Alta Val d'Agri: a contribution to the evaluation of the industrial risk and strategic sustainable development

    NASA Astrophysics Data System (ADS)

    Loperte, S.; Cosmi, C.

    2015-01-01

    This study presents the preliminary environmental balance of the Alta Val d'Agri (Basilicata Region, Southern Italy), an area of great naturalistic interest characterized by the presence of huge oil and gas fields. The DPSIR methodology has been used to outline the background in terms of environmental impacts mainly caused by the oil extraction activities, as well as existing potential responses. The study aims at providing stakeholders with an exhaustive framework to identify the existing data, the main sources of pollution, their potential impacts, the associated industrial risks and the existing policy strategies. Moreover, the DPSIR approach allows identifying the vulnerable areas and defining targeted actions for a sustainable development of the area.

  4. The environmental balance of the Alta Val d'Agri: a contribution to the evaluation of the industrial risk and strategic sustainable development

    NASA Astrophysics Data System (ADS)

    Loperte, S.; Cosmi, C.

    2015-09-01

    This study presents the preliminary environmental balance of the Alta Val d'Agri (Basilicata Region, Southern Italy), an area of great naturalistic interest characterized by the presence of huge oil and gas fields. The Driving Forces-Pressure-State-Impact-Responses (DPSIR) methodology was used to outline the background in terms of environmental impacts mainly caused by oil extraction activities, as well as potential existing responses. The study aims at providing stakeholders with an exhaustive framework to identify the existing data, the main sources of pollution, their potential impacts, the associated industrial risks and the existing policy strategies. Moreover, the DPSIR approach allows the identification of the vulnerable areas and the definition of targeted actions for a sustainable development of the area.

  5. Genetics Home Reference: familial HDL deficiency

    MedlinePlus

    ... hypoalphalipoproteinemia ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific articles on PubMed (1 link) PubMed OMIM (1 link) HYPOALPHALIPOPROTEINEMIA, PRIMARY Sources for This Page Batal R, Tremblay M, ...

  6. Oregovomab: anti-CA-125 monoclonal antibody B43.13--AltaRex, B43.13, MAb B43.13, monoclonal antibody B43.13.

    PubMed

    2006-01-01

    ViRexx Medical Corp is developing the murine monoclonal antibody oregovomab [OvaRex, MAb B43.13] for the treatment of ovarian cancer. Oregovomab targets the circulating tumour-associated antigen CA 125, which is shed from the surface of human ovarian cancer cells; the antibodies induce broad cellular and humoral immune responses against CA 125 via complex formation. Unlike free CA 125, CA 125-oregovomab complexes can prime dendritic cells, leading to downstream activation of T cells. The antibody is undergoing advanced clinical development. AltaRex, the originator of oregovomab, was acquired by, and merged into, ViRexx Medical Corp in December 2004. AltaRex (now ViRexx Medical Corp) has established several strategic corporate alliances for the development and/or commercialisation of oregovomab. Unither Pharmaceuticals, a subsidiary of United Therapeutics Corporation, entered into a licensing agreement with ViRexx in April 2002. The agreement covers most territories worldwide, except Europe and the Middle East, which are covered by other agreements (see below); ViRexx did retain the rights to most member nations of the EU and certain other countries. In August 2003, the agreement was extended, granting United Therapeutics Corporation development rights for Germany. AltaRex and Dompe entered into a distribution agreement for oregovomab in July 2004. Territories included in the agreement are Italy, Spain, Portugal, Hungary, Poland, Czech Republic, Switzerland, Austria and certain other Eastern European countries. Under the terms of the agreement, ViRexx retains responsibility for product development and registration of the antibody, upon commercialisation in the agreed territory. The two companies will work closely to achieve product registration throughout Europe. In June 2001, Dompe entered into a sublicensing agreement with FAES for the commercialisation of oregovomab in Spain and Portugal. ViRexx is also seeking collaboration partners for Northern European markets

  7. The Association of Pediatric LDL-cholesterol and HDL-cholesterol Dyslipidemia Classifications and Change in Dyslipidemia Status with Carotid Intima-Media Thickness in Adulthood: Evidence from the Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study, and the Childhood Determinants of Adult Health (CDAH) Study

    PubMed Central

    Magnussen, Costan G.; Venn, Alison; Thomson, Russell; Juonala, Markus; Srinivasan, Sathanur R.; Viikari, Jorma S.A.; Berenson, Gerald S.; Dwyer, Terence; Raitakari, Olli T.

    2009-01-01

    Objectives – To determine which of the National Cholesterol Education Program (NCEP) or National Health and Nutrition Examination Survey (NHANES) LDL-cholesterol and HDL-cholesterol classifications of dyslipidemia status in adolescents is most effective at predicting high common carotid artery intima-media thickness (IMT) in adulthood. Background – Two classifications of pediatric dyslipidemia status have been proposed. No study has assessed which of these is most effective for predicting adolescents who will develop preclinical atherosclerosis in adulthood. Methods – Three population-based, prospective cohort studies that collected lipoprotein measurements on 1711 adolescents aged 12–18 years who were re-measured as young adults aged 29–39 years. Lipoproteins in adolescence were classified according to NCEP and NHANES cut-points, while high IMT in adulthood was defined as those at or above the age, sex, race, and cohort specific 90th percentile of IMT. Results – Independent of the classification employed, adolescents with dyslipidemia were at significantly increased risk of having high IMT in adulthood (relative risks from 1.6 to 2.5). Differences in predictive capacity between both classifications were minimal. Overweight or obese adolescents with dyslipidemia had increased carotid IMT (males, 0.11mm; females, 0.08mm) in adulthood compared with those who did not have both risk factors. Adolescent dyslipidemia status was more strongly associated with high IMT in adulthood than change in dyslipidemia status. Conclusions – Pediatric dyslipidemia classifications perform equally in the prediction of adolescents who are at increased risk of high IMT in young adulthood. Our data suggest that dyslipidemia screening could be limited to overweight or obese adolescents. PMID:19264243

  8. A nutrient-dense, high fiber, fruit-based supplement bar increases HDL, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-week trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary intake modulates disease risk, but little is known as to how components within food mixtures affect pathophysiology. Here, a low-calorie, high-fiber, fruit-based nutrient-dense bar of defined composition (e.g., vitamins/minerals, fruit polyphenolics, B-glucan, docosahexaenoic acid (DHA)) app...

  9. Estudio de la fotoabsorción y fotoionización de la molécula de alta relevancia atmosférica no a través de los estados Rydberg con la metodología MQDO

    NASA Astrophysics Data System (ADS)

    Bustos, E.; Velasco, A. M.; Martín, I.; Lavín, C.

    Los procesos de fotoionización son de una importancia fundamental [1] y encuentran aplicación en un gran número de contextos científicos: Astrofísica [2], química de las radiaciones, biología. Los investigadores de dichos campos, necesitan de valores de fiables de secciones eficaces para la fotoionización parcial, la Fotoabsorción, así como para los procesos de fotofragmentación en amplios intervalos espectrales, particularmente en estudios de modelización [3-5]. En este trabajo se ha centrado la atención sobre el oxido nítrico, que se ha considerado apropiado y relevante por varios motivos: por el trascendental papel que representa en la física y química de la alta atmosfera [6], aparte de por estar íntimamente relacionado con los problemas de contaminación. Los procesos de recombinación disociativa [7] del NO, donde los estados Rydberg se encuentran directamente implicados, son relevantes, por ejemplo, en las regiones E y F de la ionosfera [7]. En este trabajo se estudia la fotoionización del NO desde el estado fundamental con la versión molecular del método del orbital de defecto cuántico (MQDO). Para ello se calcula el diferencial de las fuerzas de oscilador parciales que constituyen los canales de fotoionización del NO desde el estado fundamental. La continuidad del diferencial de fuerza de oscilador calculada a través del umbral de fotoionización, esto es, en las regiones del espectro discreta y del continua, se adopta como criterio de calidad la escasez de datos comparativos [8].

  10. COLD-SAT orbital experiment configured for Altas launch

    NASA Technical Reports Server (NTRS)

    Schuster, J. R.; Bennett, F. O.; Wachter, J. P.

    1990-01-01

    A study was done of the feasibility of conducting liquid hydrogen orbital storage, acquisition, and transfer experiments aboard a spacecraft launched by a commercial Atlas launch vehicle. Three hydrogen tanks are mated to a spacecraft bus that is similar to that used for three-axis-controlled satellites. The bus provides power, communications, and attitude control along with acceleration levels ranging from 10 exp -6 to 10 exp -4 g. At launch, all the liquid hydrogen is contained in the largest tank, which has an insulation system designed for both space operation and the short-term launch pad and ascent environment. This tank is much lighter and lower in cost than a vacuum-jacketed design, and is made possible by the experiment tanking options available due to the hydrogen-fueled Centaur upper stage of the Atlas I.

  11. Natural killer cells after altaïr mission

    NASA Astrophysics Data System (ADS)

    Konstantinova, I. V.; Rykova, M.; Meshkov, D.; Peres, C.; Husson, D.; Schmitt, D. A.

    Reduced in vitro NK cytotoxic activity have routinely been observed after both prolonged and short-term space flights. This study investigated the effects of space flight on NK cell functions, NK cell counts and the production of IL-2 and TNF by lymphocytes of French-Russian crew members. In the French cosmonaut, after 21 days space flight, the cytotoxic activity of NK cells, the capacity the NK cells to bind and lyse the individual target cells and the percentage of NK cells were decreased. In this cosmonaut a twofold reduction TNF production in cultures of lymphocytes stimulated with PMA and with the mixture of PHA and PMA was observed on the first day after landing. However, the activity of the production of TNF in 48-hour PHA-cultures of lymphocytes was unchanged and the biological activity of IL-2 was not reduced. The immunological examination did not detecte any substantial deviations from the norm in both russian cosmonauts after 197 days space flight. Various explanations for decreased cytotoxicity in cosmonauts after space flight can be proposed, and these include the defective function of NK cells and reduced numbers of circulating effector cells.

  12. Proposed scheme for parallel 10Gb/s VSR system and its verilog HDL realization

    NASA Astrophysics Data System (ADS)

    Zhou, Yi; Chen, Hongda; Zuo, Chao; Jia, Jiuchun; Shen, Rongxuan; Chen, Xiongbin

    2005-02-01

    This paper proposes a novel and innovative scheme for 10Gb/s parallel Very Short Reach (VSR) optical communication system. The optimized scheme properly manages the SDH/SONET redundant bytes and adjusts the position of error detecting bytes and error correction bytes. Compared with the OIF-VSR4-01.0 proposal, the scheme has a coding process module. The SDH/SONET frames in transmission direction are disposed as follows: (1) The Framer-Serdes Interface (FSI) gets 16×622.08Mb/s STM-64 frame. (2) The STM-64 frame is byte-wise stripped across 12 channels, all channels are data channels. During this process, the parity bytes and CRC bytes are generated in the similar way as OIF-VSR4-01.0 and stored in the code process module. (3) The code process module will regularly convey the additional parity bytes and CRC bytes to all 12 data channels. (4) After the 8B/10B coding, the 12 channels is transmitted to the parallel VCSEL array. The receive process approximately in reverse order of transmission process. By applying this scheme to 10Gb/s VSR system, the frame size in VSR system is reduced from 15552×12 bytes to 14040×12 bytes, the system redundancy is reduced obviously.

  13. Extra Virgin Olive Oil Polyphenols Promote Cholesterol Efflux and Improve HDL Functionality

    PubMed Central

    Berrougui, Hicham; Ikhlef, Souad; Khalil, Abdelouahed

    2015-01-01

    Results of the present work give evidence from the beneficial role of extra virgin olive of oil (EVOO) consumption towards oxidative stress and cardiovascular diseases. Polyphenols contained in EVOO are responsible for inhibiting lipoproteins oxidative damages and promoting reverse cholesterol transport process via ABCA1 pathway. PMID:26495005

  14. Molecular models need to be tested: the case of a solar flares discoidal HDL model.

    PubMed

    Shih, Amy Y; Sligar, Stephen G; Schulten, Klaus

    2008-06-01

    In the absence of atomic structures of high-density lipoproteins in their lipid-bound states, many molecular models have been produced based on experimental data. Using molecular dynamics, we show that a recently proposed "solar-flares" model of discoidal high-density lipoprotein is implausible. Our simulations show a collapse of the protruding solar-flare loops and a notable protein rearrangement due to an energetically unfavorable orientation of the hydrophobic protein surface toward the aqueous solvent. PMID:18375520

  15. Genetic variants associated with VLDL, LDL and HDL particle size differ with race/ethnicity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason f...

  16. Adiponectin and the mediation of HDL cholesterol change with improved lifestyle: The Look AHEAD Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adipose tissue dysfunction plays a key role in the development of the metabolic abnormalities characteristic of type 2 diabetes (T2DM) and participates actively in lipid metabolism. Adiponectin, found abundantly in circulation and a marker of adipose health, is decreased in obese persons with T2DM. ...

  17. Sustainability of Blood Pressure and HDL-C improvements following a community participatory walking intervention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our purpose was to assess the sustainability of biologic and anthropometric effects on participants enrolled in a 6-month walking intervention developed through a community participatory process in a rural Mississippi Delta community. Participants in walking groups led by trained volunteers were ev...

  18. Dysfunctional HDL containing L159R apoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, the effect of the mutation L159R apoA-I or apoA-IL159R (FIN) was assessed. apoA-IL159R (FIN) is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Transgenic mice lines were created through strategic mati...

  19. On two new trends in evolvable hardware: employment of HDL-based structuring, and design of multi-functional circuits

    NASA Technical Reports Server (NTRS)

    Stoica, A.; Keymeulen, D.; Zebulum, R. S.; Ferguson, M. I.; Guo, X.

    2002-01-01

    This paper comments on some directions of growth for evolvable hardware, proposes research directions that address the scalability problem and gives examples of results in novel areas approached by EHW.

  20. Summary of Hydrologic and Geochemical Investigations of the Albion Basin, Little Cottonwood Canyon, Alta, Utah

    NASA Astrophysics Data System (ADS)

    Skalbeck, J.; Clancy, J.; Kraus, J.

    2013-12-01

    This hydrologic and geochemical investigation of the Albion Basin was initiated in August 2005 as a background study that included reviewing existing reports, publications, maps, and other available data and preparing a phased research plan. Annual field investigations have continued with the goal to evaluate watershed characteristics of the Albion Basin and provide scientific information that can be used in watershed management decisions. In August 2006, ten piezometers were installed in the Albion Basin for water level and water chemistry monitoring at three wetland areas (Albion Basin Fen, Catherine's Pass, and Collins/Sugarloaf) and in the streambed of Little Cottonwood Creek. In August 2012, a single piezometer was installed in the Patsy Marley wetland area. The August 2013 field season represents the 8th monitoring period for this investigation. Annual monitoring consists of collecting: (1) automated water levels using pressure transducers, (2) manual water levels using an electronic sounder, (3) field water parametes (temperature, pH, electrical conductivity), and (4) water samples for laboratory chemical analysis of major cations and anions. Water samples have been collected from piezometers, springs, and surface water to characterize the potential source water for the wetland areas. In 2011 and 2012, snow samples were collected for laboratory chemical analysis to characterize the water chemistry from precipitation. A reconnaissance survey of springs located in each of the wetland areas within the basin was performed during the August 2013 record general vegetation and rock type, water field water parameter measurements, and relative flow characteristics. The goal is to assess the contribution of source water for each of the wetland areas and to identify water source areas and flow paths within the basin. In general the water sample results represent calcium, magnesium bicarbonate fresh water. These results, along with the snow sample results, provide for evaluation of precipitation input to the wetlands based on water chemistry. The water chemistry results combined with the water level signatures indicate three distinct characteristics for these wetland areas. The Catherine's Pass wetland is groundwater dominant while the Albion Basin Fen area is precipitation (surface water) dominant. The wetland area at Collins/Sugarloaf is a mixture of groundwater and surface water and the wetland may persist due to perched water. Data from the new Patsy Marley area and the spring survey are still being evaluated. Spring flow data looks promising for evaluating baseflow conditions within the watershed areas. This study is instrumental for describing the uniqueness of the Albion Basin Fen, discussing the hydrologic connections of the Albion Basin Fen, and assessing effects on the Albion Basin Fen from proposed water diversions. The proposed diversions were judged to result in a permanent loss of water from the Albion Basin and would affect the natural stream and wetland environment in the Albion Basin Fen wetland study area.

  1. 77 FR 38823 - Notice of Availability of the Alta East Wind Project Draft Environmental Impact Statement...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-29

    ... July 15, 2011 (FR 41817-41819). The BLM held one joint public scoping meeting with Kern County in... Eagles and California Condors, special status species, cultural resources, geology and soils, hazards...

  2. Estudio de Maseres Circunestelares de Monoxido de Silicio con muy alta Resolucion Espacial

    NASA Astrophysics Data System (ADS)

    Soria-Ruiz, Rebeca

    2006-03-01

    We present high-spatial and high-spectral resolution studies of SiO masers in the circumstellar envelopes of late-type stars. These masers occur in the inner layers of the CSEs, in a region dominated by the stellar pulsation, thus being good (if not the only) probes available to understand the physics in these regions. Using the NRAO Very Long Baseline Array, we have produced maps of the 28SiO v=1 and v=2 J=1-0 and J=2-1 transitions towards several AGB stars: two Mira-type (TXCam and RLeo), one OH/IR (IRC+10011) and one S-type (xCyg) stars. The 29SiO v=0 J=1-0 and J=2-1 emission has also been studied. The spatial distributions retrieved, some of them for the first time, are in clear contradiction with the predictions of the models developed to date. We suggest that spectral line overlap may explain the results obtained. This work has been conducted by Dr. Javier Alcolea Jimenez and Dr. Francisco Colomer Sanmartin, at Observatorio Astronomico Nacional (Spain). The PhD thesis manuscript, in spanish, is available at ftp://ftp.oan.es/pub/users/r.soria/TESIS-RSoria.pdf .

  3. Effects of cholesteryl ester transfer protein inhibition on apolipoprotein (apo) A-II-containing HDL subspecies and apoA-II metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages...

  4. The effect of a novel intergenic polymorphism (rs11774572) on HDL cholesterol concentrations depends on the TaqIB polymorphism in the cholesterol ester transfer protein gene

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Plasma lipid levels have a strong genetic component and many different loci, including those identified by genome-wide association studies, affect lipoprotein metabolism in humans. Hence, the study of gene-gene interactions may be useful to provide additional predictive value as well as ...

  5. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the estrogen receptor alpha gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. We studied the effect of sin...

  6. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the ut...

  7. Diseno de un Interferometro de Rotacion de Frente de Onda Para Obtencion de Imagenes de Alta Resolucion Espacial

    NASA Astrophysics Data System (ADS)

    Tinoco, S.; Cuevas, S.

    1987-05-01

    The mechanical and optical design of an instrument for high resolution imaging is described. It consists of an Roddier rotation shearing interferometer working on the telescope pupil plane and one additional path allowing the acquisition of the image plane speckles.

  8. 78 FR 11672 - Notice of Availability of the Final Environmental Impact Statement for the Alta East Wind Project...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-19

    ... East Wind Project, Kern County, CA, and Proposed Land Use Plan Amendment AGENCY: Bureau of Land... hazardous materials, hydrology and water quality, land use, noise, recreation, traffic, visual resources... Project was published in the Federal Register on July 15, 2011 (76 FR 41817) followed by a joint...

  9. Argument in Transition: Proceedings of the Summer Conference on Argumentation (3rd, Alta, Utah, July 28-31, 1983).

    ERIC Educational Resources Information Center

    Zarefsky, David, Ed.; And Others

    Prepared by scholars from across the United States, the more than 80 papers in this collection address new developments and recurrent problems in the theory, practice, criticism, and teaching of argumentation. The papers are organized according to 10 broad categories: argumentation theory, argumentation in special fields, political argumentation,…

  10. 78 FR 33101 - Notice of Availability of the Record of Decision for the Alta East Wind Project, Kern County...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-03

    ...-energy generation facility on a 2,592- acre site (public and private lands) with 106 wind turbines... turbines capable of generating up to 153 megawatts. The project site is within the planning boundary of the... AEWP on February 15, 2013 (78 FR 11171), initiated a 30-day protest period for the proposed...

  11. Low High-Density Lipoprotein and Risk of Myocardial Infarction.

    PubMed

    Ramirez, A; Hu, P P

    2015-01-01

    Low HDL is an independent risk factor for myocardial infarction. This paper reviews our current understanding of HDL, HDL structure and function, HDL subclasses, the relationship of low HDL with myocardial infarction, HDL targeted therapy, and clinical trials and studies. Furthermore potential new agents, such as alirocumab (praluent) and evolocumab (repatha) are discussed. PMID:26692765

  12. Low High-Density Lipoprotein and Risk of Myocardial Infarction

    PubMed Central

    Ramirez, A.; Hu, P. P.

    2015-01-01

    Low HDL is an independent risk factor for myocardial infarction. This paper reviews our current understanding of HDL, HDL structure and function, HDL subclasses, the relationship of low HDL with myocardial infarction, HDL targeted therapy, and clinical trials and studies. Furthermore potential new agents, such as alirocumab (praluent) and evolocumab (repatha) are discussed. PMID:26692765

  13. Change in composition of high density lipoprotein during gemfibrozil therapy.

    PubMed

    Sorisky, A; Ooi, T C; Simo, I E; Meuffels, M; Hindmarsh, J T; Nair, R

    1987-10-01

    We investigated the high density lipoprotein cholesterol (HDL-C) response in 20 middle-aged males during a 12-week course of gemfibrozil. Three aspects of the increase in HDL-C (25%) were studied and our observations are as follows: (1) subfraction analysis showed that HDL3-C rose earlier and to a larger extent (28%) than HDL2-C (15%), (2) analysis of variance group--time interaction effect and correlation studies of HDL-C and total triglycerides suggest the increase in HDL-C was due to a direct effect of gemfibrozil on HDL metabolism, and (3) HDL-C was the only one of 4 HDL components to increase. Apoprotein A-I (apo A-I) and HDL-phospholipid (HDL-PL) did not change, and HDL-triglyceride (HDL-TG) decreased. This pattern is consistent with a change in composition of HDL, i.e. cholesterol enrichment and triglyceride depletion. PMID:3118893

  14. Association of the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio and concentrations of plasma lipids with high-density lipoprotein subclass distribution in the Chinese population

    PubMed Central

    2010-01-01

    Background To evaluate the relationship between the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio and HDL subclass distribution and to further examine and discuss the potential impact of LDL-C and HDL-C together with TG on HDL subclass metabolism. Results Small-sized preβ1-HDL, HDL3b and HDL3a increased significantly while large-sized HDL2a and HDL2b decreased significantly as the LDL-C/HDL-C ratio increased. The subjects in low HDL-C level (< 1.03 mmol/L) who had an elevation of the LDL-C/HDL-C ratio and a reduction of HDL2b/preβ1-HDL regardless of an undesirable or high LDL-C level. At desirable LDL-C levels (< 3.34 mmol/L), the HDL2b/preβ1-HDL ratio was 5.4 for the subjects with a high HDL-C concentration (≥ 1.55 mmol/L); however, at high LDL-C levels (≥ 3.36 mmol/L), the ratio of LDL-C/HDL-C was 2.8 in subjects, and an extremely low HDL2b/preβ1-HDL value although with high HDL-C concentration. Conclusion With increase of the LDL-C/HDL-C ratio, there was a general shift toward smaller-sized HDL particles, which implied that the maturation process of HDL was blocked. High HDL-C concentrations can regulate the HDL subclass distribution at desirable and borderline LDL-C levels but cannot counteract the influence of high LDL-C levels on HDL subclass distribution. PMID:20615262

  15. Lipoprotein subclasses in genetic studies: The Berkeley Data Set

    SciTech Connect

    Krauss, R.M.; Williams, P.T.; Blanche, P.J.; Cavanaugh, A.; Holl, L.G.; Austin, M.A.

    1992-10-01

    Data from the Berkeley Data Set was used to investigate familial correlations of HDL-subclasses. Analysis of the sibling intraclass correlation coefficient by HDL particle diameter showed that sibling HDL levels were significantly correlated for HDL{sub 2b}, HDL{sub 3a} and HDL{sub 3b} subclasses. The percentage of the offsprings` variance explained by their two parents. Our finding that parents and offspring-have the highest correlation for HDL{sub 2b} is consistent with published reports that show higher heritability estimates for HDL{sub 2} compared with HDL{sub 3}{minus} cholesterol.

  16. Estatística de lentes gravitacionais e o gás de chaplygin generalizado

    NASA Astrophysics Data System (ADS)

    Oliveira, A. L. S.

    2003-08-01

    A estatística de lentes gravitacionais constitui uma poderosa ferramenta utilizada na obtenção de vínculos sobre parâmetros cosmológicos, principalmente sobre modelos com uma constante cosmológica. Embora de forma às vezes controversa, antes de 1998, a análise tradicional mostrava que modelos com o parâmetro de densidade da matéria da ordem da unidade são preferidos. Esse resultado começou a ser questionado, alguns anos atrás, com as indicações, advindas da análise de supernovas com alto valor de desvio para o vermelho, de que nosso Universo está acelerando. Atualmente há enorme interesse em saber qual é a natureza da componente responsável pela aceleração cósmica. Energia escura é a denominação usual dessa componente e sua característica principal é possuir pressão negativa. Nos modelos cosmológicos tradicionais, além da energia escura, considera-se também uma outra componente de origem desconhecida. Ela é denominada matéria escura e possui pressão nula. Mais recentemente modelos unificadores em que energia escura e matéria escura são manifestações distintas de um mesmo fluido (altas densidades matéria escura, baixas densidades energia escura) foram sugeridos. Um desses modelos é conhecido como Gás de Chaplygin Generalizado que é o modelo que investigaremos. Em nosso trabalho apresentamos vínculos sobre parâmetros desse modelo usando a estatística de lentes gravitacionais. Usamos observações de quasares na faixa do visível e consideramos extinção em nosso estudo. Análises semelhantes anteriores com esse tipo de objetos e que não consideram extinção são inconsistentes. Comparação dos vínculos obtidos através de lentes gravitacionais com outros advindos de outros testes será também apresentada.

  17. A MULTIPLE TESTING OF THE ABC METHOD AND THE DEVELOPMENT OF A SECOND GENERATION MODEL. PART I, PRELIMINARY DISCUSSIONS OF METHODOLOGY. SUPPLEMENT, COMPUTER PROGRAMS OF THE HDL INFORMATION SYSTEMS.

    ERIC Educational Resources Information Center

    ALTMANN, BERTHOLD; BROWN, WILLIAM G.

    THE FIRST-GENERATION APPROACH BY CONCEPT (ABC) STORAGE AND RETRIEVAL METHOD, A METHOD WHICH UTILIZES AS A SUBJECT APPROACH APPROPRIATE STANDARDIZED ENGLISH-LANGUAGE STATEMENTS PROCESSED AND PRINTED IN A PERMUTED INDEX FORMAT, UNDERWENT A PERFORMANCE TEST, THE PRIMARY OBJECTIVE OF WHICH WAS TO SPOT DEFICIENCIES AND TO DEVELOP A SECOND-GENERATION…

  18. Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation.

    PubMed

    Evans, Malkanthi; Rumberger, John A; Azumano, Isao; Napolitano, Joseph J; Citrolo, Danielle; Kamiya, Toshikazu

    2014-01-01

    High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to 16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines. PMID:24600231

  19. Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation

    PubMed Central

    Evans, Malkanthi; Rumberger, John A; Azumano, Isao; Napolitano, Joseph J; Citrolo, Danielle; Kamiya, Toshikazu

    2014-01-01

    High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines. PMID:24600231

  20. Leptin promoter variant G2548A is associated with serum leptin and HDL-C levels in a case control observational study in association with obesity in a Pakistani cohort.

    PubMed

    Shabana, -; Hasnain, Shahida

    2016-06-01

    Leptin is a protein hormone synthesized by adipocytes and is involved in the regulation of food intake and energy expenditure. We hypothesized that any change in the promoter sequence can affect the expression of the gene and hence leptin protein levels in the serum. The aim of the current study was to investigate the relationship of such a promoter variant of the leptin gene, G-2548A polymorphism, with obesity and its effect on various anthropometric and metabolic parameters in a Pakistani cohort consisting of 250 obese and 225 non-obese control subjects. Body weight, height, waist circumference (WC), hip circumference (HC) and blood pressure (BP) were measured by standard methods and levels of fasting blood glucose (FBG), total cholesterol, triglycerides, HDLC, LDLC, and leptin were determined. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the LEP G-2548A polymorphism showed significant association with obesity in Pakistan. In addition, the polymorphism showed association with weight, height, BMI, WC, HDLC and serum leptin levels. The findings suggest that the leptin promoter G-2548A variant may play its part in the progression to obesity by not only affecting the body's fat distribution but also by changing the serum leptin and HDLC levels. PMID:27240985

  1. The problem of intermixing of metals possessing no mutual solubility upon explosion welding (Cu-Ta, Fe-Ag, Al-Ta)

    SciTech Connect

    Greenberg, B.A.; Ivanov, M.A.; Rybin, V.V.; Elkina, O.A.; Antonova, O.V.; Patselov, A.M.; Inozemtsev, A.V.; Plotnikov, A.V.; Volkova, A.Yu.; Besshaposhnikov, Yu.P.

    2013-01-15

    On the basis of the results obtained for joints of dissimilar metals such as copper-tantalum and iron-silver, the reason of immiscible suspensions mixing upon explosion welding has been cleared out. It has been found that the interface (plain or wavy) is not smooth and contains inhomogeneities, namely, cusps and local melting zones. The role of granulating fragmentation providing partitioning of initial materials as a main channel of input energy dissipation has been revealed. It has been shown that in joints of metals possessing normal solubility the local melting zones are true solutions, but if metals possess no mutual solubility the local melting zones are colloidal solutions. Realization of either emulsion or suspension variant takes place. The results can be used in the development of new joints of metals possessing no mutual solubility. - Highlights: Black-Right-Pointing-Pointer Immiscible pairs Ta/Cu and Fe/Ag are welded successfully by explosive welding. Black-Right-Pointing-Pointer Fragmentation provides for partitioning as the main energy dissipation channel. Black-Right-Pointing-Pointer Immiscible metals form colloidal solid solutions during solidification. Black-Right-Pointing-Pointer Melting and boiling temperatures ratio determines the colloidal solution type. Black-Right-Pointing-Pointer Local melting zones being in suspension form enhance welds hardening.

  2. [The incidence of caries in a school-age population sample of U.S.L. n. 15 Alta Val di Cecina-Volterra].

    PubMed

    Benetti, G L; Dini, M

    1990-01-01

    It was made a screening on children of some filter classes (1st and 3d class of primary school and 1st class of secondary school) of the Volterra's schools to estimate the incidence of caries and, if necessary, to activate programs for an adequate prevention. We examined 749 children arrived to the Dental Department of the Sanitary District owing an invitation letter; a set of question was given to their parents testing mainly alimentary and oral hygienic uses of the children examined by dentists. Elaboration of data obtained from replies and demonstrated that caries incidence in our population is of 65.29%, prevailing on male sex, and that this pathology is predominant on people taking insufficient care of oral hygiene, making no use of fluoridated toothpaste and eating any of cakes (especially between meals). These data show the high incidence of caries in evolutional age and how much this is strictly connected with wrong alimentary and hygienic uses. Therefore, to reduce this phenomenon, it's necessary to operate interventions of sanitary education and dental checking examinations, at least every 6-12 months, beginning in preschool age. PMID:2075102

  3. Guidelines for Holding a Governor's Conference on Libraries: A Step-by-Step How to Do It Manual. ALTA Publication Number Three.

    ERIC Educational Resources Information Center

    Lynch, Mrs. Weldon

    This document is a revision of "Guidelines for Holding a Governor's Conference on Libraries (American Library Association, American Trustee Association, 1963). The report discusses what governor's conferences on libraries are and how they may be helpful. Many aspects of planning for such a conference are presented, including how much time to leave…

  4. Serum amyloid A changes high density lipoprotein's cellular affinity. A clue to serum amyloid A's principal function.

    PubMed

    Kisilevsky, R; Subrahmanyan, L

    1992-06-01

    The affinity of high density lipoproteins (HDL), or HDL carrying serum amyloid A (HDL/SAA), for hepatocytes or peritoneal macrophages was examined, as part of an investigation exploring the principal function of SAA and how this may be related to amyloidogenesis. The binding results in conjunction with SAA's existence primarily on HDL during inflammation, and HDL's known "reverse cholesterol transport" function suggest a clear role for SAA in the afferent arm of the reverse cholesterol transport pathway during the process of inflammation. The presence of SAA reduced HDL's affinity for normal hepatocytes by a factor of 2. In contrast, HDL/SAA had a 3- to 4-fold higher affinity for macrophages than HDL alone. Furthermore, the number of binding sites for HDL/SAA increased on macrophages during inflammation, while decreasing on hepatocytes. The net effect was a significant shift in HDL cholesterol carrying capacity towards the macrophage. Competition experiments demonstrated that HDL/SAA is only half as effective as HDL in inhibiting radiolabeled HDL binding to macrophages. This is in keeping with the reduced apolipoprotein A-1 content in HDL/SAA. Strikingly, although HDL contains twice as much apolipoprotein A-1 as HDL/SAA, it is only one-tenth as effective as HDL/SAA in inhibiting radiolabeled HDL/SAA binding to macrophages. The latter results suggest that there is a specific SAA binding site on macrophages. PMID:1602745

  5. Estudio multiespectral del remanente de supernova W 28

    NASA Astrophysics Data System (ADS)

    Dubner, G.; Velázquez, P.; Castelletti, G.

    Se presentan observaciones en continuo de radio con muy alta resolución angular y sensibilidad del remanente de supernova (RSN) W28. Las observaciones fueron realizadas con el interferómetro Very Large Array (Estados Unidos), en las configuraciones C y D, en 1415 y 324 MHz. Por la gran extensión de este remanente (diámetro ~ 1o), las observaciones en 1415 MHz se realizaron en modo mosaico, combinando 48 apuntamientos diferentes en una única imagen. En ambas frecuencias los datos se procesaron con el agregado de observaciones de menor resolución angular, a fin de recuperar información en todas las frecuencias espaciales y obtener estimaciones precisas de densidad de flujo. Las imágenes resultantes muestran por primera vez la presencia de extensiones con forma de arco, cuya naturaleza se investiga. Las observaciones en radio se comparan con una imagen óptica de W28, y con la emisión en rayos X, observada con el satélite ROSAT. Este remanente muestra una clara morfología híbrida, tipo cáscara en frecuencias de radio y de centro lleno en las bandas óptica y de rayos X blandos.

  6. Evolução temporal de discos circunstelares em estrelas Be

    NASA Astrophysics Data System (ADS)

    Fernandes, M. V. M.; Leister, N. V.; Levenhagen, R. S.

    2003-08-01

    A pesquisa do mecanismo que leva uma estrela do tipo Be a perder massa e formar um envelope circunstelar, nomeado como fenômeno Be, é uma questão em aberto, intrigante, e que adquire contornos interessantes em face às informações espectroscópicas de alta resolução. Nesta última década, consolida-se a idéia de que a forma destes envelopes é de tipo discóide, obedecendo a uma lei Kepleriana de velocidades, e mais ainda, recentemente há evidências de que a distribuição de matéria nestes discos pode assumir um caráter de anel. Medidas de algumas dimensões de discos circunstelares puderam ser obtidas pela análise de espectros de alta resolução e alta relação sinal-ruído para as estrelas Be: alpha Eri (HD 10144, B3Vpe), omicron And (HD 217675, B6IIIpe), e eta Cen (HD el972, B1.5Vne), no período dos anos de 1991 a 2001. Alguns modelos clássicos de envelope predizem uma distribuição de massa que decresce suavemente a partir da superfície estelar. Entretanto, considerando que a separação de picos de emissão em perfis de linhas do HeI e H-alpha, alargados por efeitos cinemáticos, é função do raio estelar e da velocidade rotacional projetada (vsini); nossos resultados sugerem a presença de um anel de matéria circunstelar, que aparece logo após a ejeção do material fotosférico, imediatamente acima da superfície estelar, e que se expande para raios maiores ao longo do tempo, eventualmente desconectando-se da superfície por uma região de densidade de matéria mínima. Tais interpretações revivem a idéia de que anéis de matéria circunstelar podem ser os responsáveis por algumas variabilidades em perfis de linhas de emissão, como as variações V/R.

  7. Apolipoprotein AI Deficiency Inhibits Serum Opacity Factor Activity against Plasma High Density Lipoprotein via a Stabilization Mechanism

    PubMed Central

    Rosales, Corina; Patel, Niket; Gillard, Baiba K.; Yelamanchili, Dedipya; Yang, Yaliu; Courtney, Harry S.; Santos, Raul D.; Gotto, Antonio M.; Pownall, Henry J.

    2016-01-01

    The reaction of Streptococcal serum opacity factor (SOF) against plasma high-density lipoproteins (HDL) produces a large cholesteryl ester-rich microemulsion (CERM), a smaller neo HDL that is apolipoprotein (apo) AI-poor, and lipid-free apo AI. SOF is active vs. both human and mouse plasma HDL. In vivo injection of SOF into mice reduces plasma cholesterol ~40% in 3 hours while forming the same products observed in vitro, but at different ratios. Previous studies supported the hypothesis that labile apo AI is required for the SOF reaction vs. HDL. Here we further tested that hypothesis by studies of SOF against HDL from apo AI-null mice. When injected into apo AI-null mice, SOF reduced plasma cholesterol ~35% in three hours. The reaction of SOF vs. apo AI-null HDL in vitro produced a CERM and neo HDL, but no lipid-free apo. Moreover, according to the rate of CERM formation, the extent and rate of the SOF reaction vs. apo AI-null mouse HDL was less than that against wild-type (WT) mouse HDL. Chaotropic perturbation studies using guanidine hydrochloride showed that apo AI-null HDL was more stable than WT HDL. Human apo AI added to apo AI-null HDL was quantitatively incorporated, giving reconstituted HDL. Both SOF and guanidine hydrochloride displaced apo AI from the reconstituted HDL. These results support the conclusion that apo AI-null HDL is more stable than WT HDL because it lacks apo AI, a labile protein that is readily displaced by physico-chemical and biochemical perturbations. Thus, apo AI-null HDL is less SOF-reactive than WT HDL. The properties of apo AI-null HDL can be partially restored to those of WT HDL by the spontaneous incorporation of human apo AI. It remains to be determined what other HDL functions are affected by apo AI deletion. PMID:25790332

  8. Apolipoprotein AI deficiency inhibits serum opacity factor activity against plasma high density lipoprotein via a stabilization mechanism.

    PubMed

    Rosales, Corina; Patel, Niket; Gillard, Baiba K; Yelamanchili, Dedipya; Yang, Yaliu; Courtney, Harry S; Santos, Raul D; Gotto, Antonio M; Pownall, Henry J

    2015-04-14

    The reaction of Streptococcal serum opacity factor (SOF) against plasma high-density lipoproteins (HDL) produces a large cholesteryl ester-rich microemulsion (CERM), a smaller neo HDL that is apolipoprotein (apo) AI-poor, and lipid-free apo AI. SOF is active versus both human and mouse plasma HDL. In vivo injection of SOF into mice reduces plasma cholesterol ∼40% in 3 h while forming the same products observed in vitro, but at different ratios. Previous studies supported the hypothesis that labile apo AI is required for the SOF reaction vs HDL. Here we further tested that hypothesis by studies of SOF against HDL from apo AI-null mice. When injected into apo AI-null mice, SOF reduced plasma cholesterol ∼35% in 3 h. The reaction of SOF vs apo AI-null HDL in vitro produced a CERM and neo HDL, but no lipid-free apo. Moreover, according to the rate of CERM formation, the extent and rate of the SOF reaction versus apo AI-null mouse HDL were less than that against wild-type (WT) mouse HDL. Chaotropic perturbation studies using guanidine hydrochloride showed that apo AI-null HDL was more stable than WT HDL. Human apo AI added to apo AI-null HDL was quantitatively incorporated, giving reconstituted HDL. Both SOF and guanidine hydrochloride displaced apo AI from the reconstituted HDL. These results support the conclusion that apo AI-null HDL is more stable than WT HDL because it lacks apo AI, a labile protein that is readily displaced by physicochemical and biochemical perturbations. Thus, apo AI-null HDL is less SOF-reactive than WT HDL. The properties of apo AI-null HDL can be partially restored to those of WT HDL by the spontaneous incorporation of human apo AI. It remains to be determined what other HDL functions are affected by apo AI deletion. PMID:25790332