Science.gov

Sample records for alta densidade hdl

  1. Waist-to-height ratio (WHtR) and triglyceride to HDL-C ratio (TG/HDL-c) as predictors of cardiometabolic risk.

    PubMed

    Weiler Miralles, Clara Silvana; Wollinger, Luana Maria; Marin, Débora; Genro, Julia Pasqualini; Contini, Veronica; Morelo Dal Bosco, Simone

    2015-05-01

    Introducción: La concentracion excesiva de grasa en la region abdominal se relaciona con un mayor riesgo de desarrollar enfermedad cardiovascular (ECV). Se han realizado estudios para identificar los indicadores simples y eficaces de la obesidad abdominal y el riesgo cardiometabolico asociados con el uso de parametros simples, como las medidas antropometricas y bioquimicas. El / alta densidad de colesterol de lipoproteinas de trigliceridos (TG / HDL-c) se ha propuesto como un enfoque mas practico y facil de usar marcador aterogenico, junto con la relacion cintura-estatura (RCEst), lo que hace que una herramienta superior para separar cardiometabolico riesgos relacionados con el sobrepeso / obesidad cuando se compara con el indice de masa corporal (IMC). Objetivo: Verificar la aplicabilidad de la RCEst y la relacion TG / HDL-c como predictores de riesgo cardiometabolico. Métodos: Este estudio transversal se llevo a cabo en el Departamento de Nutricion del Centro Universitario UNIVATES, donde se recogieron datos antropometricos y bioquimicos de los participantes. El analisis estadistico se realizo mediante el paquete estadistico para el software de Ciencias Sociales (SPSS) 20,0, con un nivel de significacion del 5% (p.

  2. HDL endocytosis and resecretion.

    PubMed

    Röhrl, Clemens; Stangl, Herbert

    2013-11-01

    HDL removes excess cholesterol from peripheral tissues and delivers it to the liver and steroidogenic tissues via selective lipid uptake without catabolism of the HDL particle itself. In addition, endocytosis of HDL holo-particles has been debated for nearly 40years. However, neither the connection between HDL endocytosis and selective lipid uptake, nor the physiological relevance of HDL uptake has been delineated clearly. This review will focus on HDL endocytosis and resecretion and its relation to cholesterol transfer. We will discuss the role of HDL endocytosis in maintaining cholesterol homeostasis in tissues and cell types involved in atherosclerosis, focusing on liver, macrophages and endothelium. We will critically summarize the current knowledge on the receptors mediating HDL endocytosis including SR-BI, F1-ATPase and CD36 and on intracellular HDL transport routes. Dependent on the tissue, HDL is either resecreted (retro-endocytosis) or degraded after endocytosis. Finally, findings on HDL transcytosis across the endothelial barrier will be summarized. We suggest that HDL endocytosis and resecretion is a rather redundant pathway under physiologic conditions. In case of disturbed lipid metabolism, however, HDL retro-endocytosis represents an alternative pathway that enables tissues to maintain cellular cholesterol homeostasis.

  3. [ANTIOXIDANT DYSFUNCTIONALITY OF HIGH-DENSITY LIPOPROTEINS (HDL) IN DECOMPENSATED DIABETIC PATIENTS].

    PubMed

    Awad, Fernanda; Contreras-Duarte, Susana; Molina, Patricia; Quiñones, Verónica; Serrano, Valentina; Abbott, Eduardo; Maiz, Alberto; Busso, Dolores; Rigotti, Attilio

    2015-09-01

    Introducción: las lipoproteínas de alta densidad (HDL) tienen un importante efecto protector cardiovascular mediado por su función durante el transporte reverso del colesterol, así como por otras actividades, incluyendo una significativa acción antiinflamatoria y antioxidante. La funcionalidad antiinflamatoria y antioxidante de las HDL está alterada en los pacientes diabéticos crónicos estables, aunque no existe mayor información en caso de una crisis hiperglicémica. Objetivo: determinar si durante un estado de descompensación diabética aguda las partículas de HDL exhiben un deterioro de su función antioxidante y si esta logra recuperarse una vez resuelto el cuadro agudo. Métodos: la actividad antioxidante de las HDL se midió mediante un ensayo de fluorescencia in vitro en muestras plasmáticas de pacientes diabéticos con descompensación aguda obtenidas tanto al ingreso, alcanzada la resolución intrahospitalaria del evento agudo, así como en un control ambulatorio post-hospitalización. Como comparación, se analizaron partículas de HDL de algunos sujetos sanos como condición control. Resultados: la actividad antioxidante de las HDL en pacientes con descompensación diabética aguda fue significativamente menor a la observada en el grupo control sano, y esta se fue recuperando progresivamente hasta normalizarse en el momento del control ambulatorio. La crisis hiperglicémica también demostró una baja actividad plasmática de la enzima antioxidante paraoxonasa- 1, la cual aumentó significativamente en el control ambulatorio. Conclusión: las partículas de HDL presentes en pacientes con una descompensación diabética aguda presentan una reducción significativa y reversible de su capacidad antioxidante, probablemente como consecuencia de una alteración en la actividad de la paraoxonasa-1.

  4. HDL genetic defects.

    PubMed

    Nair, Devaki R; Nair, Arun; Jain, Anjly

    2014-01-01

    High density lipoprotein cholesterol (HDL-C) and its related apolipoproteins form part of the reverse cholesterol transport system that removes excessive cholesterol from the periphery to the liver. Many transport proteins and enzymes that are involved in this process are susceptible to genetic defects that influence plasma HDL-C concentrations and HDL function. The HDL-C concentration in the blood may not be as important as the function of this lipid fraction. The genetic defects affecting plasma HDL-C concentrations do not always show a consistent relationship with atherosclerosis. Familial hypoalphalipoproteinaemia is associated with mutations in genes responsible for the transport proteins or the enzymes involved in the biogenesis of HDL-C. Inheritance of a Milano mutation of apolipoprotein A1 decreases the risk of atherosclerotic disease despite low circulating levels of HDL-C. Tangier disease and Fish Eye disease are caused by mutations in the ATP binding cassette A1 (ABCA1), a transport protein, and lecithin cholesterol acyl transferase (LCAT), an enzyme, involved in the esterification of cholesterol, respectively. Patients with these conditions have very low levels of HDL-C concentration. The association between both these conditions and the risk of cardiovascular disease (CVD) is variable and inconsistent. Understanding the molecular mechanism of HDL biogenesis not only helped in defining the pathophysiology of low and high HDL-C syndromes, but also in developing new treatment options to raise HDL-C levels. PMID:24953397

  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 and endothelial protection

    PubMed Central

    Tran-Dinh, A; Diallo, D; Delbosc, S; Varela-Perez, L Maria; Dang, QB; Lapergue, B; Burillo, E; Michel, JB; Levoye, A; Martin-Ventura, JL; Meilhac, O

    2013-01-01

    High-density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apoA-I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity. PMID:23488589

  7. 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

    ... and Alta IX to interconnect the full planned capacity of Petitioners' wind and solar generation... 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...

  8. Novel concepts in HDL pharmacology

    PubMed Central

    Remaley, Alan T.; Norata, Giuseppe D.; Catapano, Alberico L.

    2014-01-01

    High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these new HDL based therapies will also be discussed. PMID:24951539

  9. 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

  10. 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

  11. 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

  12. 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

  13. Solar Innovator | Alta Devices

    ScienceCinema

    Mattos, Laila; Le, Minh

    2016-07-12

    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 .

  14. 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 .

  15. Metabolism of HDL and its regulation.

    PubMed

    Kardassis, D; Mosialou, I; Kanaki, M; Tiniakou, I; Thymiakou, E

    2014-01-01

    Epidemiological studies have shown that low plasma levels of High Density Lipoprotein Cholesterol (HDL-C) are associated with an increased risk for myocardial infarction. These studies suggested that by increasing HDL-C levels one could reduce cardiovascular risk. However, emerging evidence from studies in animals and humans indicate that high levels of HDL-C are not sufficient to confer atheroprotection but that the functionality of the HDL particles is equally important. The picture is complicated further by the finding that HDL functionality is compromised in patients with chronic inflammatory diseases such as Coronary Artery Disease (CAD), diabetes and rheumatoid arthritis. Despite these obstacles, HDL raising is still a promising strategy for the reduction of CAD risk. Low HDL-C can be caused by inactivating mutations in apoA-I, ATP Binding Cassette Transporter A1 (ABCA1) or Lecithin-Cholesterol Acyl Transferase (LCAT) which affect HDL biogenesis and maturation whereas high HDL-C can be caused by mutations in Cholesteryl Ester Transfer Protein (CETP) or Scavenger receptor Class B Type I (SR-BI). Recent studies suggest that heterogeneity in HDL levels in the population is polygenic in origin. One approach to raise plasma HDL-C is to increase the rate of HDL biosynthesis by capitalizing on the mechanisms that control the transcription of genes that play key roles in HDL biogenesis. We review some of the genetic and non-genetic factors that affect plasma HDL levels and functions and discuss the mechanisms that regulate HDL metabolism at the level of gene transcription in the liver focusing on apoA-I, ABCA1 and apoM. PMID:24606515

  16. 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

  17. HDL drug carriers for targeted therapy.

    PubMed

    Liu, Xing; Suo, Rong; Xiong, Sheng-Lin; Zhang, Qing-Hai; Yi, Guang-Hui

    2013-01-16

    Plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are strongly and inversely associated with cardiovascular risk. HDL is not a simple lipid transporter, but possesses multiple anti-atherosclerosis activities because it contains special proteins, signaling lipid, and microRNAs. Natural or recombinant HDLs have emerged as potential carriers for delivering a drug to a specified target. However, HDL function also depends on enzymes that alter its structure and composition, as well as cellular receptors and membrane micro-domains that facilitate interactions with the microenvironment. In this review, four mechanisms predicted to enhance functions or targeted therapy of HDL in vivo are discussed. The first involves caveolae-mediated recruitment of HDL signal to bind their receptors. The second involves scavenger receptor class B type I (SR-BI) mediating anchoring and fluidity for signal-lipid of HDL. The third involves lecithin-cholesterol acyltransferase (LCAT) concentrating the signaling lipid at the surface of the HDL particle. The fourth involves microRNAs (miRNAs) being delivered in the blood to special targets by HDL. Exploitation of these four mechanisms will promote HDL to carry targeted drugs and increase HDL's clinical value. PMID:23063777

  18. HDL in innate and adaptive immunity.

    PubMed

    Catapano, Alberico Luigi; Pirillo, Angela; Bonacina, Fabrizia; Norata, Giuseppe Danilo

    2014-08-01

    During infections or acute conditions high-density lipoproteins cholesterol (HDL-C) levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity. The aim of this review is to provide an overview of the connection between HDL and immunity in atherosclerosis and beyond. PMID:24935428

  19. 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

  20. 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

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

    PubMed

    Mani, Preethi; Rohatgi, Anand

    2015-08-01

    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.

  2. 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

  3. 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...

  4. Biomimetic, synthetic HDL nanostructures for lymphoma

    PubMed Central

    Yang, Shuo; Damiano, Marina G.; Zhang, Heng; Tripathy, Sushant; Luthi, Andrea J.; Rink, Jonathan S.; Ugolkov, Andrey V.; T. K. Singh, Amareshwar; Dave, Sandeep S.; Gordon, Leo I.; Thaxton, C. Shad

    2013-01-01

    New therapies that challenge existing paradigms are needed for the treatment of cancer. We report a nanoparticle-enabled therapeutic approach to B-cell lymphoma using synthetic high density lipoprotein nanoparticles (HDL-NPs). HDL-NPs are synthesized using a gold nanoparticle template to control conjugate size and ensure a spherical shape. Like natural HDLs, biomimetic HDL-NPs target scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Functionally, compared with natural HDL, the gold NP template enables differential manipulation of cellular cholesterol flux in lymphoma cells, promoting cellular cholesterol efflux and limiting cholesterol delivery. This combination of scavenger receptor type B-1 binding and relative cholesterol starvation selectively induces apoptosis. HDL-NP treatment of mice bearing B-cell lymphoma xenografts selectively inhibits B-cell lymphoma growth. As such, HDL-NPs are biofunctional therapeutic agents, whose mechanism of action is enabled by the presence of a synthetic nanotemplate. HDL-NPs are active in B-cell lymphomas and potentially, other malignancies or diseases of pathologic cholesterol accumulation. PMID:23345442

  5. Interrelationships among HDL metabolism, aging, and atherosclerosis.

    PubMed

    Walter, Michael

    2009-09-01

    HDL plasma concentrations decline with age in prospective studies. Decline in HDL concentration and function may occur secondary because of hormonal changes, inflammatory processes, and diabetes mellitus. Beyond these effects specific aging processes may be involved. Replicative aging, the telomere-driven loss of divisional capacity, is a species-specific aging mechanism that may decrease HDL concentration and function. Cross-sectionally, by contrast, HDL levels do not change much or even slightly increase with age, suggesting that only people with still high HDL concentrations survive. A selection bias by HDL lowering genetic variation may explain why HDL deficiency is extremely rare among centenarians. Vice versa, HDL may modulate the aging process, not only by its well-known antiatherogenic effects, eg, its ability to remove cellular lipids and by antiatherogenic pleiotropic effects on cell survival, but possibly also by direct interfering with aging signaling or survival factor KLOTHO. Most of the current findings, however, are based on cell culture and selected animal experiments and await further confirmation by appropriate in vivo models.

  6. 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

  7. 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.

  8. 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

  9. microRNAs and HDL life cycle

    PubMed Central

    Canfrán-Duque, Alberto; Ramírez, Cristina M.; Goedeke, Leigh; Lin, Chin-Sheng; Fernández-Hernando, Carlos

    2014-01-01

    miRNAs have emerged as important regulators of lipoprotein metabolism. Work over the past few years has demonstrated that miRNAs control the expression of most of the genes associated with high-density lipoprotein (HDL) metabolism, including the ATP transporters, ABCA1 and ABCG1, and the scavenger receptor SRB1. These findings strongly suggest that miRNAs regulate HDL biogenesis, cellular cholesterol efflux, and HDL cholesterol (HDL-C) uptake in the liver, thereby controlling all of the steps of reverse cholesterol transport. Recent work in animal models has demonstrated that manipulating miRNA levels including miR-33 can increase circulating HDL-C. Importantly, antagonizing miR-33 in vivo enhances the regression and reduces the progression of atherosclerosis. These findings support the idea of developing miRNA inhibitors for the treatment of dyslipidaemia and related cardiovascular disorders such as atherosclerosis. This review article focuses on how HDL metabolism is regulated by miRNAs and how antagonizing miRNA expression could be a potential therapy for treating cardiometabolic diseases. PMID:24895349

  10. microRNAs and HDL life cycle.

    PubMed

    Canfrán-Duque, Alberto; Ramírez, Cristina M; Goedeke, Leigh; Lin, Chin-Sheng; Fernández-Hernando, Carlos

    2014-08-01

    miRNAs have emerged as important regulators of lipoprotein metabolism. Work over the past few years has demonstrated that miRNAs control the expression of most of the genes associated with high-density lipoprotein (HDL) metabolism, including the ATP transporters, ABCA1 and ABCG1, and the scavenger receptor SRB1. These findings strongly suggest that miRNAs regulate HDL biogenesis, cellular cholesterol efflux, and HDL cholesterol (HDL-C) uptake in the liver, thereby controlling all of the steps of reverse cholesterol transport. Recent work in animal models has demonstrated that manipulating miRNA levels including miR-33 can increase circulating HDL-C. Importantly, antagonizing miR-33 in vivo enhances the regression and reduces the progression of atherosclerosis. These findings support the idea of developing miRNA inhibitors for the treatment of dyslipidaemia and related cardiovascular disorders such as atherosclerosis. This review article focuses on how HDL metabolism is regulated by miRNAs and how antagonizing miRNA expression could be a potential therapy for treating cardiometabolic diseases. PMID:24895349

  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. Familial correlations of HDL subclasses based on gradient gel electrophoresis.

    PubMed

    Williams, P T; Vranizan, K M; Austin, M A; Krauss, R M

    1992-12-01

    We used nondenaturing polyacrylamide gradient gel electrophoresis to examine the familial correlations of high density lipoprotein (HDL) subclasses for 150 offspring in 47 nuclear families. The absorbance of protein stain was used as an index of mass concentrations at intervals of 0.01 nm within five HDL subclasses: HDL3c (7.2-7.8 nm), HDL3b (7.8-8.2 nm), HDL3a (8.2-8.8 nm), HDL2a (8.8-9.7 nm), and HDL2b (9.7-12 nm). Parent-offspring correlations were computed for two different characterizations of the parents: 1) by sex (i.e., mother versus father) and 2) by their relative values (highest versus lowest HDL). Sibling resemblance was assessed by using the intraclass correlations coefficient. Family members were significantly related for the following subclasses: HDL3c (sibling and father-offspring), HDL3b (sibling), HDL3a (sibling and mother-offspring), HDL2a (mother-offspring), and HDL2b (sibling, father-offspring, and mother-offspring). The offsprings' HDL3c and HDL2b values were more strongly related to their fathers' than to their mothers' values, whereas their HDL2a levels were more strongly related to their mothers' than their fathers' values. In addition, fathers' HDL2b levels were inversely correlated with the offsprings' HDL3b. The parents' HDL subclass levels were more strongly related to subclass levels of their younger (< or = 20 years) than their older offspring. Among all subclasses, HDL2b showed the strongest parent-offspring relation, with the parents' HDL values accounting for over 30% of the variance in offsprings' HDL2b.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Early postoperative changes of HDL subfraction profile and HDL-associated enzymes after laparoscopic sleeve gastrectomy.

    PubMed

    Doğan, Serdar; Aslan, Ibrahim; Eryılmaz, Ramazan; Ensari, Cemal Ozben; Bilecik, Tuna; Aslan, Mutay

    2013-12-01

    This study aimed to determine early postoperative changes of LDL/HDL subfraction profile and HDL-associated enzymes following laparoscopic sleeve gastrectomy (LSG). Thirteen obese patients (mean body mass index (BMI) 52.74 ± 10.97 kg/m(2)) underwent LSG and normal weight control patients (mean BMI 23.56 ± 1.92 kg/m(2)) underwent laparoscopic abdominal surgery. Fasting blood samples were collected prior to surgery, at day 1 after surgery, and after postoperation oral feeding. LDL and HDL subfraction analysis was done by continuous disk polyacrylamide gel electrophoresis. Plasma levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay. Measurement of CETP and LCAT activity was performed via fluorometric analysis. LDL subfraction profile showed no change in both LSG and control group patients. No significant difference was observed in HDL cholesterol, HDL-subfraction distribution, and apoA-I levels in the control group. LSG patients showed a significant increase in HDL-large and a significant decrease in HDL-small fractions at postoperation day 1 compared to preoperation. HDL cholesterol significantly decreased and apoA-I significantly increased in LSG patients after postoperation oral feeding compared to both preoperation and postoperation day 1. Changes in HDL subfraction profile at postoperation day 1 after LSG were accompanied by a significant decrease in CETP protein, LCAT protein, and LCAT activity as compared to preoperation levels. Early changes in HDL subfraction profile and HDL-associated enzymes following LSG suggest that the surgical procedure, irrespective of changes in body weight, affects reverse cholesterol transport. PMID:23760763

  14. HDL and cholesterol handling in the brain.

    PubMed

    Vitali, Cecilia; Wellington, Cheryl L; Calabresi, Laura

    2014-08-01

    Cholesterol is an essential component of both the peripheral nervous system and central nervous system (CNS) of mammals. Brain cholesterol is synthesized in situ by astrocytes and oligodendrocytes and is almost completely isolated from other pools of cholesterol in the body, but a small fraction can be taken up from the circulation as 27-hydroxycholesterol, or via the scavenger receptor class B type I. Glial cells synthesize native high-density lipoprotein (HDL)-like particles, which are remodelled by enzymes and lipid transfer proteins, presumably as it occurs in plasma. The major apolipoprotein constituent of HDL in the CNS is apolipoprotein E, which is produced by astrocytes and microglia. Apolipoprotein A-I, the major protein component of plasma HDL, is not synthesized in the CNS, but can enter and become a component of CNS lipoproteins. Low HDL-C levels have been shown to be associated with cognitive impairment and various neurodegenerative diseases. On the contrary, no clear association with brain disorders has been shown in genetic HDL defects, with the exception of Tangier disease. Mutations in a wide variety of lipid handling genes can result in human diseases, often with a neuronal phenotype caused by dysfunctional intracellular lipid trafficking.

  15. 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

  16. [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

  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.

  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. 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

  1. 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.

  2. 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

  3. Serum Amyloid A in Uremic HDL Promotes Inflammation

    PubMed Central

    Kopecky, Chantal; Kubicek, Markus; Haidinger, Michael; Döller, Dominik; Katholnig, Karl; Suarna, Cacang; Eller, Philipp; Tölle, Markus; Gerner, Christopher; Zlabinger, Gerhard J.; van der Giet, Markus; Hörl, Walter H.; Stocker, Roland

    2012-01-01

    Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and α-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia. PMID:22282592

  4. Large-Scale Candidate Gene Analysis of HDL Particle Features

    PubMed Central

    Kaess, Bernhard M.; Tomaszewski, Maciej; Braund, Peter S.; Stark, Klaus; Rafelt, Suzanne; Fischer, Marcus; Hardwick, Robert; Nelson, Christopher P.; Debiec, Radoslaw; Huber, Fritz; Kremer, Werner; Kalbitzer, Hans Robert; Rose, Lynda M.; Chasman, Daniel I.; Hopewell, Jemma; Clarke, Robert; Burton, Paul R.; Tobin, Martin D.

    2011-01-01

    Background HDL cholesterol (HDL-C) is an established marker of cardiovascular risk with significant genetic determination. However, HDL particles are not homogenous, and refined HDL phenotyping may improve insight into regulation of HDL metabolism. We therefore assessed HDL particles by NMR spectroscopy and conducted a large-scale candidate gene association analysis. Methodology/Principal Findings We measured plasma HDL-C and determined mean HDL particle size and particle number by NMR spectroscopy in 2024 individuals from 512 British Caucasian families. Genotypes were 49,094 SNPs in >2,100 cardiometabolic candidate genes/loci as represented on the HumanCVD BeadChip version 2. False discovery rates (FDR) were calculated to account for multiple testing. Analyses on classical HDL-C revealed significant associations (FDR<0.05) only for CETP (cholesteryl ester transfer protein; lead SNP rs3764261: p = 5.6*10−15) and SGCD (sarcoglycan delta; rs6877118: p = 8.6*10−6). In contrast, analysis with HDL mean particle size yielded additional associations in LIPC (hepatic lipase; rs261332: p = 6.1*10−9), PLTP (phospholipid transfer protein, rs4810479: p = 1.7*10−8) and FBLN5 (fibulin-5; rs2246416: p = 6.2*10−6). The associations of SGCD and Fibulin-5 with HDL particle size could not be replicated in PROCARDIS (n = 3,078) and/or the Women's Genome Health Study (n = 23,170). Conclusions We show that refined HDL phenotyping by NMR spectroscopy can detect known genes of HDL metabolism better than analyses on HDL-C. PMID:21283740

  5. 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

  6. [Role of HDL in Cholesterol Efflux and Reverse Cholesterol Transport].

    PubMed

    Ayaori, Makoto

    2016-01-01

    Low plasma levels of HDL-cholesterol (HDL-C) have been consistently associated with an increased risk of atherosclerotic cardiovascular diseases (CVD), and it is thus considered to be an anti-atherogenic lipoprotein. The development of novel therapies to enhance the atheroprotective properties of HDL may have the potential to further reduce the residual risk. Reverse cholesterol transport (RCT) is believed to be a primary atheroprotective property of HDL and its major protein, apolipoprotein A-I(apoA-I). HDL and apoA-I have been shown to promote the efflux of excess cholesterol from macrophage-derived foam cells via the cholesterol transporters, ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B, type I (SR-BI), and then transport it back to the liver for excretion into bile and eventually into the feces. In this regard, a validated murine assay that quantifies macrophage RCT may be a better predictor of atherosclerosis than the steady-state plasma concentration of HDL-C. Indeed, a recent clinical study demonstrated that the ability of serum HDL to mediate cholesterol efflux from macrophages was independently and negatively associated with the CVD risk even after adjustment for HDL-C levels, suggesting that HDL functionality is more important than its quantity. Therefore, the future development of HDL-targeted therapy should take both aspects into consideration to further reduce the residual risk.

  7. [Role of HDL in Cholesterol Efflux and Reverse Cholesterol Transport].

    PubMed

    Ayaori, Makoto

    2016-01-01

    Low plasma levels of HDL-cholesterol (HDL-C) have been consistently associated with an increased risk of atherosclerotic cardiovascular diseases (CVD), and it is thus considered to be an anti-atherogenic lipoprotein. The development of novel therapies to enhance the atheroprotective properties of HDL may have the potential to further reduce the residual risk. Reverse cholesterol transport (RCT) is believed to be a primary atheroprotective property of HDL and its major protein, apolipoprotein A-I(apoA-I). HDL and apoA-I have been shown to promote the efflux of excess cholesterol from macrophage-derived foam cells via the cholesterol transporters, ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B, type I (SR-BI), and then transport it back to the liver for excretion into bile and eventually into the feces. In this regard, a validated murine assay that quantifies macrophage RCT may be a better predictor of atherosclerosis than the steady-state plasma concentration of HDL-C. Indeed, a recent clinical study demonstrated that the ability of serum HDL to mediate cholesterol efflux from macrophages was independently and negatively associated with the CVD risk even after adjustment for HDL-C levels, suggesting that HDL functionality is more important than its quantity. Therefore, the future development of HDL-targeted therapy should take both aspects into consideration to further reduce the residual risk. PMID:27192798

  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. 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

  10. Approach to the Patient with Extremely Low HDL-Cholesterol

    PubMed Central

    deGoma, Emil M.

    2012-01-01

    Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear. Therapeutic interventions address reversible causes of low HDL-C, multiorgan abnormalities that may accompany primary disorders and cardiovascular risk modification when appropriate. Uncommon encounters with patients exhibiting extremely low HDL-C provide an opportunity to directly observe the role of HDL metabolism in atherosclerosis and beyond the vascular system. PMID:23043194

  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. Inflammation Modulates Human HDL Composition and Function in vivo

    PubMed Central

    de la Llera Moya, Margarita; McGillicuddy, Fiona C; Hinkle, Christine C; Byrne, Michael; Joshi, Michelle R; Nguyen, Vihn; Tabita-Martinez, Jennifer; Wolfe, Megan L; Badellino, Karen; Pruscino, Leticia; Mehta, Nehal N; Asztalos, Bela F; Reilly, Muredach P

    2012-01-01

    Objectives Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans. Methods and Results We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (-32.2 ± 9.3% at 24h, p<0.05) as well as small (-23.0 ± 5.1%, p<0.01, at 24h) and medium (-57.6 ± 8.0% at 16h, p<0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (~36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (-20.8 ± 3.4% at 24h, p<0.01) and cholesterol ester transfer protein mass (-22.2 ± 6.8% at 24h, p<0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models. Conclusions These data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels. PMID:22456230

  13. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

    PubMed

    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

    2015-03-18

    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.

  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. 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.

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

    PubMed

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

    2016-01-18

    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.

  17. 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

  18. 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

  19. 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. PMID:27579193

  20. Non-HDL Cholesterol and Evaluation of Cardiovascular Disease Risk

    PubMed Central

    2010-01-01

    Cardiovascular disease (CVD), such as coronary heart disease (CHD), is the most frequent cause of death worldwide, especially in developed countries. The latest recommendations of European and American Cardiological Associations emphasize the role of non-HDL cholesterol (non-HDL-C) in evaluating the risk of CVD. Although this parameter has a lot of advantages, it is rarely used by general practitioners in lipid profile assessment. The aim of this article is to present the recent informations on the usage of non-HDL-C in the primary prevention of cardiovascular disease and to compare its diagnostic value to traditional and new CVD risk factors.

  1. 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

  2. Prospective study of coronary heart disease vs HDL2, HDL3, and other lipoproteins in Gofman’s Livermore Cohort

    PubMed Central

    Williams, Paul T.; Feldman, Daniel E.

    2013-01-01

    Objective To assess the relationship of lipoprotein subfractions to coronary heart disease (CHD). Methods Prospective 29.1 year follow-up of 1905 men measured for lipoprotein mass concentrations by analytic ultracentrifugation between 1954 and 1957. Vital status was determined for 97.2% of the cohort. Blinded physician medical record and death certificate review confirmed 179 CHD deaths. Follow-up questionnaires identified 182 nonfatal myocardial infarctions and 93 revascularization procedures from 1,346 (98.3%) of the surviving cohort and from the next-of-kin of 153 men who died. Results When adjusted for age, total incident CHD was inversely related to HDL2-mass (P=0.0001) and HDL3-mass (P=0.02), and concordantly related to LDL-mass (P<10−11), IDL-mass (P<10−7), and small (P<10−7) and large VLDL-mass concentrations (P=0.003). The hazard reduction per mg/dl of HDL was greater for HDL2-mass than HDL3-mass (P=0.04). The lowest quartiles of both HDL2-mass (P=0.007) and HDL3-mass (P=0.001) independently predicted total incident CHD when adjusted for traditional risk factors. Risk for premature CHD (≤ 65 years old) was significantly greater in men within the lowest HDL2 (P=0.03) and HDL3 quartiles (P=0.04) and having higher LDL-mass concentrations (P=0.001). Serum cholesterol’s relationship to incident CHD (P<10−8) was accounted for by adjustment for LDL-mass concentrations (adjusted P=0.90). Conclusions Lipoprotein subfractions differ in their relationship to CHD. PMID:21109246

  3. 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.

  4. Variability of plasma HDL subclass concentrations in men and women over time.

    PubMed

    Williams, P T; Dreon, D M; Blanche, P J; Krauss, R M

    1997-04-01

    Plasma HDL subclasses were examined by gradient gel electrophoresis in repeated samples to assess variability over time. Absorbance of the protein stain was used as an index of mass concentrations at 0.01-nm intervals within five HDL subclasses: HDL3c (7.2 to 7.8 nm), HDL3b (7.8 to 8.2 nm), HDL3a (8.2 to 8.8 nm), HDL2a (8.8 to 9.7 nm), and HDL2b (9.7 to 12 nm). Three separate longitudinal studies of men showed that repeated samples of HDL over time were correlated most strongly within HDL2b, somewhat less within HDL2a, and more weakly within HDL3a, HDL3b, and HDL3c. As in men, repeated samples in women from two studies were significantly correlated within the HDL2b, HDL2a, and HDL3b intervals. Plasma HDL2b levels were significantly more stable in men than in women. Although the variability of HDL subclass measurements includes both methodological and physiological sources, differences in laboratory measurement error do not appear to explain the differences in correlations among subclasses. Specifically, analysis of 288 replications from frozen aliquots suggested that laboratory error had the least effect on correlations involving HDL3 subclasses and only slightly greater effect on correlations involving HDL2 subclasses. Our results suggest that for plasma sampled over time, the stability of HDL subclass levels increases with particle size. Prior reports of subclass-specific correlations between HDL and other variables (eg, diet, exercise, and other lipids) are unlikely to be artifacts of laboratory precision but could arise from subclass differences in variability that are physiological.

  5. Pharmacological measures to increase HDL-C among high risk isolated low HDL cases: A randomized study amongst north Indians

    PubMed Central

    Kumar, Sudeep; Rai, Himanshu; Kapoor, Aditya; Tewari, Satyendra; Sinha, Nakul

    2013-01-01

    Background & objectives: Low serum levels of high density lipoprotein cholesterol (HDL-C) is an established risk factor for coronary heart disease (CHD). Among a variety of lipid modifying drugs, the best single drug therapy to increase HDL-C levels, especially among high risk, isolated low HDL-C (ILHDL-C) cases is yet to be identified. The objectives of the present study were to evaluate the best pharmacological measure among atorvastatin, fenofibrate and niacin aimed to raise HDL-C and its effect in decreasing the estimated Framingham-10-year CHD risk percentage (CHD-RP) among high risk ILHDL-C cases in north India. Methods: Two hundred CHD equivalent (CHD-RP≥20), ILHDL-C cases were randomly assigned for treatment either with atorvastatin 10 mg/day (n=70), micronized fenofibrate 160 mg/day (n=65) or niacin-extended release (ER) 750 mg/day (n=65). After 6 wk of treatment, the dosages of drugs were doubled and the patients were finally assessed after 12 wk for their lipid values. Results: Baseline characteristics were similar in the three groups. Niacin therapy 750 mg and 1.5 g/day resulted in a significant rise in HDL-C by 8.10 ± 3.19 and 12.41 ± 4.39 per cent (P<0.001), respectively. Fenofibrate 160 and 320 mg/day also resulted in a significant rise in HDL-C by 3.85 ± 3.48 and 6.24 ± 4.43 per cent (P<0.001), respectively, while atorvastatin 10 and 20 mg/day resulted in a non-significant increase in HDL-C by 0.13 ± 2.92 per cent and 0.51 ± 2.63 per cent, respectively. By increasing HDL-C values, niacin was found to be most effective in reduction of 10-year CHD-RP (P<0.001), followed by fenofibrate (P=0.010), while atorvastatin had no effect. Interpretation & conclusions: Our findings indicate that niacin rather than fibrates or statins seems to provide a safe and effective therapy for increasing HDL-C, thus reducing the cumulative CHD risk among ILHDL-C cases. PMID:24521629

  6. 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

  7. 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

  8. 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.

  9. 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

  10. Plasma lipidomics discloses metabolic syndrome with a specific HDL phenotype.

    PubMed

    Jové, Mariona; Naudí, Alba; Portero-Otin, Manuel; Cabré, Rosanna; Rovira-Llopis, Susana; Bañuls, Celia; Rocha, Milagros; Hernández-Mijares, Antonio; Victor, Victor M; Pamplona, Reinald

    2014-12-01

    Lipidomics reveals a remarkable diversity of lipids in human plasma. In this study, we have performed an in-depth lipidomic analysis of human plasma from healthy individuals and subjects with metabolic syndrome (MetS) in order to determine the lipidomic profile that allows prognosis of a pathological subpopulation with altered high-density lipoprotein (HDL) metabolism. The MetS population was categorized as having pathological or nonpathological HDL. Anthropometric parameters, cardiovascular risk markers, and lipoprotein subclasses of HDL and low-density lipoproteins were also evaluated. Lipidomic analysis revealed 357 differential molecules that were clustered (k means) in the two groups. The molecules identified in the whole lipidome showed that MetS subjects presented lower levels of glycerolipids and higher levels of glycerophospholipids with respect to control subjects. In contrast, when only statistically differential lipids were taken into account, differences were found between the two groups in almost cases. Furthermore, levels of saturated fatty acids were higher in patients with pathological HDL levels than in controls, whereas levels of unsaturated fatty acids were lower. These results highlight the potential of lipidomics as a clinical tool for risk assessment and monitoring of disease.

  11. 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

  12. 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... its intersection with Dillard Road, section 6, T6N, R7E (Elk Grove Quadrangle); then (5) Proceed northeast 2.6 miles on Dillard Road to its intersection with Lee Shorthorn Road, T7N, R7E...

  13. 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... its intersection with Dillard Road, section 6, T6N, R7E (Elk Grove Quadrangle); then (5) Proceed northeast 2.6 miles on Dillard Road to its intersection with Lee Shorthorn Road, T7N, R7E...

  14. 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... its intersection with Dillard Road, section 6, T6N, R7E (Elk Grove Quadrangle); then (5) Proceed northeast 2.6 miles on Dillard Road to its intersection with Lee Shorthorn Road, T7N, R7E...

  15. 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... its intersection with Dillard Road, section 6, T6N, R7E (Elk Grove Quadrangle); then (5) Proceed northeast 2.6 miles on Dillard Road to its intersection with Lee Shorthorn Road, T7N, R7E...

  16. 27 CFR 9.195 - Alta Mesa.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... County, California, and is entirely within the Lodi viticultural area (27 CFR 9.107). The Alta Mesa... its intersection with Dillard Road, section 6, T6N, R7E (Elk Grove Quadrangle); then (5) Proceed northeast 2.6 miles on Dillard Road to its intersection with Lee Shorthorn Road, T7N, R7E...

  17. 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.

  18. Outdoor temperature is associated with serum HDL and LDL

    PubMed Central

    Halonen, Jaana I.; Zanobetti, Antonella; Sparrow, David; Vokonas, Pantel S.; Schwartz, Joel

    2015-01-01

    Background While exposures to high and low air temperatures are associated with cardiovascular mortality, the underlying mechanisms are poorly understood. The risk factors for cardiovascular disease include high levels of total cholesterol and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL). We investigated whether temperature was associated with changes in circulating lipid levels, and whether this might explain part of the association with increased cardiovascular events. Methods The study cohort consisted of 478 men in the greater Boston area with a mean age of 74.2 years. They visited the clinic every 3–5 years between 1995–2008 for physical examination and to complete questionnaires. We excluded from analyses all men taking statin medication and all days with missing data, resulting in a total of 862 visits. Associations between three temperature variables (ambient, apparent, and dew point temperature) and serum lipid levels (total cholesterol, HDL, LDL, and triglycerides) were studied with linear mixed models that included possible confounders such as air pollution and a random intercept for each subject. Results We found that HDL decreased −1.76% (95% CI: −3.17 – −0.32, lag 2 days), and −5.58% (95% CI: −8.87 – −2.16, moving average of 4 weeks) for each 5°C increase in mean ambient temperature. For the same increase in mean ambient temperature, LDL increased by 1.74% (95% CI: 0.07 – 3.44, lag 1 day) and 1.87% (95% CI: 0.14 – 3.63, lag 2 days). These results were also similar for apparent and dew point temperatures. No changes were found in total cholesterol or triglycerides in relation to temperature increase. Conclusions Changes in HDL and LDL levels associated with an increase in ambient temperature may be among the underlying mechanisms of temperature-related cardiovascular mortality. PMID:21172696

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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 ...

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

    PubMed Central

    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

    2015-01-01

    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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Higher hdl levels are a preventive factor for metabolic syndrome in obese Turkish children.

    PubMed

    Özer, Samet; Yılmaz, Resul; Özlem Kazanci, Nafia; Sönmezgöz, Ergün; Karaaslan, Erhan; Altuntaş, Buket; Emre Kuyucu, Yunus

    2014-10-03

    Objetivo: El síndrome metabólico infantil no ha sido definido aún con claridad. La obesidad infantil se está incrementando progresivamente al igual que la incidencia del síndrome metabólico infantil. Nuestro objetivo ha sido mostrar los componentes del síndrome metabólico y sus factores preventivos en los niños obesos. Metodología: Este estudio analizó de forma retrospectiva a 187 niños y adolescentes obesos de entre 5 y 18 años. Los datos demográficos, las medidas antropomórficas, los índices de masa corporal, los valores de presión sanguínea, los niveles de insulina, los resultados de test de tolerancia a la glucosa oral, el total de colesterol, las lipoproteínas de gran densidad y los niveles de triglicéridos fueron obtenidos de registros hospitalarios. Una masa corporal con un índice superior a 95 percentiles fue considerada como obesidad. La resistencia a la insulina se calculó de acuerdo con el test de tolerancia a la glucosa oral con 1,75 g/kg de glucosa y un máximo de 75 gramos de glucosa. Se calculó y comparó el índice de sensibilidad a la insulina y la evaluación del modelos homeostático- resistencia a la insulina (HOMA IR). El síndrome metabólico fue diagnosticado de acuerdo con los nuevos criterios de la OMS adaptados a los síndromes metabólicos infantiles. Resultados: Se observó una homeostasis de glucosa anormal en el 53% de los casos. La dislipidemia estaba presente en el 45,7% de los pacientes y la hipertensión en un 16,6%. El síndrome metabólico fue identificado en un 24,6% de los niños y adolescentes obesos. Altos valores de HOMA-IR y de glucosa, triglicéridos elevados y niveles bajos de HDL eran indicadores de síndrome metabólico. Conclusión: La obesidad y la resistencia a la insulina son factores significativos para el desarrollo del síndrome metabólico en niños y adolescentes. En niños obesos altos niveles de HDL son un factor preventivo del síndrome metabólico. Prevenir la obesidad y la

  11. Low HDL cholesterol, aggression and altered central serotonergic activity.

    PubMed

    Buydens-Branchey, L; Branchey, M; Hudson, J; Fergeson, P

    2000-03-01

    Many studies support a significant relation between low cholesterol levels and poor impulse, aggression and mood control. Evidence exists also for a causal link between low brain serotonin (5-HT) activity and these behaviors. Mechanisms linking cholesterol and hostile or self-destructive behavior are unknown, but it has been suggested that low cholesterol influences 5-HT function. This study was designed to explore the relationship between plasma cholesterol, measures of impulsivity and aggression, and indices of 5-HT function in personality disordered cocaine addicts. Thirty-eight hospitalized male patients (age 36.8+/-7.1) were assessed with the DSM-III-R, the Buss-Durkee Hostility Inventory (BDHI), the Barratt Impulsiveness Scale (BIS) and the Brown-Goodwin Assessment for Life History of Aggression. Fasting basal cholesterol (total, LDL and HDL) was determined 2 weeks after cocaine discontinuation. On the same day 5-HT function was assessed by neuroendocrine (cortisol and prolactin) and psychological (NIMH and 'high' self-rating scales) responses following meta-chlorophenylpiperazine (m-CPP) challenges. Reduced neuroendocrine responses, 'high' feelings and increased 'activation-euphoria' following m-CPP have been interpreted as indicating 5-HT alterations in a variety of psychiatric conditions. Significantly lower levels of HDL cholesterol were found in patients who had a history of aggression (P=0.005). Lower levels of HDL cholesterol were also found to be significantly associated with more intense 'high' and 'activation-euphoria' responses as well as with blunted cortisol responses to m-CPP (P=0.033, P=0.025 and P=0.018, respectively). This study gives further support to existing evidence indicating that in some individuals, the probability of exhibiting impulsive and violent behaviors may be increased when cholesterol is low. It also suggests that low cholesterol and alterations in 5-HT activity may be causally related.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. HDL-apoA-I Exchange: Rapid Detection and Association with Atherosclerosis

    PubMed Central

    Borja, Mark S.; Zhao, Lei; Hammerson, Bradley; Tang, Chongren; Yang, Richard; Carson, Nancy; Fernando, Gayani; Liu, Xiaoqin; Budamagunta, Madhu S.; Genest, Jacques; Shearer, Gregory C.; Duclos, Franck; Oda, Michael N.

    2013-01-01

    High density lipoprotein (HDL) cholesterol levels are associated with decreased risk of cardiovascular disease, but not all HDL are functionally equivalent. A primary determinant of HDL functional status is the conformational adaptability of its main protein component, apoA-I, an exchangeable apolipoprotein. Chemical modification of apoA-I, as may occur under conditions of inflammation or diabetes, can severely impair HDL function and is associated with the presence of cardiovascular disease. Chemical modification of apoA-I also impairs its ability to exchange on and off HDL, a critical process in reverse cholesterol transport. In this study, we developed a method using electron paramagnetic resonance spectroscopy (EPR) to quantify HDL-apoA-I exchange. Using this approach, we measured the degree of HDL-apoA-I exchange for HDL isolated from rabbits fed a high fat, high cholesterol diet, as well as human subjects with acute coronary syndrome and metabolic syndrome. We observed that HDL-apoA-I exchange was markedly reduced when atherosclerosis was present, or when the subject carries at least one risk factor of cardiovascular disease. These results show that HDL-apoA-I exchange is a clinically relevant measure of HDL function pertinent to cardiovascular disease. PMID:24015188

  17. [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

  18. Effects of cigarette smoking on HDL quantity and function: implications for atherosclerosis.

    PubMed

    He, Bai-mei; Zhao, Shui-ping; Peng, Zhen-yu

    2013-11-01

    Cigarette smoking has been identified as an independent and preventable risk factor for atherosclerosis and cardiovascular disease. Population studies have shown that plasma high density lipoprotein (HDL) cholesterol levels are inversely related to the risk of developing cardiovascular disease. Cigarette smoking is associated with reduced HDL cholesterol levels. Cigarette smoking can alter the critical enzymes of lipid transport, lowering lecithin: cholesterol acyltransferase (LCAT) activity and altering cholesterol ester transfer protein (CETP) and hepatic lipase activity, which attributes to its impact on HDL metabolism and HDL subfractions distribution. In addition, HDL is susceptible to oxidative modifications by cigarette smoking, which makes HDL become dysfunctional and lose its atheroprotective properties in smokers. Therefore, cigarette smoking has a negative impact on both HDL quantity and function, which can explain, in part, the increased risk of cardiovascular disease in smokers. PMID:23852759

  19. 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

  20. 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.

  1. Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach.

    PubMed

    Gadkar, Kapil; Lu, James; Sahasranaman, Srikumar; Davis, John; Mazer, Norman A; Ramanujan, Saroja

    2016-01-01

    The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate.

  2. Targeted next-generation sequencing to diagnose disorders of HDL cholesterol[S

    PubMed Central

    Sadananda, Singh N.; Foo, Jia Nee; Toh, Meng Tiak; Cermakova, Lubomira; Trigueros-Motos, Laia; Chan, Teddy; Liany, Herty; Collins, Jennifer A.; Gerami, Sima; Singaraja, Roshni R.; Hayden, Michael R.; Francis, Gordon A.; Frohlich, Jiri; Khor, Chiea Chuen; Brunham, Liam R.

    2015-01-01

    A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS. PMID:26255038

  3. 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

  4. 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

    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.

  5. An update on testosterone, HDL and cardiovascular risk in men

    PubMed Central

    Thirumalai, Arthi; Rubinow, Katya B; Page, Stephanie T

    2015-01-01

    Testosterone prescriptions have risen steadily and sharply in the USA despite a lack of clear understanding of the relationship between androgens and cardiovascular disease. In men with increasing age, testosterone levels decline and cardiovascular disease risk goes up. Ties between hypogonadism and cardiovascular disease are suggested by observational data, yet therapy with testosterone replacement has not been shown to mitigate that risk. To the contrary, recent literature has raised concern for increased cardiovascular disease in certain groups of men receiving testosterone therapy. In this article, we review current literature in an attempt to better understand what it suggests is the true relationship between testosterone and cardiovascular disease. We also take a closer look at effects of testosterone on lipids and HDL in particular, to see if this explains the cardiovascular effects seen in clinical studies. PMID:26257830

  6. 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

  7. 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…

  8. Serum opacity factor enhances HDL-mediated cholesterol efflux, esterification and anti inflammatory effects.

    PubMed

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

    2010-12-01

    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.

  9. 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

  10. 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.

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

    PubMed Central

    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.

    2016-01-01

    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

  12. Carotid intima media thickness and low high-density lipoprotein (HDL) in South Asian immigrants: could dysfunctional HDL be the missing link?

    PubMed Central

    Dong, Lei; Guirgis, Faheem W.; Reddy, Srinivasa T.

    2014-01-01

    Introduction South Asian immigrants (SAIs) in the US exhibit higher prevalence of coronary artery disease (CAD) and its risk factors compared with other ethnic populations. Conventional CAD risk factors do not explain the excess CAD risk; therefore there is a need to identify other markers that can predict future risk of CAD in high-risk SAIs. The objective of the current study is to assess the presence of sub-clinical CAD using common carotid artery intima-media thickness (CCA-IMT), and its association with metabolic syndrome (MS) and pro-inflammatory/dysfunctional HDL (Dys-HDL). Material and methods A community-based study was conducted on 130 first generation SAIs aged 35–65 years. Dys-HDL was determined using the HDL inflammatory index. Analysis was completed using logistic regression and Fisher's exact test. Results Sub-clinical CAD using CCA-IMT ≥ 0.8 mm (as a surrogate marker) was seen in 31.46%. Age and gender adjusted CCA-IMT was significantly associated with type 2 diabetes (p = 0.008), hypertension (p = 0.012), high-sensitivity C-reactive protein (p < 0.001) and homocysteine (p = 0.051). Both the presence of MS and Dys-HDL was significantly correlated with CCA-IMT, even after age and gender adjustment. The odds of having Dys-HDL with CCA-IMT were 5 times (95% CI: 1.68, 10.78). Conclusions There is a need to explore and understand non-traditional CAD risk factors with a special focus on Dys-HDL, knowing that SAIs have low HDL levels. This information will not only help to stratify high-risk asymptomatic SAI groups, but will also be useful from a disease management point of view. PMID:25395937

  13. Xanthophylls, phytosterols and pre-β1-HDL are differentially affected by fenofibrate and niacin HDL-raising in a cross-over study.

    PubMed

    Niesor, Eric J; Gauthamadasa, Kekulawalage; Silva, R A Gangani D; Suchankova, Gabriela; Kallend, David; Gylling, Helena; Asztalos, Bela; Damonte, Elisabetta; Rossomanno, Simona; Abt, Markus; Davidson, W Sean; Benghozi, Renee

    2013-12-01

    Fenofibrate and extended-release (ER) niacin similarly raise high-density lipoprotein cholesterol (HDL-C) concentration but their effects on levels of potent plasma antioxidant xanthophylls (lutein and zeaxanthin) and phytosterols obtained from dietary sources, and any relationship with plasma lipoproteins and pre-β1-HDL levels, have not been investigated. We studied these parameters in 66 dyslipidemic patients treated for 6 week with fenofibrate (160 mg/day) or ER-niacin (0.5 g/day for 3 week, then 1 g/day) in a cross-over study. Both treatments increased HDL-C (16 %) and apolipoprotein (apo) A-I (7 %) but only fenofibrate increased apoA-II (28 %). Lutein and zeaxanthin levels were unaffected by fenofibrate but inversely correlated with percentage change in apoB and low-density lipoprotein cholesterol and positively correlated with end of treatment apoA-II. ApoA-II in isolated HDL in vitro bound more lutein than apoA-I. Xanthophylls were increased by ER-niacin (each ~30 %) without any correlation to lipoprotein or apo levels. Only fenofibrate markedly decreased plasma markers of cholesterol absorption; pre-β1-HDL was significantly decreased by fenofibrate (-19 %, p < 0.0001), with little change (3.4 %) for ER-niacin. Although fenofibrate and ER-niacin similarly increased plasma HDL-C and apoA-I, effects on plasma xanthophylls, phytosterols and pre-β1-HDL differed markedly, suggesting differences in intestinal lipidation of HDL. In addition, the in vitro investigations suggest an important role of plasma apoA-II in xanthophyll metabolism.

  14. [Low HDL-cholesterol--an important risk factor for cardiovascular diseases].

    PubMed

    Reiner, Zeljko; Muacević-Katanec, Diana; Katanec, Davor; Tedeschi-Reiner, Eugenia

    2011-01-01

    It has been known for quite a long time that the concentration of HDL-cholesterol correlates inversely with cardiovascular disease (CVD) risk and that low HDL-cholesterol is an independent CVD risk factor. This review aims to highlight evidence on several topics concerning the role of HDL particles and the importance of HDL-cholesterol. The main antiatherogenic functions of HDL particles are presented in details--reverse cholesterol transport, but also their anti-oxidant, anti-inflammatory, anti-thrombotic and anti-apoptotic properties as well as endothelial stabilizing and repair properties. Lifestyle management of low HDL-cholesterol is explained, particularly physical activity and aerobic exercise, smoking cessation, weight reduction in the overweight individuals and composition of the diet but also moderate alcohol consumption stressing the fact that HDL particles from alcoholics are dysfunctional. This is important since it has been shown that it is not only the quantity of HDL particles, and thus HDL-cholesterol level in plasma, that matters, but their quality and impaired functionality as well. HDL from diabetic subjects also lose some of their antiatherogenic properties but a common feature of patients with diabetes type 2 is atherogenic dyslipidemia which is characterized exactly by low HDL-cholesterol and high triglycerides. Diabetic patients with such dyslipidemia are at particularly high CVD risk and the results of recent studies such as ACCORD-Lipid suggest that in them treatment of these lipid abnormalities may be beneficial. Treatment options with fibrates, particularly fenofibrate, and niacin are discussed based upon published trials, as well as combination therapy with these medicines and other lipid-lowering drugs.

  15. 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

  16. Subjects with Low Plasma HDL Cholesterol Levels Are Characterized by an Inflammatory and Oxidative Phenotype

    PubMed Central

    Holven, Kirsten B.; Retterstøl, Kjetil; Ueland, Thor; Ulven, Stine M.; Nenseter, Marit S.; Sandvik, Marit; Narverud, Ingunn; Berge, Knut E.; Ose, Leiv; Aukrust, Pål; Halvorsen, Bente

    2013-01-01

    Background Epidemiological studies have shown that low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risk of cardiovascular disease, but the mechanisms for the possible atheroprotective effects of HDL cholesterol have still not been fully clarified, in particular in relation to clinical studies. Objective To examine the inflammatory, anti-oxidative and metabolic phenotype of subjects with low plasma HDL cholesterol levels. Methods and Results Fifteen subjects with low HDL cholesterol levels (eleven males and four females) and 19 subjects with high HDL (three males and 16 females) were recruited. Low HDL cholesterol was defined as ≤10th age/sex specific percentile and high HDL-C was defined as ≥90 age/sex specific percentile. Inflammatory markers in circulation and PBMC gene expression of cholesterol efflux mediators were measured. Our main findings were: (i) subjects with low plasma HDL cholesterol levels were characterized by increased plasma levels of CRP, MMP-9, neopterin, CXCL16 and ICAM-1 as well as low plasma levels of adiponectin, suggesting an inflammatory phenotype; (ii) these individuals also had reduced paraoxonase (PON)1 activity in plasma and PON2 gene expression in peripheral blood mononuclear cells (PBMC) accompanied by increased plasma levels of oxidized LDL suggesting decreased anti-oxidative capacity; and (iii) PBMC from low HDL subjects also had decreased mRNA levels of ABCA1 and ABCG1, suggesting impaired reverse cholesterol transport. Conclusion Subjects with low plasma HDL cholesterol levels are characterized by an inflammatory and oxidative phenotype that could contribute to the increased risk of atherosclerotic disorders in these subjects with low HDL levels. PMID:24244297

  17. Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE.

    PubMed

    Yuan, Quan; Bie, Jinghua; Wang, Jing; Ghosh, Siddhartha S; Ghosh, Shobha

    2013-11-01

    Liver is the sole organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or bile acids. High density lipoprotein (HDL)-derived cholesterol is the major source of biliary sterols and represents a mechanism for the removal of cholesterol from peripheral tissues including artery wall-associated macrophage foam cells. Via selective uptake through scavenger receptor BI (SR-BI), HDL-cholesterol is thought to be directly secreted into bile, and HDL cholesteryl esters (HDL-CEs) enter the hepatic metabolic pool and need to be hydrolyzed prior to conversion to bile acids. However, the identity of hepatic CE hydrolase (CEH) as well as the role of SR-BI in bile acid synthesis remains elusive. In this study we examined the role of human hepatic CEH (CES1) in facilitating hydrolysis of SR-BI-delivered HDL-CEs. Over-expression of CEH led to increased hydrolysis of HDL-[³H]CE in primary hepatocytes and SR-BI expression was required for this process. Intracellular CEH associated with BODIPY-CE delivered by selective uptake via SR-BI. CEH and SR-BI expression enhanced the movement of [³H]label from HDL-[³H]CE to bile acids in vitro and in vivo. Taken together, these studies demonstrate that SR-BI-delivered HDL-CEs are hydrolyzed by hepatic CEH and utilized for bile acid synthesis. PMID:23990661

  18. 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

  19. Plasma triglyceride/HDL-cholesterol ratio, insulin resistance, and cardiometabolic risk in young adults

    PubMed Central

    Murguía-Romero, Miguel; Jiménez-Flores, J. Rafael; Sigrist-Flores, Santiago C.; Espinoza-Camacho, Miguel A.; Jiménez-Morales, Mayra; Piña, Enrique; Méndez-Cruz, A. René; Villalobos-Molina, Rafael; Reaven, Gerald M.

    2013-01-01

    Studies in mature adults suggest that the plasma concentration ratio of triglyceride (TG)/HDL-cholesterol (HDL-C) provides a simple way to identify apparently healthy individuals who are insulin resistant (IR) and at increased cardiometabolic risk. This study extends these observations by examining the clinical utility of the TG/HDL-C ratio and the metabolic syndrome (MetS) in 2,244 healthy college students (17–24 years old) of Mexican Mestizo ancestry. The TG/HDL-C ratio separating the 25% with the highest value was used to identify IR and increased cardiometabolic risk. Cardiometabolic risk factors were more adverse in men and women whose TG/HDL-C ratios exceeded 3.5 and 2.5, respectively, and approximately one third were identified as being IR. The MetS identified fewer individuals as being IR, but their risk profile was accentuated. In conclusion, both a higher TG/HDL-C ratio and a diagnosis of the MetS identify young IR individuals with an increased cardiometabolic risk profile. The TG/HDL-C ratio identified a somewhat greater number of “high risk” subjects, whereas the MetS found a group whose risk profile was somewhat magnified. These findings suggest that the TG/HDL-C ratio may serve as a simple and clinically useful approach to identify apparently healthy, young individuals who are IR and at increased cardiometabolic risk. PMID:23863983

  20. Statins, atherosclerosis regression and HDL: Insights from within the plaque.

    PubMed

    Feig, Jonathan E; Feig, Jessica L; Kini, Annapoorna S

    2015-06-15

    The idea that atheroma can regress is no longer a dream. We and others have discovered that decreasing the lipid content can directly lead to macrophage egress and plaque healing. The question, however, has remained as to how to translate these findings to the bedside. Taking advantage of imaging modalities such as intravascular ultrasound (IVUS) and near infrared spectroscopy (NIRS), we demonstrated in the YELLOW (Reduction in Yellow Plaque by Intensive Lipid Lowering Therapy) trial that short term treatment of high dose rosuvastatin treatment can lead to a decrease in lipid content in plaques. It is important to note that optical coherence tomography (OCT), a high resolution imaging modality, was not performed during the first study and therefore, only a very limited assessment of the effect of statin therapy on measures of plaque stabilization could be made. The YELLOW II trial is the first to our knowledge to determine whether these data can be extrapolated and how it relates to HDL function, alterations in macrophage gene expression, and plaque morphology. While tremendous progress has been made, our research serves as a reminder that angiography is simply luminography and it is features such as thin cap fibroatheroma and lipid burden, for example, that likely modulate the syndromes seen in clinical practice. Ongoing studies such as ours may provide novel pathways for diagnosis and therapy, with the ultimate goal of reducing the burden of cardiovascular disease.

  1. 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

  2. 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

  3. Large HDL Subfraction But Not HDL-C Is Closely Linked With Risk Factors, Coronary Severity and Outcomes in a Cohort of Nontreated Patients With Stable Coronary Artery Disease: A Prospective Observational Study.

    PubMed

    Li, Jian-Jun; Zhang, Yan; Li, Sha; Cui, Chuan-Jue; Zhu, Cheng-Gang; Guo, Yuan-Lin; Wu, Na-Qiong; Xu, Rui-Xia; Liu, Geng; Dong, Qian; Sun, Jing

    2016-01-01

    High-density lipoprotein (HDL) is highly heterogeneous in its size and composition. Till now, the link of HDL subfractions to coronary risk is less clear. We aimed to investigate the associations of HDL subfractions with traditional risk factors (RFs), coronary severity, and outcomes in a cohort of nontreated patients with stable coronary artery disease (CAD). We prospectively enrolled 591 eligible patients. Baseline HDL subfractions were separated by Lipoprint system. HDL subfractions (large, medium, and small) and HDL-cholesterol (HDL-C) levels were dichotomized into low and high group according to the 50 percentile. Coronary severity was evaluated by SYNTAX, Gensini, and Jeopardy scoring systems. Patients were followed up annually for major adverse cardiovascular events (MACEs). Cox proportional hazards' models were used to evaluate the risk of HDL subfractions on MACEs. Patients with high large HDL-C levels had a decreased number of RFs. Significantly, large HDL-C levels were negatively associated with coronary severity assessed by SYNTAX and Gensini score (both P < 0.05). New MACEs occurred in 67 (11.6%) patients during a median 17.0 months follow-up. Moreover, the log-rank test revealed that there was a significant difference between high and low large HDL-C groups in event-free survival analysis (P = 0.013), but no differences were observed in total HDL-C groups and medium or small HDL-C groups (both P > 0.05). In particular, the multivariate Cox-proportional hazards model revealed that high large HDL-C was associated with lower MACEs risk (hazard ratio [95% confidence interval] 0.531 [0.295-0.959]) independent of potential confounders. Higher large HDL-C but not medium, small, or total HDL-C is associated with lower cardiovascular risk, highlighting the potential beneficial of HDL subfractionation.

  4. Lipoprotein subfraction profile and HDL-associated enzymes in sickle cell disease patients.

    PubMed

    Ozturk, Oktay H; Can, Yesim; Yonden, Zafer; Motor, Sedat; Oktay, Gonul; Kaya, Hasan; Aslan, Mutay

    2013-12-01

    Although hypocholesterolemia is a reported finding in sickle cell disease (SCD), low-density lipoprotein (LDL)/high-density lipoprotein (HDL) subfractions and HDL-associated enzymes have not been determined in SCD patients. Blood was collected from 38 hemoglobin (Hb)A volunteers and 45 homozygous HbSS patients who had not received blood transfusions in the last 3 months. Serum lipids were measured by automated analyzer while LDL and HDL subfraction analysis was done by continuous disc polyacrylamide gel electrophoresis. Serum levels of cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-I) were determined by enzyme-linked immunosorbent assay (ELISA). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels were significantly decreased, while TG levels were significantly increased in SCD patients compared to controls. A significant decrease in intermediate-density lipoprotein (IDL)-C, IDL-B, IDL-A and LDL-1 fractions were seen in SCD patients, while no significant difference was observed in small dense LDL particles. A significant decrease was seen in HDL-large, HDL-intermediate and HDL-small fractions in SCD patients versus controls. Levels of LCAT and ApoA-1 protein measured in SCD patients were significantly lower while no significant difference was observed in CETP and ApoB protein levels compared to controls. The reduction observed in LDL- and HDL-C in SCD patients was reflected as significantly decreased IDL, LDL-1 and HDL-subfractions. Decreased HDL subfractions may possibly lead to the reduced ApoA-1 and LCAT protein levels observed in SCD patients. PMID:24113910

  5. 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.

  6. 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

  7. 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.

  8. Role of HDL in cholesteryl ester metabolism of lipopolysaccharide-activated P388D1 macrophages.

    PubMed

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

    2013-11-01

    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

  9. Evidence of linkage of HDL level variation to APOC3 in two samples with different ascertainment.

    PubMed

    Gagnon, France; Jarvik, Gail P; Motulsky, Arno G; Deeb, Samir S; Brunzell, John D; Wijsman, Ellen M

    2003-11-01

    The APOA1-C3-A4-A5 gene complex encodes genes whose products are implicated in the metabolism of HDL and/or triglycerides. Although the relationship between polymorphisms in this gene cluster and dyslipidemias was first reported more than 15 years ago, association and linkage results have remained inconclusive. This is due, in part, to the oligogenic and multivariate nature of dyslipidemic phenotypes. Therefore, we investigate evidence of linkage of APOC3 and HDL using two samples of dyslipidemic pedigrees: familial combined hyperlipidemia (FCHL) and isolated low-HDL (ILHDL). We used a strategy that deals with several difficulties inherent in the study of complex traits: by using a Bayesian Markov Chain Monte Carlo (MCMC) approach we allow for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. By using this approach on extended pedigrees we provide evidence of linkage of APOC3 and HDL level variation in two samples with different ascertainment. In addition to APOC3, we estimate that two to three genes, each with a substantial effect on total variance, are responsible for HDL variation in both data sets. We also provide evidence, using the FCHL data set, for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus.

  10. Modulation of HDL metabolism by the niacin receptor GPR109A in mouse hepatocytes.

    PubMed

    Li, Xiaoyu; Millar, John S; Brownell, Nicholas; Briand, François; Rader, Daniel J

    2010-11-01

    The niacin receptor GPR109A is a G(i)-protein-coupled receptor which mediates the effects of niacin on inhibiting intracellular triglyceride lipolysis in adipocytes. However, the role of GPR109A in mediating the effects of niacin on high density lipoprotein (HDL) metabolism is unclear. We found niacin has no effect on HDL-C in GPR109A knockout mice. Furthermore, niacin lowered intracellular cAMP in primary hepatocytes mediated by GPR109A. We used an adeno-associated viral (AAV) serotype 8 vector encoding GPR109A under the control of the hepatic-specific thyroxine-binding globulin promoter to specifically overexpress GPR109A in mouse liver. Plasma HDL-C, hepatic ABCA1 and the HDL cholesterol production rate were significantly reduced in mice overexpressing GPR109A. Overexpression of GPR109A reduced primary hepatocyte free cholesterol efflux to apoA-I; conversely, GPR109A deficient hepatocytes had increased ABCA1-mediated cholesterol efflux. These data support the concept that the HDL-C lowering effect of niacin in wild-type mice is mediated through stimulation of GPR109A in hepatocytes; such an effect then leads to reduced hepatocyte ABCA1 expression and activity, decreased cholesterol efflux to nascent apoA-I, and reduced HDL-C levels. These results indicate that niacin-mediated activation of GP109A in liver lowers ABCA1 expression leading to reduced hepatic cholesterol efflux to HDL.

  11. Pleiotropic effects on subclasses of HDL, adiposity and glucose metabolism in adult Alaskan Eskimos

    PubMed Central

    Tejero, ME; Voruganti, VS; Cai, G; Cole, SA; Laston, S; Wenger, CR; MacCluer, JW; Dyke, B; Devereux, R; Ebbesson, SO; Fabsitz, RR; Howard, BV; Comuzzie, AG

    2012-01-01

    The aim of the present study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity and glucose metabolism in adult Alaskan Eskimos. The present family study included 1214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 ± 0.11 for LDL2 (intermediate) to 0.89 ± 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions and HDL size and measures of adiposity, LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity and glucose regulation. PMID:19950191

  12. Pro-oxidant HDL predicts poor outcome in patients with ST-elevation acute coronary syndrome.

    PubMed

    Distelmaier, Klaus; Schrutka, Lore; Seidl, Veronika; Winter, Max P; Wurm, Raphael; Mangold, Andreas; Perkmann, Thomas; Maurer, Gerald; Adlbrecht, Christopher; Lang, Irene M

    2015-07-01

    Oxidative stress affects clinical outcome in patients with ST-elevation acute coronary syndrome (STE-ACS). Although high-density lipoprotein (HDL) particles are generally considered protective, deleterious properties of HDL have been observed in patients with acute myocardial infarction. Here, we analysed the association between pro-oxidant HDL and all-cause mortality in STE-ACS patients. We determined the antioxidant function of HDL in 247 prospectively enrolled patients undergoing primary percutaneous coronary intervention for STE-ACS. Patients were stratified as by a pro-oxidant serum HDL oxidant index (HOI≥ 1) or with an antioxidant serum HOI (HOL< 1) capacity. Multivariate regression analysis was used to relate HOI to survival. The median follow-up time was 23 months (IQR 14.4-40.0 months). Pro-oxidant HDL was observed in 44.1 % of STE-ACS patients and was independently associated with all-cause mortality with a hazard ratio of 3.30(95 %CI 1.50-7.27, p = 0.003). Mortality rates were higher in patients with baseline pro-oxidant HDL compared to patients with preserved HDL function at 30 days (11.9 % vs 2.2 %, p=0.002), and at 4 years (22.9 % vs 8.7 %, p=0.002). Elevated neutrophil counts were a strong and independent predictor for pro-oxidant HDL with an odds ratio per standard deviation of 1.50 (95 %CI 1.11-2.03, p=0.008), as was history of prior acute myocardial infarction, elevated triglycerides levels and reduced glomerular filtration rate. In conclusion, pro-oxidant HDL represents a strong and independent predictor of long-term as well as short-term all-cause mortality in STE-ACS patients. Elevated neutrophil counts predicted the presence of serum pro-oxidant HDL. The maintenance of HDL functions might be a promising therapeutic target in STE-ACS patients.

  13. 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

  14. 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

  15. 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

  16. Anti-Brownian ELectrokinetic (ABEL) Trapping of Single High Density Lipoprotein (HDL) Particles

    NASA Astrophysics Data System (ADS)

    Bockenhauer, Samuel; Furstenberg, Alexandre; Wang, Quan; Devree, Brian; Jie Yao, Xiao; Bokoch, Michael; Kobilka, Brian; Sunahara, Roger; Moerner, W. E.

    2010-03-01

    The ABEL trap is a novel device for trapping single biomolecules in solution for extended observation. The trap estimates the position of a fluorescently-labeled object as small as ˜10 nm in solution and then applies a feedback electrokinetic drift every 20 us to trap the object by canceling its Brownian motion. We use the ABEL trap to study HDL particles at the single-copy level. HDL particles, essential in regulation of ``good'' cholesterol in humans, comprise a small (˜10 nm) lipid bilayer disc bounded by a belt of apolipoproteins. By engineering HDL particles with single fluorescent donor/acceptor probes and varying lipid compositions, we are working to study lipid diffusion on small length scales. We also use HDL particles as hosts for single transmembrane receptors, which should enable study of receptor conformational dynamics on long timescales.

  17. 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.

  18. Omega-3 fatty acids and HDL. How do they work in the prevention of cardiovascular disease?

    PubMed

    Burillo, Elena; Martín-Fuentes, Paula; Mateo-Gallego, Rocío; Baila-Rueda, Lucía; Cenarro, Ana; Ros, Emilio; Civeira, Fernando

    2012-07-01

    Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) from marine origin have been strongly associated with cardiovascular protection, even at low doses ( < 1g/d). Despite the research performed in this promising area, basic aspects, such as the ideal doses and the mechanisms by which ω-3 PUFAs act, are not precisely defined. The best known biological property of ω-3 PUFAs is their hypotriglyceridemic effect, but other cardioprotective actions, such as reduction of arrhythmia susceptibility, antithrombotic, antiinflammatory and antioxidant effects, improvement of endothelial function, and delayed atherosclerosis development have received an increased interest in recent years. Some of these actions are also ascribable to high-density lipoproteins (HDL). Abundant epidemiological evidence links increasing HDL-cholesterol concentrations to cardiovascular protection. Recently, the protein cargo (proteome) of HDL particles has been attributed a key role in their functionality. In this review, we summarize the main effects of ω-3 PUFAs on HDL-cholesterol, HDL subfractions, and its main proteins, apolipoproteins (apo) AI and AII. The shared cardioprotective actions of ω-3 PUFAs and HDL are reviewed as well.

  19. Omega-3 fatty acids and HDL. How do they work in the prevention of cardiovascular disease?

    PubMed

    Burillo, Elena; Martín-Fuentes, Paula; Mateo-Gallego, Rocío; Baila-Rueda, Lucía; Cenarro, Ana; Ros, Emilio; Civeira, Fernando

    2012-07-01

    Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) from marine origin have been strongly associated with cardiovascular protection, even at low doses ( < 1g/d). Despite the research performed in this promising area, basic aspects, such as the ideal doses and the mechanisms by which ω-3 PUFAs act, are not precisely defined. The best known biological property of ω-3 PUFAs is their hypotriglyceridemic effect, but other cardioprotective actions, such as reduction of arrhythmia susceptibility, antithrombotic, antiinflammatory and antioxidant effects, improvement of endothelial function, and delayed atherosclerosis development have received an increased interest in recent years. Some of these actions are also ascribable to high-density lipoproteins (HDL). Abundant epidemiological evidence links increasing HDL-cholesterol concentrations to cardiovascular protection. Recently, the protein cargo (proteome) of HDL particles has been attributed a key role in their functionality. In this review, we summarize the main effects of ω-3 PUFAs on HDL-cholesterol, HDL subfractions, and its main proteins, apolipoproteins (apo) AI and AII. The shared cardioprotective actions of ω-3 PUFAs and HDL are reviewed as well. PMID:22339302

  20. Grape Polyphenols Increase the Activity of HDL Enzymes in Old and Obese Rats

    PubMed Central

    Zagayko, Andriy L.; Kravchenko, Ganna B.; Krasilnikova, Oksana A.; Ogai, Yuri O.

    2013-01-01

    HDL particles are protein-rich particles that act as a vehicle for reverse cholesterol transport from tissues to the liver. The purpose of this study was to investigate age-dependent changes in the functional activity of HDL and the effect of high-energy diet on this index, as well as to correct it under the influence of grape polyphenols from “Enoant” obtained from Vitis vinifera grapes. We observed the age-dependent composition changes in HDL particle. It was shown that total lipids and triacylglycerol (TG) levels were higher in 24-month-old animals. In obese rats, HDL total lipids and TG levels were higher in 24-month-old than in the 3-month-old and 12-month-old groups but did not differ from 24-month-old group. The plasma HDL paraoxonase (PON) and lecithin:cholesterol acyltransferase (LCAT) activity levels were decreased in old-aged rats, and cholesteryl ester transfer protein (CETP) activity was higher in old rats. Keeping 12-month-old animals on high-fructose diet completely leveled the age differences in the data that have been measured between 12-month-old and 24-month-old rats. After “Enoant” administration, an increase of HDL PON and LCAT activity levels and a reduction of CETP activity were found in 24-month-old and obese rats. PMID:23936611

  1. Can novel Apo A-I polymorphisms be responsible for low HDL in South Asian immigrants?

    PubMed Central

    Dodani, Sunita; Dong, Yanbin; Zhu, Haidong; George, Varghese

    2008-01-01

    Coronary artery disease (CAD) is the leading cause of death in the world. Even though its rates have decreased worldwide over the past 30 years, event rates are still high in South Asians. South Asians are known to have low high-density lipoprotein (HDL) levels. The objective of this study was to identify Apolipoprotein A-I (Apo A-I) polymorphisms, the main protein component of HDL and explore its association with low HDL levels in South Asians. A pilot study on 30 South Asians was conducted and 12-h fasting samples for C-reactive protein, total cholesterol, HDL, low-density lipoprotein (LDL), triglycerides, Lipoprotein (a), Insulin, glucose levels, DNA extraction, and sequencing of Apo A-I gene were done. DNA sequencing revealed six novel Apo A-I single nucleotide polymorphisms (SNPs) in South Asians, one of which (rs 35293760, C938T) was significantly associated with low (<40 mg/dl) HDL levels (P = 0.004). The association was also seen with total cholesterol (P = 0.026) and LDL levels (P = 0.032). This pilot work has highlighted some of the gene-environment associations that could be responsible for low HDL and may be excess CAD in South Asians. Further larger studies are required to explore and uncover these associations that could be responsible for excess CAD risk in South Asians. PMID:20300285

  2. The role of HDL in plaque stabilization and regression: basic mechanisms and clinical implications.

    PubMed

    Feig, Jonathan E; Feig, Jessica L; Dangas, George D

    2016-11-01

    On the basis of studies that extend back to the early 1900s, regression and stabilization of atherosclerosis in humans has progressed from being a concept to one that is achievable. Successful attempts at regression generally applied robust measures to improve plasma lipoprotein profiles. Possible mechanisms responsible for lesion shrinkage include decreased retention of atherogenic apolipoprotein B within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of lesional foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris as well as other components of the plaque. Currently available clinical agents, however, still fail to stop most cardiovascular events. For years, HDL has been considered the 'good cholesterol.' Clinical intervention studies to causally link plasma HDL-C levels to decreased progression or to the regression of atherosclerotic plaques are relatively few because of the lack of therapeutic agents that can selectively and potently increase HDL-C. The negative results of studies that were carried out have led to uncertainty as to the role that HDL plays in atherosclerosis. It is becoming clearer, however, that HDL function rather than quantity is most crucial and, therefore, discovery of agents that enhance the quality of HDL should be the goal.

  3. 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

  4. Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice

    PubMed Central

    Churchill, Gary A.

    2010-01-01

    Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J × DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain. PMID:20858711

  5. Grape polyphenols increase the activity of HDL enzymes in old and obese rats.

    PubMed

    Zagayko, Andriy L; Kravchenko, Ganna B; Krasilnikova, Oksana A; Ogai, Yuri O

    2013-01-01

    HDL particles are protein-rich particles that act as a vehicle for reverse cholesterol transport from tissues to the liver. The purpose of this study was to investigate age-dependent changes in the functional activity of HDL and the effect of high-energy diet on this index, as well as to correct it under the influence of grape polyphenols from "Enoant" obtained from Vitis vinifera grapes. We observed the age-dependent composition changes in HDL particle. It was shown that total lipids and triacylglycerol (TG) levels were higher in 24-month-old animals. In obese rats, HDL total lipids and TG levels were higher in 24-month-old than in the 3-month-old and 12-month-old groups but did not differ from 24-month-old group. The plasma HDL paraoxonase (PON) and lecithin:cholesterol acyltransferase (LCAT) activity levels were decreased in old-aged rats, and cholesteryl ester transfer protein (CETP) activity was higher in old rats. Keeping 12-month-old animals on high-fructose diet completely leveled the age differences in the data that have been measured between 12-month-old and 24-month-old rats. After "Enoant" administration, an increase of HDL PON and LCAT activity levels and a reduction of CETP activity were found in 24-month-old and obese rats. PMID:23936611

  6. 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

  7. Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism.

    PubMed

    Almasy, L; Hixson, J E; Rainwater, D L; Cole, S; Williams, J T; Mahaney, M C; VandeBerg, J L; Stern, M P; MacCluer, J W; Blangero, J

    1999-06-01

    Common disorders with genetic susceptibilities involve the action of multiple genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An important route to the disentangling of this complex inheritance is through the study of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol (HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle-size classes and the concentrations and proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigrees implicated two loci, one on chromosome 8 and the other on chromosome 15, that influence a component of HDL-C-namely, unesterified HDL2a-C. Multivariate analyses of multiple HDL phenotypes and simultaneous multilocus analysis of the quantitative-trait loci identified permit further characterization of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, whereas the chromosome 15 locus appears to influence both HDL-C concentration and distribution of cholesterol among HDL particle sizes.

  8. HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol.

    PubMed

    Ramsamy, Tanya A; Boucher, Jonathan; Brown, Robert J; Yao, Zemin; Sparks, Daniel L

    2003-04-01

    We have previously shown that hepatic lipase (HL) is inactive when bound to purified heparan sulfate proteoglycans and can be liberated by HDL and apolipoprotein A-I (apoA-I), but not by LDL or VLDL. In this study, we show that HDL is also able to displace HL directly from the surface of the hepatoma cell line, HepG2, and Chinese hamster ovary cells stably overexpressing human HL. ApoA-I is more efficient at displacing cell surface HL than is HDL, and different HDL classes vary in their ability to displace HL from the cell surface. HDL2s have a greater capacity to remove HL from the cell surface and intracellular compartments, as compared with the smaller HDL particles. The different HDL subclasses also uniquely affect the activity of the enzyme. HDL2 stimulates HL-mediated hydrolysis of VLDL-triacylglycerol, while HDL3 is inhibitory. Inhibition of VLDL hydrolysis appears to result from a decreased interlipoprotein shuttling of HL between VLDL and the smaller, more dense HDL particles. This study suggests that high HDL2 levels are positively related to efficient triacylglycerol hydrolysis by their ability to enhance the liberation of HL into the plasma compartment and by a direct stimulation of VLDL-triacylglycerol hydrolysis.

  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.

  10. 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

  11. Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome

    PubMed Central

    Jones, Jennifer J; Ackerman, Daniela; Barona, Jacqueline; Calle, Mariana; Comperatore, Michael V; Kim, Jung-Eun; Andersen, Catherine; Leite, Jose O; Volek, Jeff S; McIntosh, Mark; Kalynych, Colleen; Najm, Wadie; Lerman, Robert H

    2010-01-01

    Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD. PMID:21286407

  12. Low HDL cholesterol is associated with increased atherogenic lipoproteins and insulin resistance in women classified with metabolic syndrome.

    PubMed

    Fernandez, Maria Luz; Jones, Jennifer J; Ackerman, Daniela; Barona, Jacqueline; Calle, Mariana; Comperatore, Michael V; Kim, Jung-Eun; Andersen, Catherine; Leite, Jose O; Volek, Jeff S; McIntosh, Mark; Kalynych, Colleen; Najm, Wadie; Lerman, Robert H

    2010-12-01

    Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD.

  13. Genetic variants in ABCA1 promoter affect transcription activity and plasma HDL level in pigs.

    PubMed

    Dang, Xiao-yong; Chu, Wei-wei; Shi, Heng-chuan; Yu, Shi-gang; Han, Hai-yin; Gu, Shu-Hua; Chen, Jie

    2015-01-25

    Excess accumulation of cholesterol in plasma may result in coronary artery disease. Numerous studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for plasma high density lipoprotein (HDL) formation. Higher plasma levels of HDL are associated with lower risk for cardiovascular disease. Studies of human disease and animal models had shown that an increased hepatic ABCA1 activity relates to an enhanced plasma HDL level. In this study, we hypothesized that functional mutations in the ABCA1 promoter in pigs may affect gene transcription activity, and consequently the HDL level in plasma. The promoter region of ABCA1 was comparatively scanned by direct sequencing with pool DNA of high- and low-HDL groups (n=30 for each group). Two polymorphisms, c. - 608A>G and c. - 418T>A, were revealed with reverse allele distribution in the two groups. The two polymorphisms were completely linked and formed only G-A or A-T haplotypes when genotyped in a larger population (n=526). Furthermore, we found that the G-A/G-A genotype was associated with higher HDL and ABCA1 mRNA level than A-T/A-T genotype. Luciferase assay also revealed that G-A haplotype promoter had higher activity than A-T haplotype. Single-nucleotide mutant assay showed that c.-418T>A was the causal mutation for ABCA1 transcription activity alteration. Conclusively, we identified two completely linked SNPs in porcine ABCA1 promoter region which have influence on the plasma HDL level by altering ABCA1 gene transcriptional activity.

  14. 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

  15. 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

  16. Combination of estrogen replacement and exercise protects against HDL oxidation in post-menopausal women.

    PubMed

    Lawler, J M; Hu, Z; Green, J S; Crouse, S F; Grandjean, P W; Bounds, R G

    2002-10-01

    The incidence of atherosclerosis and cardiovascular disease (CVD) in women increases following menopause and has been associated with a reduction in circulating estrogen. Increased CVD risk is also perpetuated by sedentary lifestyle. Growing evidence indicates that oxidation of lipoproteins leads to a powerful immune response, disruption of normal lipoprotein function, and deposition of atherosclerotic plaques. For example, once high-density lipoproteins (HDL) are oxidized, they lose the ability to a) participate in reverse transport of cholesterol to the liver, and b) protect low-density lipoproteins (LDL) against oxidation. The purpose of this study was to determine the effects of combining estrogen replacement and exercise upon lipid peroxidation of the HDL fraction (HDL-ox). Blood samples were drawn from 34 post-menopausal women from four groups: women who were not receiving estrogen replacement and who were sedentary (NSD) (n = 9); women who were not receiving estrogen replacement and who were participating in regular exercise (NEX) (n = 8); women who were receiving estrogen replacement and who were sedentary (ESD) (n = 8); and women who were receiving estrogen replacement and who were participating in regular exercise (EEX) (n = 9). Total-HDL cholesterol was significantly higher (p<0.05) in EEX when compared with NEX, NSD, and ESD. HDL-ox was assessed via malondialdehyde (MDA). Mean (+/- SEM) values for HDL MDA expressed in nM are as follows: NSD = 903.3 +/- 118.4; NEX = 1226.7 +/- 247.7; ESD = 876.7 +/- 116.3; EEX = 537.4 +/- 74.8. EEX lipid peroxidation was significantly (p = 0.02) lower than NEX. Lipid peroxidation tended to be lower in EEX than in NSD and ESD (p = 0.07). These data indicate that the combination of estrogen replacement and regular exercise in post-menopausal women may be most effective in reducing oxidation of HDL in vivo.

  17. 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

  18. The specific amino acid sequence between helices 7 and 8 influences the binding specificity of human apolipoprotein A-I for high density lipoprotein (HDL) subclasses: a potential for HDL preferential generation.

    PubMed

    Carnemolla, Ronald; Ren, Xuefeng; Biswas, Tapan K; Meredith, Stephen C; Reardon, Catherine A; Wang, Jianjun; Getz, Godfrey S

    2008-06-01

    Humans have two major high density lipoprotein (HDL) sub-fractions, HDL(2) and HDL(3), whereas mice have a monodisperse HDL profile. Epidemiological evidence has suggested that HDL(2) is more atheroprotective; however, currently there is no direct experimental evidence to support this postulate. The amino acid sequence of apoA-I is a primary determinant of HDL subclass formation. The majority of the alpha-helical repeats in human apoA-I are proline-punctuated. A notable exception is the boundary between helices 7 and 8, which is located in the transitional segment between the stable N-terminal domain and the C-terminal hydrophobic domain. In this study we ask whether the substitution of a proline-containing sequence (PCS) separating other helices in human apoA-I for the non-proline-containing sequence (NPCS) between helices 7 and 8 (residues 184-190) influences HDL subclass association. The human apoA-I mutant with PCS2 replacing NPCS preferentially bound to HDL(2). In contrast, the mutant where PCS3 replaced NPCS preferentially associated with HDL(3). Thus, the specific amino acid sequence between helices 7 and 8 influences HDL subclass association. The wild-type and mutant proteins exhibited similar physicochemical properties except that the two mutants displayed greater lipid-associated stability versus wild-type human apoA-I. These results focus new attention on the influence of the boundary between helices 7 and 8 on the properties of apoA-I. The expression of these mutants in mice may result in the preferential generation of HDL(2) or HDL(3) and allow us to examine experimentally the anti-atherogenicity of the HDL subclasses.

  19. 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

  20. 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.

  1. Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach[S

    PubMed Central

    Gadkar, Kapil; Lu, James; Sahasranaman, Srikumar; Davis, John; Mazer, Norman A.; Ramanujan, Saroja

    2016-01-01

    The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate. PMID:26522778

  2. Incubation of MDCO-216 (ApoA-IMilano/POPC) with Human Serum Potentiates ABCA1-Mediated Cholesterol Efflux Capacity, Generates New Prebeta-1 HDL, and Causes an Increase in HDL Size.

    PubMed

    Kempen, Herman J; Schranz, Dorota B; Asztalos, Bela F; Otvos, James; Jeyarajah, Elias; Drazul-Schrader, Denise; Collins, Heidi L; Adelman, Steven J; Wijngaard, Peter L J

    2014-01-01

    MDCO-216 is a complex of dimeric ApoA-IMilano and palmitoyl oleoyl phosphatidylcholine (POPC), previously shown to reduce atherosclerotic plaque burden. Here we studied the effect of incubation of human plasma or serum with MDCO-216 on cholesterol efflux capacity from J774 cells, on prebeta-1 high density lipoprotein (prebeta-1 HDL) and on HDL size assessed by proton nuclear magnetic resonance ((1)H-NMR). MDCO-216 incubated in buffer containing 4% human serum albumin stimulated both ABCA1-mediated efflux and ABCA1-independent cholesterol efflux from J774 macrophages. When incubated with human serum a dose- and time-dependent synergistic increase of the ABCA1-mediated efflux capacity were observed. Using a commercially available ELISA for prebeta-1 HDL, MDCO-216 as such was poorly detected (12-15% of nominal amount of protein). Prebeta-1 HDL was rapidly lost when human plasma alone is incubated at 37°C. In contrast, incubation of human plasma with MDCO-216 at 37°C produced a large amount of new prebeta-1 HDL. Native 2D electrophoresis followed by immunoblotting with an apoA-I antibody, which also detects ApoA-I Milano, confirmed the increase in prebeta-1 HDL upon incubation at 37°C. With the increase of prebeta-1 HDL, the concomitant disappearance of the small alpha-3 and alpha-4 HDL and MDCO-216 and an increase in the large alpha-1 and alpha-2 HDL were observed. Immunoblotting with Mab 17F3 specific for ApoA-I Milano showed the appearance of ApoA-I Milano in alpha-1 and alpha-2, but not in prebeta-1 HDL. (1)H-NMR analysis of plasma incubated with MDCO-216 confirmed rapid disappearance of small-sized HDL particles and increase of medium- and large-sized HDL particles accompanied with a decrease in total HDL particle number. In conclusion, incubation of human plasma or serum with MDCO-216 strongly enhanced ABCA1-mediated cholesterol efflux, caused a strong increase of prebeta-1 HDL, and drastically changed the distribution of HDL subpopulations. Overall, the

  3. Incubation of MDCO-216 (ApoA-IMilano/POPC) with Human Serum Potentiates ABCA1-Mediated Cholesterol Efflux Capacity, Generates New Prebeta-1 HDL, and Causes an Increase in HDL Size

    PubMed Central

    Schranz, Dorota B.; Asztalos, Bela F.; Otvos, James; Drazul-Schrader, Denise; Wijngaard, Peter L. J.

    2014-01-01

    MDCO-216 is a complex of dimeric ApoA-IMilano and palmitoyl oleoyl phosphatidylcholine (POPC), previously shown to reduce atherosclerotic plaque burden. Here we studied the effect of incubation of human plasma or serum with MDCO-216 on cholesterol efflux capacity from J774 cells, on prebeta-1 high density lipoprotein (prebeta-1 HDL) and on HDL size assessed by proton nuclear magnetic resonance (1H-NMR). MDCO-216 incubated in buffer containing 4% human serum albumin stimulated both ABCA1-mediated efflux and ABCA1-independent cholesterol efflux from J774 macrophages. When incubated with human serum a dose- and time-dependent synergistic increase of the ABCA1-mediated efflux capacity were observed. Using a commercially available ELISA for prebeta-1 HDL, MDCO-216 as such was poorly detected (12–15% of nominal amount of protein). Prebeta-1 HDL was rapidly lost when human plasma alone is incubated at 37°C. In contrast, incubation of human plasma with MDCO-216 at 37°C produced a large amount of new prebeta-1 HDL. Native 2D electrophoresis followed by immunoblotting with an apoA-I antibody, which also detects ApoA-I Milano, confirmed the increase in prebeta-1 HDL upon incubation at 37°C. With the increase of prebeta-1 HDL, the concomitant disappearance of the small alpha-3 and alpha-4 HDL and MDCO-216 and an increase in the large alpha-1 and alpha-2 HDL were observed. Immunoblotting with Mab 17F3 specific for ApoA-I Milano showed the appearance of ApoA-I Milano in alpha-1 and alpha-2, but not in prebeta-1 HDL. 1H-NMR analysis of plasma incubated with MDCO-216 confirmed rapid disappearance of small-sized HDL particles and increase of medium- and large-sized HDL particles accompanied with a decrease in total HDL particle number. In conclusion, incubation of human plasma or serum with MDCO-216 strongly enhanced ABCA1-mediated cholesterol efflux, caused a strong increase of prebeta-1 HDL, and drastically changed the distribution of HDL subpopulations. Overall, the results

  4. 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.

  5. 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

  6. Macrophage apoAI protects against dyslipidemia-induced dermatitis and atherosclerosis without affecting HDL.

    PubMed

    Tavori, Hagai; Su, Yan Ru; Yancey, Patricia G; Giunzioni, Ilaria; Wilhelm, Ashley J; Blakemore, John L; Zabalawi, Manal; Linton, MacRae F; Sorci-Thomas, Mary G; Fazio, Sergio

    2015-03-01

    Tissue cholesterol accumulation, macrophage infiltration, and inflammation are features of atherosclerosis and some forms of dermatitis. HDL and its main protein, apoAI, are acceptors of excess cholesterol from macrophages; this process inhibits tissue inflammation. Recent epidemiologic and clinical trial evidence questions the role of HDL and its manipulation in cardiovascular disease. We investigated the effect of ectopic macrophage apoAI expression on atherosclerosis and dermatitis induced by the combination of hypercholesterolemia and absence of HDL in mice. Hematopoietic progenitor cells were transduced to express human apoAI and transplanted into lethally irradiated LDL receptor(-/-)/apoAI(-/-) mice, which were then placed on a high-fat diet for 16 weeks. Macrophage apoAI expression reduced aortic CD4(+) T-cell levels (-39.8%), lesion size (-25%), and necrotic core area (-31.6%), without affecting serum HDL or aortic macrophage levels. Macrophage apoAI reduced skin cholesterol by 39.8%, restored skin morphology, and reduced skin CD4(+) T-cell levels. Macrophage apoAI also reduced CD4(+) T-cell levels (-32.9%) in skin-draining lymph nodes but had no effect on other T cells, B cells, dendritic cells, or macrophages compared with control transplanted mice. Thus, macrophage apoAI expression protects against atherosclerosis and dermatitis by reducing cholesterol accumulation and regulating CD4(+) T-cell levels, without affecting serum HDL or tissue macrophage levels.

  7. HDL: bridging past and present with a look at the future

    PubMed Central

    Scanu, Angelo M.; Edelstein, Celina

    2008-01-01

    Clinical and epidemiological studies have shown that HDLs, a class of plasma lipoproteins, heterogeneous in size and density, have an atheroprotective role attributed, for years, to their capacity to promote the efflux of cholesterol from activated cholesterol-loaded arterial macrophages. Recent studies, however, have recognized that the physical heterogeneity of HDLs is associated with multiple functions that involve both the protein and the lipid components of these particles. ApoA-I, quantitatively the major protein constituent, has an amphipathic structure suited for transport of lipids. It readily interacts with the ATP-binding cassette transporter ABCA1, the SR-B1 scavenger receptor; activates the enzyme lecithin-cholesterol acyl transferase (LCAT), which is critical for HDL maturation. It also has antioxidant and antiinflammatory properties, along with the HDL-associated enzymes paraoxonase, platelet activating factor acetylhydrolase (PAF), and glutathione peroxidase. Regarding the lipid moiety, an atheroprotective role has been recognized for lysosphingolipids, particularly sphingosine-1-phosphate (S1P). All of these atheroprotective functions are lost in the post-translational dependent dysfunctional plasma HDLs of subjects with systemic inflammation, coronary heart disease, diabetes, and chronic renal disease. The emerging notion that particle quality has more predictive power than quantity has stimulated further exploration of the HDL proteome, already revealing unsuspected pro- or antiatherogenic proteins/peptides associated with HDL.—Scanu, A. M., Edelstein, C. HDL: bridging past and present with a look at the future. PMID:18716026

  8. 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

  9. Functional genomics of the human HDL receptor scavenger receptor BI: An old dog with new tricks

    PubMed Central

    Chadwick, Alexandra C.; Sahoo, Daisy

    2014-01-01

    Purpose of review The athero-protective role of scavenger receptor BI (SR-BI) is primarily attributed to its ability to selectively transfer cholesteryl esters from high density lipoproteins (HDL) to the liver during reverse cholesterol transport (RCT). In this review, we highlight recent findings that reveal the impact of SR-BI on lipid levels and cardiovascular disease in humans. Moreover, additional responsibilities of SR-BI in modulating adrenal and platelet function, as well as female fertility in humans, are discussed. Recent findings Heterozygote carriers of P297S-, S112F- and T175A- mutant SR-BI receptors were identified in patients with high HDL-cholesterol levels. HDL from P297S-SR-BI carriers was unable to mediate macrophage cholesterol efflux, while hepatocytes expressing P297S-SR-BI were unable to mediate the selective uptake of HDL-cholesteryl esters. S112F- and T175A-mutant receptors exhibited similar impaired cholesterol transport functions in vitro. Reduced SR-BI function in P297S carriers was also associated with decreased steroidogenesis and altered platelet function. Further, human population studies identified SCARB1 variants associated with female infertility. Summary Identification of SR-BI variants confirms the key role of this receptor in influencing lipid levels and RCT in humans. Deeper understanding of the contributions of SR-BI to steroidogenesis, platelet function and fertility is required in light of exploration of HDL-raising therapies aimed at reducing cardiovascular risk. PMID:23403740

  10. Enhanced placental cholesterol efflux by fetal HDL in Smith–Lemli–Opitz syndrome

    PubMed Central

    Jenkins, Katie T.; Merkens, Louise S.; Tubb, Matthew R.; Myatt, Leslie; Davidson, W. Sean; Steiner, Robert D.; Woollett, Laura A.

    2010-01-01

    Previous studies from this laboratory have shown that maternal-derived cholesterol can be effluxed from trophoblasts to fetal HDL and plasma. We had the opportunity to study for the first time the ability of HDL and plasma from a fetus with the Smith–Lemli–Opitz syndrome (SLOS) to efflux cholesterol from trophoblasts. It was unclear whether cholesterol could be effluxed to fetuses with SLOS since lipoprotein levels are often very low. To answer this question, cord blood was collected from the placentas of an SLOS fetus and unaffected fetuses just after delivery. Plasma cholesterol concentrations were very low in the affected fetus; cholesterol, 7-dehydrocholesterol, and 8-dehydocholesterol concentrations were 14.1, 4.5, and 5.2 mg/dl, respectively. The HDL from the fetal SLOS effluxed ≈50% more cholesterol from a trophoblast cell line, were smaller in size, and had a lower cholesterol to phospholipid ratio as compared to HDL from unaffected fetuses or adults. Plasma from the SLOS fetus effluxed cholesterol to a similar percentage as unaffected fetal plasma or adult plasma, possibly due to fewer HDL particles as demonstrated in previous SLOS patients. These novel data demonstrate that the cholesterol-deficient SLOS fetus is able to obtain cholesterol from trophoblasts at a time when cholesterol is playing a critical role in development, and has implications for design of treatments for cholesterol deficiency syndromes as well as understanding of prenatal cholesterol transport in humans. PMID:18346920

  11. 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

  12. HDL-Associated Paraoxonase 1 as a Bridge between Postmenopausal Osteoporosis and Cardiovascular Disease

    PubMed Central

    Ellidag, Hamit Yasar; Aydin, Ozgur; Yılmaz, Necat

    2014-01-01

    The association of postmenopausal osteoporosis (PMOP) with both atherosclerosis and vascular/valvular calcification is well known. Recently, ample evidence has suggested a common etiologic factor, namely, reduced HDL-associated paraoxonase 1 (PON1) activity, as a causative factor in the development of PMOP and cardiovascular disease (CVD). This common etiologic factor not only contributes to atherosclerotic diseases but also to PMOP following an almost identical mechanism including dysfunctional HDL and lipid oxidation. According to recent studies, lipid oxidation might improve osteoblastic transformation of vascular cells and obstruct such transformation in bone cells. The primary objective of this current review was to summarize the evidence revealing the role of HDL-associated PON1 enzyme in PMOP. Additionally, the review aimed to address some of the subjects that need further investigation in order to define whether hyperhomocysteinemia and sensitivity to lipid oxidation may be risk factors for PMOP. PMID:25568841

  13. 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

  14. [Physiological variations of LpA1, HDL2 and principal lipid markers in athletes].

    PubMed

    Choukaifé, A; Fradin, S; Bureau, F; Sesboüe, B; Arhan, P; Drosdowsky, M A

    1994-01-01

    An original approach of the influence of physical activities on lipid metabolism is presented in this work: the authors studied the physiological variations of the lipoparticle LpA1, high-density lipoprotein subfraction HDL2 and the most important lipid markers in serum of a presumably healthy population of 55 high-level sportsmen. They were 18-45 years old and practised endurance sports, whether individual (cycling, long-distance running), or collective activities (soccer, basketball). The authors observed an important increase of LpA1 (+20%, p < 0.001) and C-HDL2 (+23.3%, p < 0.01) after an intense physical activity (CK = 430 +/- 312 U/l); they also found a good correlation between LpA1 and HDL2 (r = 0.85, p < 0.0001) and between LpA1 and CK (r = 0.62, p < 0.001).

  15. 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

  16. CNR1 Genotype Influences HDL-Cholesterol Response to Change in Dietary Fat Intake

    PubMed Central

    Keil, Charles D.; Jiang, Lan; Feng, Qiping; Chiu, Sally; Krauss, Ronald M.; Wilke, Russell A.

    2012-01-01

    Background Success in further reducing the burden of cardiovascular disease (CVD) is threatened by the increasing prevalence of obesity-related atherogenic dyslipidemia. HDL-cholesterol (HDL-C) level is inversely correlated with CVD risk; each 1 mg/dl decrease in HDL-C is associated with a 6% reduction in risk. We previously showed that a common CNR1 haplotype, H3 (frequency 20%), is protective against the reduction in HDL-C that typically accompanies weight gain. In the present study, we extend that observation by reporting the effect of CNR1 haplotype on HDL-C response to modification of dietary fat intake in weight maintenance and weight loss. Methods Six haplotype tagging SNPs that cover the CNR1 gene locus were genotyped in 590 adults of varying body mass index (cohort 1 is 411 males with BMI 18.5–30.0 kg/m2; cohort 2 is 71 females with BMI18.5–30.0 kg/m2; and cohort 3 is 108 females with BMI 30–39.9 kg/m2). Dietary intakes were modified so that fat intake in the “high fat” condition was 15–20% greater than in the “low fat” condition, and lipid profiles were compared between carriers versus noncarriers for each of the five commonly observed CNR1 haplotypes (H1–H5). Results In normal to overweight subjects on eucaloric diets, the H3 haplotype was significantly associated with short-term high fat diet induced changes in HDL-C level in females (carriers 5.9 mg/dl>noncarriers, p = 0.007). The H3 haplotype was also significantly associated with HDL-C level after 16 weeks on high fat calorie restricted diet in obese females (carriers 6.8 mg/dl>noncarriers, p = 0.009). Conclusion Variability within the CNR1 gene locus contributes to gender-related differences in the HDL-cholesterol response to change in dietary fat intake. Functional characterization of this relationship in vitro may offer insights that potentially yield therapeutic guidance targeting dietary macronutrient composition, a direction much needed in the current epidemic of

  17. [Lipoproteins HDL and coronary artery disease: a molecular mechanism of fibrate].

    PubMed

    Kaletha, Krystian; Chodorowski, Zygmunt; Anand, Izabela Sein; Rybakowska, Iwona; Nagel-Starczynowska, Gabriela

    2003-01-01

    The importance of dyslipidemia in the development of cardiovascular disease is now recognized as a central factor of equal, if not greater significance than any other risk factor. Although correction of high level of low-density lipoproteins (LDL) has been regarded now as the main goal of therapy, it has now been reaffirmed that the contribution of low level of high-density lipoproteins (HDL) to the risk of ischaemic heart disease should also be considered. In the therapy of dislipidemias with hipertriglyceridemia and decreased level of HDL lipoprotein fibrates play an especially important role. In the article the molecular mechanism of fibrates action is presented.

  18. Prosopis farcta beans increase HDL cholesterol and decrease LDL cholesterol in ostriches (Struthio camelus).

    PubMed

    Omidi, Arash; Ansari nik, Hossein; Ghazaghi, Mahmood

    2013-02-01

    Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase (γ-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and γ-GT activity decreased significantly.

  19. Seven Direct Methods for Measuring HDL and LDL Cholesterol Compared with Ultracentrifugation Reference Measurement Procedures

    PubMed Central

    Miller, W. Greg; Myers, Gary L.; Sakurabayashi, Ikunosuke; Bachmann, Lorin M.; Caudill, Samuel P.; Dziekonski, Andrzej; Edwards, Selvin; Kimberly, Mary M.; Korzun, William J.; Leary, Elizabeth T.; Nakajima, Katsuyuki; Nakamura, Masakazu; Nilsson, Göran; Shamburek, Robert D.; Vetrovec, George W.; Warnick, G. Russell; Remaley, Alan T.

    2015-01-01

    BACKGROUND Methods from 7 manufacturers and 1 distributor for directly measuring HDL cholesterol (C) and LDL-C were evaluated for imprecision, trueness, total error, and specificity in nonfrozen serum samples. METHODS We performed each direct method according to the manufacturer’s instructions, using a Roche/Hitachi 917 analyzer, and compared the results with those obtained with reference measurement procedures for HDL-C and LDL-C. Imprecision was estimated for 35 runs performed with frozen pooled serum specimens and triplicate measurements on each individual sample. Sera from 37 individuals without disease and 138 with disease (primarily dyslipidemic and cardiovascular) were measured by each method. Trueness and total error were evaluated from the difference between the direct methods and reference measurement procedures. Specificity was evaluated from the dispersion in differences observed. RESULTS Imprecision data based on 4 frozen serum pools showed total CVs <3.7% for HDL-C and <4.4% for LDL-C. Bias for the nondiseased group ranged from −5.4% to 4.8% for HDL-C and from −6.8% to 1.1% for LDL-C, and for the diseased group from −8.6% to 8.8% for HDL-C and from −11.8% to 4.1% for LDL-C. Total error for the nondiseased group ranged from −13.4% to 13.6% for HDL-C and from −13.3% to 13.5% for LDL-C, and for the diseased group from −19.8% to 36.3% for HDL-C and from −26.6% to 31.9% for LDL-C. CONCLUSIONS Six of 8 HDL-C and 5 of 8 LDL-C direct methods met the National Cholesterol Education Program total error goals for nondiseased individuals. All the methods failed to meet these goals for diseased individuals, however, because of lack of specificity toward abnormal lipoproteins. PMID:20378768

  20. 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

  1. Detergent-Mediated Phospholipidation of Plasma Lipoproteins Increases HDL Cholesterophilicity and Cholesterol Efflux Via SR-BI†

    PubMed Central

    Pownall, Henry J.

    2008-01-01

    Cellular cholesterol efflux is an early, obligatory step in reverse cholesterol transport, the putative antiatherogenic mechanism by which human plasma high density lipoproteins (HDL) transport cholesterol from peripheral tissue to the liver for recycling or disposal. HDL-phospholipid content is the essential cholesterol-binding component of lipoproteins and therefore a major determinant of cholesterol efflux. Thus, increased phospholipidation of lipoproteins, particularly HDL, is one strategy for increasing cholesterol efflux. This study validates a simple, new detergent perturbation method for the phospholipidation of plasma lipoproteins; we have quantified the cholesterophilicity of human plasma lipoproteins and the effects of lipoprotein phospholipidation on cholesterophilicity and cellular cholesterol efflux mediated by the class B type I scavenger receptor (SR-BI). We determined that low density lipoproteins (LDL) are more cholesterophilic than HDL and that LDL has a higher affinity for phospholipids than HDL whereas HDL has a higher phospholipid capacity than LDL. Phospholipidation of total human plasma lipoproteins enhances cholesterol efflux, an effect that occurs largely through the preferential phospholipidation of HDL. We conclude that increasing HDL phospholipid increases its cholesterophilicity thereby making it a better acceptor of cellular cholesterol efflux. Phospholipidation of lipoproteins by detergent perturbation is a simple way to increase HDL cholesterophilicity and cholesterol efflux in a way that may be clinically useful. PMID:16981711

  2. 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

  3. 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

  4. Manufacturing performance of the ALTA 3000 mask laser writer

    NASA Astrophysics Data System (ADS)

    Grenon, Brian J.; Defibaugh, D. C.; Sprout, Donna M.; Taft, C. J.

    1995-12-01

    This paper describes the manufacturing performance of the ALTA 3000 laser writer at the IBM mask fabrication facility in Essex Junction, Vermont. Current mask parametric performance for feature size control (x-bar and 3-sigma), registration and defect density of 4x and 5x reticles is presented. In addition, reliability data and write-time data for typical 64 Mb and 256 Mb reticles are provided.

  5. The relationship between non-HDL cholesterol and macrophage phenotypes in human adipose tissue

    PubMed Central

    Poledne, Rudolf; Kralova Lesna, Ivana; Kralova, Anna; Fronek, Jiri; Cejkova, Sona

    2016-01-01

    Data from experimental animal models and in vitro studies suggest that both hyperlipoproteinemia and obesity predispose to development of proinflammatory pathways of macrophages within adipose tissue. The aim of this study was to analyze whether non-HDL cholesterol concentration in healthy living kidney donors (LKDs) is related to the number and phenotype of proinflammatory macrophages in visceral and subcutaneous adipose tissue. Adipose tissue samples were collected by cleansing the kidney grafts of LKDs obtained peroperatively. The stromal vascular fractions of these tissues were analyzed by flow cytometry. Proinflammatory macrophages were defined as CD14+ cells coexpressing CD16+ and high-expression CD36 as well (CD14+CD16+CD36+++), while CD16 negativity and CD163 positivity identified alternatively stimulated, anti-inflammatory macrophages. Non-HDL cholesterol concentration positively correlated to proinflammatory macrophages within visceral adipose tissue, with increased strength with more precise phenotype determination. On the contrary, the proportion of alternatively stimulated macrophages correlated negatively with non-HDL cholesterol. The present study suggests a relationship of non-HDL cholesterol concentration to the number and phenotype proportion of macrophages in visceral adipose tissue of healthy humans. PMID:27481939

  6. 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

  7. Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9

    PubMed Central

    2013-01-01

    Background Studies in animals showed that PCSK9 is involved in HDL metabolism. We investigated the molecular mechanism by which PCSK9 regulates HDL cholesterol concentration and also whether Pcsk9 inactivation might affect cholesterol efflux capacity of serum and atherosclerotic fatty streak volume. Methods Mass spectrometry and western blot were used to analyze the level of apolipoprotein E (APOE) and A1 (APOA1). A mouse model overexpressing human LDLR was used to test the effect of high levels of liver LDLR on the concentration of HDL cholesterol and APOE-containing HDL subfractions. Pcsk9 knockout males lacking LDLR and APOE were used to test whether LDLR and APOE are necessary for PCSK9-mediated HDL cholesterol regulation. We also investigated the effects of Pcsk9 inactivation on cholesterol efflux capacity of serum using THP-1 and J774.A1 macrophage foam cells and atherosclerotic fatty streak volume in the aortic sinus of Pcsk9 knockout males fed an atherogenic diet. Results APOE and APOA1 were reduced in the same HDL subfractions of Pcsk9 knockout and human LDLR transgenic male mice. In Pcsk9/Ldlr double-knockout mice, HDL cholesterol concentration was lower than in Ldlr knockout mice and higher than in wild-type controls. In Pcsk9/Apoe double-knockout mice, HDL cholesterol concentration was similar to that of Apoe knockout males. In Pcsk9 knockout males, THP-1 macrophage cholesterol efflux capacity of serum was reduced and the fatty streak lesion volume was similar to wild-type controls. Conclusions In mice, LDLR and APOE are important factors for PCSK9-mediated HDL regulation. Our data suggest that, although LDLR plays a major role in PCSK9-mediated regulation of HDL cholesterol concentration, it is not the only mechanism and that, regardless of mechanism, APOE is essential. Pcsk9 inactivation decreases the HDL cholesterol concentration and cholesterol efflux capacity in serum, but does not increase atherosclerotic fatty streak volume. PMID:23883163

  8. 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

  9. 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.

  10. Increased HDL cholesterol levels in mice with XX versus XY sex chromosomes

    PubMed Central

    Link, Jenny C.; Chen, Xuqi; Prien, Christopher; Borja, Mark S.; Hammerson, Bradley; Oda, Michael N.; Arnold, Arthur P.; Reue, Karen

    2015-01-01

    Objective The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels. Approach and Results We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the Four Core Genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male–female gonadal sex and XX–XY chromosome complement. Gonadectomy of adult mice revealed that the male–female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male–female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared to a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with two X chromosomes compared to mice with an X and Y chromosome. By generating mice with XX, XY and XXY chromosome complements, we determined that the presence of two X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration. Conclusions We demonstrate that having two X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels. PMID:26112012

  11. 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.

  12. 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...

  13. Genome scan for quantitative trait loci influencing HDL levels: evidence for multilocus inheritance in familial combined hyperlipidemia.

    PubMed

    Gagnon, France; Jarvik, Gail P; Badzioch, Michael D; Motulsky, Arno G; Brunzell, John D; Wijsman, Ellen M

    2005-09-01

    Several genome scans in search of high-density lipoprotein (HDL) quantitative trait loci (QTLs) have been performed. However, to date the actual identification of genes implicated in the regulation of common forms of HDL abnormalities remains unsuccessful. This may be due, in part, to the oligogenic and multivariate nature of HDL regulation, and potentially, pleiotropy affecting HDL and other lipid-related traits. Using a Bayesian Markov Chain Monte Carlo (MCMC) approach, we recently provided evidence of linkage of HDL level variation to the APOA1-C3-A4-A5 gene complex, in familial combined hyperlipidemia pedigrees, with an estimated number of two to three large QTLs remaining to be identified. We also presented results consistent with pleiotropy affecting HDL and triglycerides at the APOA1-C3-A4-A5 gene complex. Here we use the same MCMC analytic strategy, which allows for oligogenic trait models, as well as simultaneous incorporation of covariates, in the context of multipoint analysis. We now present results from a genome scan in search for the additional HDL QTLs in these pedigrees. We provide evidence of linkage for additional HDL QTLs on chromosomes 3p14 and 13q32, with results on chromosome 3 further supported by maximum parametric and variance component LOD scores of 3.0 and 2.6, respectively. Weaker evidence of linkage was also obtained for 7q32, 12q12, 14q31-32 and 16q23-24.

  14. Low Plasma Hdl Cholesterol and Elevated C Reactive Protein further Increase Cardiovascular Disease Risk in Latinos with Type 2 Diabetes

    PubMed Central

    Calle, Mariana C; Vega-López, Sonia; Segura-Pérez, Sofia; Volek, Jeff S; Pérez-Escamilla, Rafael; Fernandez, Maria Luz

    2011-01-01

    The purpose of this study was to determine whether low plasma HDL and high C reactive protein (CRP) concentrations would further increase cardiovascular disease (CVD) risk in Latinos with poorly controlled type-2 diabetes, already at high risk for CVD. Subjects (n = 68) were grouped into High-HDL (≥ or 1.03 or 1.3 mmol/L) or Low-HDL (<1.03 or 1.3 mmol/L) for men and women, respectively. Following classification, risk factors for CVD including apolipoproteins, lipoprotein size and subfraction distribution were assesed. Similarly, participants were divided according to their CRP levels (≥ or < 3mg/L) and key inflammatory markers as well as leptin and adiponectin were analyzed. The Low-HDL group had higher concentrations of the atherogenic particles, large and medium VLDL and the smaller LDL subfractions compared to the High-HDL group (p<0.001). Consistently, VLDL diameter was larger and LDL diameter smaller in the Low HDL group (p<0.001). The High-CRP group had larger waist circumference (p<0.001) and body mass index (p<0.001) than the Low-CRP group. Leptin was also higher in the High- CRP group (p< 0.01). These data suggest that Latinos with type-2 diabetes having either Low-HDL or High-CRP concentrations are at a higher risk for atherosclerosis and CVD than their counterparts who have High-HDL or Low-CRP. PMID:22407331

  15. 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.

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

    PubMed Central

    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

  17. Suppression of liver Apo E secretion leads to HDL/cholesterol immaturity in rats administered ethinylestradiol.

    PubMed

    Yamaguchi, Kosuke; Ishii, Mariko; Maeda, Naoyuki; Iwano, Hidetomo; Yokota, Hiroshi

    2016-09-01

    Ethinylestradiol (EE), a main component of the combined oral contraceptive pill, is associated with an increased risk of arterial diseases. However, the toxicity mechanism of EE is poorly understood. In this study, we found that the exposure to EE reduced the serum apolipoprotein E (Apo E) level and high-density lipoprotein (HDL)/cholesterol concentration in adult female rats. Diethylstilbestrol showed the same effects and both reductions were suppressed by coadministration of tamoxifen (TAM). Liver perfusion experiments revealed that the secretion rate of Apo E from the liver was significantly reduced. It is concluded that EE damages the maturation of HDL/cholesterol by delaying Apo E secretion from the liver, and this may lead to an increased risk of arterial diseases, such as atheromas. PMID:27642556

  18. Alcohol questionnaires and HDL: screening scores as scaled markers of alcohol consumption.

    PubMed

    Berger, Douglas; Williams, Emily C; Bryson, Chris L; Rubinsky, Anna D; Bradley, Katharine A

    2013-09-01

    Improving the quality of alcohol-related care requires practical approaches to assessing alcohol consumption to guide management and monitor outcomes. Given the increasing use of alcohol screening questionnaires to identify alcohol misuse it would be ideal if scores on screening questionnaires were also indicators of average alcohol consumption. However, the questionnaires were not designed for this purpose and include dimensions of drinking that may not reflect average consumption (e.g. heavy episodic drinking, alcohol-related problems). In a general population sample, scores on the AUDIT-C screen correlated with reports of alcohol consumption in detailed interviews, but the relationship is unknown for clinical populations and other questionnaires. Serum high-density lipoprotein cholesterol (HDL) is a biomarker routinely obtained in clinical care and is known to rise with average alcohol consumption. This cross-sectional study of 11,175 male U.S. Veterans Affairs patients enrolled in a primary care study used HDL as an objective biomarker to evaluate whether average alcohol consumption increased as scores increased on 3 brief alcohol screens - the AUDIT-C, AUDIT Question #3 (a single-item screen), and the CAGE questionnaire. Mean HDL progressively increased as screening scores increased for the AUDIT-C and AUDIT Question #3: about 12 mg/dL from the lowest to the highest scores. The association was much weaker for the CAGE questionnaire. Results were minimally affected by adjustment for covariates (e.g. age, race, medical comorbidity, smoking, medication count, and depression) but the association was modified (p = 0.008) and mildly attenuated by adherent use of lipid-lowering medications. This study using HDL as a biomarker of average alcohol consumption adds to evidence that some alcohol screening scores may also serve as scaled markers of average alcohol consumption.

  19. 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

  20. The Mechanism of Proinflammatory HDL Generation in Sickle Cell Disease Is Linked to Cell-Free Hemoglobin via Haptoglobin

    PubMed Central

    Ji, Xiang; Feng, Yimin; Tian, Hui; Meng, Wei; Wang, Weiling; Liu, Na; Zhang, Jun; Wang, Lingshu; Wang, Jian; Gao, Haiqing

    2016-01-01

    In sickle cell disease (SCD), the inflammatory properties of high-density lipoprotein (HDL) can be changed by cell-free hemoglobin (Hb), which is released into the blood during hemolysis. Hb in the plasma of SCD patients or mice can bind with HDL specifically inducing an inflammatory reaction. In our study, we found increased amounts of inflammatory factor proteins in the chronic oxidative state of SCD with higher levels of Hb, haptoglobin (Hp) and hemopexin (Hx) in the apolipoprotein A-I (ApoA-1) particles of HDL and the role of HDL is changed from being anti-inflammatory to proinflammatory. Our results also suggest Hp and Hx, the scavengers of Hb in HDL, are positively associated with inflammatory levels in SCD patients. HDL retained its inflammatory inhibition role in Hp−/− mice, with less Hb accumulation. Hx may further prevent inflammatory reaction because its level will be even higher when lack of Hx. We therefore demonstrated that Hp is indispensable during the process whereby Hb associates with HDL and plays a clear proinflammatory role. Therefore, it is essential to break the binding between Hb and Hp for treatment. The dissociation of Hb/Hp/Hx complexes may also play an important role in the study of other inflammatory angiogenesis-related diseases. PMID:27716784

  1. Predominance of large LDL and reduced HDL2 cholesterol in normolipidemic men with coronary artery disease.

    PubMed

    Campos, H; Roederer, G O; Lussier-Cacan, S; Davignon, J; Krauss, R M

    1995-08-01

    Previous studies have indicated that a predominance of small, dense LDL particles is associated with coronary artery disease (CAD) risk. In the present study we examined the LDL peak particle diameter (determined by lipid-stained 2% to 16% gradient gel electrophoresis) in 92 normolipidemic men with CAD (total cholesterol < 200 mg/dL and triglyceride < 250 mg/dL) and 92 matched healthy controls. Plasma triglyceride, LDL cholesterol, and apo B levels were similar in subjects with CAD and in control subjects, whereas subjects with CAD had decreased HDL2 cholesterol levels (mean +/- SEM, 10 +/- 0.7 compared with 15 +/- 0.7 mg/dL in control subjects; P < .0002). Mean LDL particle diameter (+/- SEM) was increased in the subjects with CAD compared with control subjects (26.8 +/- 0.08 and 26.4 +/- 0.08 nm, respectively; P < .001). The association between large LDL size and CAD was significant (P < .0001) after adjustments were made for age, body mass index, HDL cholesterol levels, and VLDL cholesterol levels. An LDL particle size distribution characterized by a predominance of the largest of three classes of LDL particles (> 26.8 nm) was more prevalent among subjects with CAD (43%) than among control subjects (25%) (P < .002). Among subjects with this LDL size profile, subjects with CAD had significantly higher (P < .05) VLDL triglyceride, VLDL cholesterol, and VLDL apo B levels and significantly lower (P < .0001) HDL2 cholesterol levels than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Comparison of synthetic HDL contrast agents for MR imaging of atherosclerosis

    PubMed Central

    Cormode, David P.; Chandrasekar, Rohith; Delshad, Amanda; Briley-Saebo, Karen C.; Calcagno, Claudia; Barazza, Alessandra; Mulder, Willem J. M.

    2009-01-01

    Determining arterial macrophage expression is an important goal in the molecular imaging of atherosclerosis. Here we compare the efficacy of two synthetic, HDL-based contrast agents for magnetic resonance imaging (MRI) of macrophage burden. Each form of HDL was labeled with gadolinium and rhodamine to allow MRI and fluorescence microscopy. Either the 37 or 18 amino acid peptide replaced the apolipoprotein A-I in these agents, which were termed 37pA-Gd or 18A-Gd. The diameters of 37pA-Gd and 18A-Gd are 7.6 nm and 8.0 nm, respectively, while the longitudinal relaxivities are 9.8 and 10.0 (mMs)-1. 37pA has better lipid binding properties. In vitro tests with J774A.1 macrophages proved the particles possessed the functionality of HDL by eliciting cholesterol efflux and were taken up in a receptor-like fashion by the cells. Both agents produced enhancements in atherosclerotic plaques of apolipoprotein E knockout mice of ~90% (n=7 per agent) and are macrophage specific as evidenced by confocal microscopy on aortic sections. The half-lives of 37pA-Gd and 18A-Gd are 2.6 and 2.1 hours, respectively. Despite the more favorable lipid interactions of 37pA, both agents gave similar, excellent contrast for the detection of atherosclerotic macrophages using MRI. PMID:19378935

  3. 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.

  4. Improvement of HDL- and LDL-cholesterol levels in diabetic subjects by feeding bread containing chitosan.

    PubMed

    Ausar, S F; Morcillo, M; León, A E; Ribotta, P D; Masih, R; Vilaro Mainero, M; Amigone, J L; Rubin, G; Lescano, C; Castagna, L F; Beltramo, D M; Diaz, G; Bianco, I D

    2003-01-01

    In this work we evaluated the efficacy and safety of a bread formulation containing chitosan in dyslipidemic type 2 diabetic subjects. For this purpose a total of 18 patients were allowed to incorporate to their habitual diets 120 g/day of bread containing 2% (wt/wt) chitosan (chitosan group, n= 9) or standard bread (control group, n= 9). Before the study and after 12 weeks on the modified diet, the following parameters were evaluated: body weight, plasma cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, and hemoglobin A(1c) (HbA(1c)). Compared with the control group, the patients receiving chitosan-containing bread decreased their mean levels of LDL-cholesterol and significantly increased their mean levels of HDL-cholesterol at the end of the study. There were no significant differences in the body weight, serum triglyceride, and HbA(1c). These results suggest that chitosan incorporated into bread formulations could improve the lipoprotein balance similar to typical biliary salts trappers, increasing the HDL- and lowering the LDL-cholesterol, without changing the triglyceride levels. These results warrant further studies over a longer period of time to evaluate if a persistent improvement in levels of lipoproteins can be attained with this strategy.

  5. Hepatic lipase promoter C-514T polymorphism influences serial changes in HDL cholesterol levels since childhood: the Bogalusa Heart Study.

    PubMed

    Chen, Wei; Srinivasan, Sathanur R; Boerwinkle, Eric; Berenson, Gerald S

    2003-07-01

    Hepatic lipase (HL) is an important determinant of high-density lipoprotein (HDL) concentrations. A common C-to-T substitution at position -514 of the promoter region of the HL gene has been shown to be associated with HL activity and HDL cholesterol (HDL-C) levels. The current study examines the influence of this polymorphism on both levels and serial changes of HDL-C from childhood to adulthood in a community-based sample of 707 white and 291 black unrelated individuals aged 4-38 years using a repeated measures analysis. The frequency of the -514T allele was lower in whites than in blacks (0.228 vs. 0.545, P<0.001). After adjusting for age and BMI, the genotype effect on longitudinal profiles of HDL-C levels was significant (P=0.003) in white males with values in the order of T/T>T/C>C/C. Although a similar trend was seen, the genotype effect was not significant in white females and blacks. Further, the slopes of the age trajectories of HDL-C were similar in three genotype groups in blacks and whites. A sex-genotype interaction effect (P=0.043) on longitudinal profiles of HDL-C levels was found in whites, but not in blacks. White males showed a stronger genotype effect (3.6 mg/dl, P=0.003) than white females (0.5 mg/dl, P=0.601). Thus, the -514T variant of the HL gene is consistently associated with higher levels of HDL-C longitudinally since childhood, but not with rate of change over time. These results suggest that the HL gene may play an important role in the regulation of HDL-C levels from childhood to adulthood, especially in white males.

  6. A lipoprotein lipase gene polymorphism interacts with consumption of alcohol and unsaturated fat to modulate serum HDL-cholesterol concentrations.

    PubMed

    Baik, Inkyung; Lee, Seungku; Kim, Seong Hwan; Shin, Chol

    2013-10-01

    There are limited data from prospective studies regarding interactions between lipoprotein lipase gene (LPL) and lifestyle factors in association with HDL-cholesterol (HDL-C) concentrations, a biomarker of coronary heart disease risk. Our prospective cohort study investigated the interactive effects of a common LPL polymorphism and lifestyle factors, including obesity, smoking, alcohol consumption, physical activity, and dietary intake, on follow-up measurements of HDL-C and triglyceride (TG) concentrations. A total of 5314 Korean men and women aged 40-69 y participated in the study. Serum HDL-C and TG concentrations were measured in all participants at baseline and 6-y follow-up examinations. On the basis of genome-wide association data for HDL-C and TG concentrations, we selected the most significant polymorphism (rs10503669), which was in high linkage disequilibrium with the serine 447 stop (S447×) mutation (D' = 0.99) of LPL. We found that carrying the T allele reflecting the LPL ×447 allele was positively associated with follow-up measurement of HDL-C concentrations (P < 0.001). In the linear regression model adjusted for baseline HDL-C concentration and potential risk factors, we observed interactive effects of the polymorphism and consumption of alcohol (P-interaction < 0.01) and unsaturated fat (P-interaction < 0.05) on follow-up measurement of HDL-C concentrations. We also observed interactive effects of the polymorphism and body mass index (P-interaction < 0.01) on follow-up measurement of TG concentrations after adjusting for the baseline level and potential risk factors. Our findings suggest that carriers of the LPL ×447 allele benefit from moderate alcohol consumption and a diet high in unsaturated fat to minimize reduction of blood HDL-C concentrations and that obese persons who do not carry the LPL ×447 allele need to control body weight to prevent hypertriglyceridemia.

  7. 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

  8. 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

  9. 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

  10. High HDL-C prevalence is common in type 1 diabetes and increases with age but is lower in Hispanic individuals.

    PubMed

    Alessa, Thamer; Szeto, Angela; Chacra, Walid; Mendez, Armando; Goldberg, Ronald B

    2015-01-01

    High HDL-cholesterol (HDL-C) based on the 85th percentile of the 2009-2010 National Health and Education Survey (NHANES) was present in more than a third of 194 unselected subjects with type 1 diabetes (T1D). Age was associated with an increase and Hispanic ethnicity with a decrease in the prevalence of high HDL-C.

  11. 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

  12. The Carboxy-Terminal Region of apoA-I is Required for the ABCA1-Dependent Formation of α-HDL but not preβ-HDL Particles In Vivo

    PubMed Central

    Chroni, Angeliki; Koukos, Georgios; Duka, Adelina; Zannis, Vassilis I.

    2008-01-01

    ABCA1-mediated lipid efflux to lipid poor apoA-I results in the gradual lipidation of apoA-I. This leads to the formation of discoidal HDL which are subsequently converted to spherical HDL by the action of LCAT. We have investigated the effect of point mutations and deletions in the carboxy-terminal region of apoA-I on the biogenesis of HDL using adenovirus-mediated gene transfer in apoA-I deficient mice. It was found that the plasma HDL levels were greatly reduced in mice expressing the carboxy-terminal deletion mutants apoA-I[Δ(185-243)] and apoA-I[Δ(220-243)], shown previously to diminish the ABCA1-mediated lipid efflux. The HDL levels were normal in mice expressing the WT apoA-I, the apoA-I[Δ(232-243)] deletion mutant or the apoA-I[E191A/H193A/K195A] point mutant, which promote normal ABCA1-mediated lipid efflux. Electron microscopy and two-dimensional gel electrophoresis showed that the apoA-I[Δ(185-243)] and apoA-I[Δ(220-243)] mutants formed mainly preβ-HDL particles and few spherical particles enriched in apoE, while WT apoA-I, apoA-I[Δ(232-243)] and apoA-I[E191A/H193A/K195A] formed spherical α-HDL particles. The findings establish that a) deletions that eliminate the 220-231 region of apoA-I prevent the synthesis of α-HDL, but allow the synthesis of preβ-HDL particles in vivo, b) the amino-terminal segment 1-184 of apoA-I can promote synthesis of preβ-HDL type particles in an ABCA1-independent process and c) the charged residues in the 191-195 region of apoA-I do not influence the biogenesis of HDL. PMID:17447731

  13. Ciprofibrate therapy in patients with hypertriglyceridemia and low high density lipoprotein (HDL)-cholesterol: greater reduction of non-HDL cholesterol in subjects with excess body weight (The CIPROAMLAT study)

    PubMed Central

    Aguilar-Salinas, Carlos A; Assis-Luores-Vale, Andréia; Stockins, Benjamín; Rengifo, Hector Mario; Filho, José Dondici; Neto, Abrahão Afiune; Rabelo, Lísia Marcílio; Torres, Kerginaldo Paulo; Oliveira, José Egídio Paulo de; Machado, Carlos Alberto; Reyes, Eliana; Saavedra, Victor; Florenzano, Fernando; Hernández, Ma Victoria; Jiménez, Sergio Hernandez; Ramírez, Erika; Vazquez, Cuauhtémoc; Salinas, Saul; Hernández, Ismael; Medel, Octavio; Moreno, Ricardo; Lugo, Paula; Alvarado, Ricardo; Mehta, Roopa; Gutierrez, Victor; Gómez Pérez, Francisco J

    2004-01-01

    Background Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response. Methods Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6–3.9 mM/l and HDL cholesterol ≤ 1.05 mM/l for women and ≤ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline. Results After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m2) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs -10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate. Conclusions Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated. PMID:15272932

  14. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database.

    PubMed

    Barter, Philip J; Brandrup-Wognsen, Gunnar; Palmer, Mike K; Nicholls, Stephen J

    2010-06-01

    The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coefficient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C.

  15. 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

  16. Significance of the hydrophobic residues 225-230 of apoA-I for the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Tiniakou, Ioanna; Kateifides, Andreas K; Gkolfinopoulou, Christina; Chroni, Angeliki; Stratikos, Efstratios; Zannis, Vassilis I; Kardassis, Dimitris

    2013-12-01

    We studied the significance of four hydrophobic residues within the 225-230 region of apoA-I on its structure and functions and their contribution to the biogenesis of HDL. Adenovirus-mediated gene transfer of an apoA-I[F225A/V227A/F229A/L230A] mutant in apoA-I⁻/⁻ mice decreased plasma cholesterol, HDL cholesterol, and apoA-I levels. When expressed in apoA-I⁻/⁻ × apoE⁻/⁻ mice, approximately 40% of the mutant apoA-I as well as mouse apoA-IV and apoB-48 appeared in the VLDL/IDL/LDL. In both mouse models, the apoA-I mutant generated small spherical particles of pre-β- and α4-HDL mobility. Coexpression of the apoA-I mutant and LCAT increased and shifted the-HDL cholesterol peak toward lower densities, created normal αHDL subpopulations, and generated spherical-HDL particles. Biophysical analyses suggested that the apoA-I[225-230] mutations led to a more compact folding that may limit the conformational flexibility of the protein. The mutations also reduced the ability of apoA-I to promote ABCA1-mediated cholesterol efflux and to activate LCAT to 31% and 66%, respectively, of the WT control. Overall, the apoA-I[225-230] mutations inhibited the biogenesis of-HDL and led to the accumulation of immature pre-β- and α4-HDL particles, a phenotype that could be corrected by administration of LCAT. PMID:24123812

  17. 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

  18. A COCONUT EXTRA VIRGIN OIL-RICH DIET INCREASES HDL CHOLESTEROL AND DECREASES WAIST CIRCUMFERENCE AND BODY MASS IN CORONARY ARTERY DISEASE PATIENTS.

    PubMed

    Cardoso, Diuli A; Moreira, Annie S B; de Oliveira, Glaucia M M; Raggio Luiz, Ronir; Rosa, Glorimar

    2015-11-01

    Introducción: el aceite de coco (Cocos nucifera L.) virgen extra contiene una alta proporción de ácidos grasos de cadena media que parecen contribuir a la reducción del peso y podría ayudar en la prevención secundaria de la enfermedad arterial coronaria (EAC). Objetivo: evaluar el efecto del tratamiento nutricional asociado con el consumo de aceite de coco virgen extra en los parámetros antropométricos y el perfil lipídico. Métodos: se realizó un estudio longitudinal de 116 adultos de ambos sexos que presentan CAD. Los pacientes fueron seguidos en dos etapas: en la primera etapa (basal-3 meses), se llevo a cabo un tratamiento nutricional intensivo. En la segunda etapa (3-6 días), los sujetos fueron divididos en dos grupos: grupo asociado con el consumo de aceite extra virgen de coco (GDOC) y el grupo de dieta (GD). Se realizaron mediciones mensuales antropométricas: peso, circunferencia de la cintura (CC), circunferencia del cuello (PP) e índice de masa corporal (IMC). Se tomó la presión arterial y muestras de sangre recogidas en ayunas durante 12 horas para el análisis de colesterol total y lipoproteínas, apoproteínas (Apo A-1 y B), glucosa, hemoglobina glucosilada (HbA1c) e insulina (I). Se compararon los promedios al principio y al final del estudio mediante el test t de Student-independiente. Se ajustó la presión arterial diastólica por el IMC mediante ANOVA. Los análisis se realizaron con el paquete estadístico SPSS, siendo significativa p < 0.05. Resultados: la edad media de la población fue de 62,4 ± 7,7 años, el 63,2% hombres, 70% mayores, el 77,6% con infarto de miocardio, el 52,6% con angina de pecho y el 100% con hipertensión arterial y dislipidemia. En la primera etapa del tratamiento nutricional se redujeron las concentraciones de insulina, peso, WC, IMC y PP, HbA1C, HOMA-IR y rápido, sin cambiar otros parámetros. En la segunda etapa del estudio se observó que la GDOC mantiene la reducción del peso, BMI, WC, con una

  19. Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development.

    PubMed

    Mei, Xiaohu; Atkinson, David

    2015-07-01

    Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1-184] forms a helix bundle while the C-terminal domain [185-243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain.

  20. 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...

  1. 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...

  2. Low HDL3 reduces the odds of men surviving to age 85 during 53-year follow-up

    PubMed Central

    Williams, Paul T.

    2013-01-01

    Objectives To identify high-density lipoprotein (HDL) subfractions associated with longevity in men. Design Fifty-three-year prospective follow-up of Gofman’s Livermore Cohort between 1954 and 2008. Setting Lawrence Livermore National Laboratory. Participants One thousand one hundred forty-four men who consented to the study, had analytic ultracentrifuge measurements of lipoprotein subfractions at baseline, and were old enough at baseline to have survived to age 85 during follow-up. Measurements Survival was determined according to participant contact, Social Security Death Index, and National Death Index. Results Three hundred ninety men survived to 85 years old (34.1%). Survivors were less likely than nonsurvivors to be in the lowest HDL3 (% (standard error) 18.5% (2.0%) vs 27.3% (1.6%), P < .001) and HDL2 (22.1% (2.1%) vs 27.7% (1.6%), P = 0.04) quartiles. Logistic regression analyses showed that the lowest HDL3 quartile significantly predicted shorter longevity (P = 0.002), whereas the linear increases per mg/dL of HDL3 did not (P = 0.38), suggesting a risk threshold proximal to the 25th percentile. Men who were above the 25th HDL3 percentile had 70% greater odds of surviving until age 85 than those below this level, which persisted when adjusted for HDL2, very low-density lipoprotein (LDL), and standard risk factors. Proportional hazard analyses of survival before age 85 showed that being in the lowest HDL3 quartile increased age-adjusted cancer risk by 39% (P = 0.05) and noncancer risk by 23% (P = 0.04) when adjusted for other risk factors. Survivors also smoked less (mean ± SD 0.31 ± 0.48 vs 0.57 ± 0.56 packs/d, P < .001), had lower systolic (118.36 ± 11.08 vs 122.81 ± 13.55 mmHg, P < .001) and diastolic (70.61 ± 8.59 vs 73.14 ± 9.22 mmHg, P < .001) blood pressures and lower LDL mass (359.55 ± 80.42 vs 374.37 ± 86.10 mg/dL, P = 0.009) and total cholesterol concentrations (229.51 ± 43.21 vs 235.89 ± 45.40 mg/dL, P = 0.04) than nonsurvivors

  3. 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

  4. HDL-related mechanisms of olive oil protection in cardiovascular disease.

    PubMed

    Lou-Bonafonte, José M; Fitó, Montse; Covas, María-Isabel; Farràs, Marta; Osada, Jesús

    2012-07-01

    The low incidence of cardiovascular disease in countries bordering the Mediterranean basin, where olive oil is the main source of dietary fat, and the negative association between this disease with high density lipoproteins has stimulated interest. This review summarizes the current knowledge gathered from human and animal studies regarding olive oil and high density lipoproteins. Cumulative evidence suggests that high density lipoprotein (HDL) cholesterol, and its main apolipoprotein A1, may be increased by consuming olive oil when compared with carbohydrate and low fat diets in humans. Conflicting results have been found in many studies when olive oil diets were compared with other sources of fat. The role of virgin olive oil minor components on its protective effect has been demonstrated by a growing number of studies although its exact mechanism remains to be elucidated. Dietary amount of olive oil, use of virgin olive oil, cholesterol intake, and physiopathological states such as genetic background, sex, age, obesity or fatty liver are variables that may offset those effects. Further studies in this field in humans and in animal models are warranted due to the complexity of HDL particles.

  5. HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders.

    PubMed

    Gautier, Emmanuel L; Westerterp, Marit; Bhagwat, Neha; Cremers, Serge; Shih, Alan; Abdel-Wahab, Omar; Lütjohann, Dieter; Randolph, Gwendalyn J; Levine, Ross L; Tall, Alan R; Yvan-Charvet, Laurent

    2013-02-11

    A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol-raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.

  6. Comparison of vegetarian diets and omnivorous diets on plasma level of HDL-c: a meta-analysis.

    PubMed

    Zhang, Zili; Wang, Jian; Chen, Sifan; Wei, Zhaoyu; Li, Zhengtu; Zhao, Siwen; Lu, Wenju

    2014-01-01

    Low plasma level of high density lipoprotein cholesterol (HDL-c) was an independent risk factor for cardio vascular disorder, and associated with poor outcomes in pulmonary arterial hypertension. To compare the effects of vegetarian diets and omnivorous diets on HDL-c in plasma, we identified cross-sectional and cohort studies related to HDL-c listed on PubMed and ISI Web of Knowledge as well as the corresponding references (until Nov, 2013). Twelve studies with a total of 4177 individuals were selected for meta-analysis. This meta-analysis indicates that vegetarian diets did not alter plasma HDL-c concentrations, as it wasn't initially expected by the authors [Standardized Mean Difference (SMD) = 0.02 mmol/l; 95% confidence interval (CI): -0.19 to 0.22 mmol/l]. In Asia and Latin America countries, no significant differences in HDL-c levels between vegetarians and omnivores were found (SMD = -0.09 mmol/l; 95% CI: -0.43 to 0.25 mmol/l). In Europe and North America countries, the plasma level of HDL-c was also not different between the two diets (SMD = 0.09 mmol/l; 95% CI: -0.19 to 0.36 mmol/l). In light of this meta-analysis, we conclude that there is no evidence that plasma HDL-c levels differs in vegetarians and omnivores, even after adjusting for cultural circumstances.

  7. 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

  8. Comparison of effects of diet versus exercise weight loss regimens on LDL and HDL particle size in obese adults

    PubMed Central

    2011-01-01

    Background Obesity is associated with an atherogenic lipid profile characterized by a predominance of small LDL and HDL particles. Weight loss, by dietary restriction or exercise, increases LDL particle size. Whether these interventions can augment HDL size in conjunction with LDL size remains unknown. Objective This study compared the effects of alternate day fasting (ADF), calorie restriction (CR), and endurance exercise on LDL and HDL particle size in overweight and obese subjects. Methods In a 12-week parallel-arm trial, adult subjects (n = 60) were randomized to 1 of 4 groups: 1) ADF (75% energy restriction for 24-h alternated with ad libitum feeding for 24-h), 2) CR (25% energy restriction every day), 3) exercise (moderate intensity training 3 x/week), or 4) control. Results Body weight was reduced (P < 0.001) by ADF, CR, and exercise (5.2 ± 1.1%, 5.0 ± 1.4%, 5.1 ± 0.9%, respectively). Plasma LDL cholesterol decreased (P < 0.05) with ADF (10 ± 4%) and CR (8 ± 4%), whereas HDL cholesterol increased (P < 0.05) with exercise (16 ± 5%). Integrated LDL particle size was augmented (P = 0.01) by ADF and CR. The proportion of small LDL particles decreased (P = 0.04) with ADF only, and the proportion of large HDL particles increased (P = 0.03) with exercise only. Conclusion These results indicate that dietary restriction increases LDL particle size, while endurance training augments HDL particle size, with minimal weight loss. None of these interventions concomitantly increased both LDL and HDL particle size, however. PMID:21767400

  9. 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

  10. Influence of Apolipoprotein (Apo) A-I Structure on Nascent High Density Lipoprotein (HDL) Particle Size Distribution*

    PubMed Central

    Vedhachalam, Charulatha; Chetty, Palaniappan Sevugan; Nickel, Margaret; Dhanasekaran, Padmaja; Lund-Katz, Sissel; Rothblat, George H.; Phillips, Michael C.

    2010-01-01

    The principal protein of high density lipoprotein (HDL), apolipoprotein (apo) A-I, in the lipid-free state contains two tertiary structure domains comprising an N-terminal helix bundle and a less organized C-terminal domain. It is not known how the properties of these domains modulate the formation and size distribution of apoA-I-containing nascent HDL particles created by ATP-binding cassette transporter A1 (ABCA1)-mediated efflux of cellular phospholipid and cholesterol. To address this issue, proteins corresponding to the two domains of human apoA-I (residues 1–189 and 190–243) and mouse apoA-I (residues 1–186 and 187–240) together with some human/mouse domain hybrids were examined for their abilities to form HDL particles when incubated with either ABCA1-expressing cells or phospholipid multilamellar vesicles. Incubation of human apoA-I with cells gave rise to two sizes of HDL particles (hydrodynamic diameter, 8 and 10 nm), and removal or disruption of the C-terminal domain eliminated the formation of the smaller particle. Variations in apoA-I domain structure and physical properties exerted similar effects on the rates of formation and sizes of HDL particles created by either spontaneous solubilization of phospholipid multilamellar vesicles or the ABCA1-mediated efflux of cellular lipids. It follows that the sizes of nascent HDL particles are determined at the point at which cellular phospholipid and cholesterol are solubilized by apoA-I; apparently, this is the rate-determining step in the overall ABCA1-mediated cellular lipid efflux process. The stability of the apoA-I N-terminal helix bundle domain and the hydrophobicity of the C-terminal domain are important determinants of both nascent HDL particle size and their rate of formation. PMID:20679346

  11. Association of metabolic and genetic factors with cholesterol esterification rate in HDL plasma and atherogenic index of plasma in a 40 years old Slovak population.

    PubMed

    Rašlová, K; Dobiášová, M; Hubáček, J A; Bencová, D; Siváková, D; Danková, Z; Franeková, J; Jabor, A; Gašparovič, J; Vohnout, B

    2011-01-01

    We assessed association between novel biomarkers of cardiovascular disease and conventional factors in 40 years old subjects (208 men and 266 women) from the general population of Slovakia. FER(HDL) (cholesterol esterification rate in HDL plasma), AIP--Atherogenic Index of Plasma [Log(TG/HDL-C)] as markers of lipoprotein particle size, and CILP2, FTO and MLXIPL polymorphisms, were examined in relation to biomarkers and conventional risk factors. Univariate analyses confirmed correlation between AIP, FER(HDL) and the most of measured parameters. Relations between AIP and CILP2, FTO and MLXIPL were not significant. However, CILP2 was significantly related to FER(HDL) in both genders. In multivariate analysis BMI was the strongest correlate of AIP levels. In multivariate model variability of FER(HDL) was best explained by AIP (R(2) = 0.55) in both genders with still significant effect of CILP2 SNP in men. In a model where AIP was omitted, TG levels explained 43 % of the FER(HDL) variability in men, while in women HDL-C was the major determinant (42 %). In conclusions, FER(HDL) and AIP related to the known markers of cardiovascular risk provide means to express their subtle interactions by one number. Our novel finding of association between CILP2 polymorphism and FER(HDL) supports its role in lipid metabolism.

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. In vivo administration of BL-3050: highly stable engineered PON1-HDL complexes

    PubMed Central

    2009-01-01

    Background Serum paraoxonase (PON1) is a high density lipoprotein (HDL)-associated enzyme involved in organophosphate (OP) degradation and prevention of atherosclerosis. PON1 comprises a potential candidate for in vivo therapeutics, as an anti-atherogenic agent, and for detoxification of pesticides and nerve agents. Because human PON1 exhibits limited stability, engineered, recombinant PON1 (rePON1) variants that were designed for higher reactivity, solubility, stability, and bacterial expression, are candidates for treatment. This work addresses the feasibility of in vivo administration of rePON1, and its HDL complex, as a potentially therapeutic agent dubbed BL-3050. Methods For stability studies we applied different challenges related to the in vivo disfunctionalization of HDL and PON1 and tested for inactivation of PON1's activity. We applied acute, repetitive administrations of BL-3050 in mice to assess its toxicity and adverse immune responses. The in vivo efficacy of recombinant PON1 and BL-3050 were tested with an animal model of chlorpyrifos-oxon poisoning. Results Inactivation studies show significantly improved in vitro lifespan of the engineered rePON1 relative to human PON1. Significant sequence changes relative to human PON1 might hamper the in vivo applicability of BL-3050 due to adverse immune responses. However, we observed no toxic effects in mice subjected to repetitive administration of BL-3050, suggesting that BL-3050 could be safely used. To further evaluate the activity of BL-3050 in vivo, we applied an animal model that mimics human organophosphate poisoning. In these studies, a significant advantages of rePON1 and BL-3050 (>87.5% survival versus <37.5% in the control groups) was observed. Furthermore, BL-3050 and rePON1 were superior to the conventional treatment of atropine-2-PAM as a prophylactic treatment for OP poisoning. Conclusion In vitro and in vivo data described here demonstrate the potential advantages of rePON1 and BL-3050 for

  19. Non-leaky vesiculation of large unilamellar vesicles (LUV) induced by plasma high density lipoproteins (HDL): Detection by HPLC

    SciTech Connect

    Tischler, U.; Rueckert, D.S.; Schubert, R.; Jaroni, H.W.; Schmidt, K.H.

    1989-05-15

    Interaction of large unilamellar phosphatidylcholine vesicles (LUV, 75nm) and plasma high density lipoproteins (HDL) resulted in a non-leaky vesiculation of LUV. This vesiculation was detected by a HPLC-system consisting of a combination of three TSK-gel columns (6000PW, 5000PW, 3000SW). With increasing incubation time liposomal (/sup 14/C)PC, entrapped (/sup 3/H)inulin, and apoprotein of HDL origin decreased. The decrease was accompanied by a formation of new particles, consisting of liposomal PC and apoprotein. These particles also enclosed (3H)inulin, reflecting a hydrophilic inner space. The formation of the particles reached a maximum after one day of incubation. Retention time was 21 minutes for LUV, 28 minutes for the new particles, and 36 minutes for HDL. In vesicles with membranes consisting of phosphatidylcholine and 30% cholesterol no interactions were observed.

  20. 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

  1. Plasma kinetics of an LDL-like nanoemulsion and lipid transfer to HDL in subjects with glucose intolerance

    PubMed Central

    Bertato, Marina P; Oliveira, Carolina P; Wajchenberg, Bernardo L; Lerario, Antonio C; Maranhão, Raul C

    2012-01-01

    OBJECTIVE: Glucose intolerance is frequently associated with an altered plasma lipid profile and increased cardiovascular disease risk. Nonetheless, lipid metabolism is scarcely studied in normolipidemic glucose-intolerant patients. The aim of this study was to investigate whether important lipid metabolic parameters, such as the kinetics of LDL free and esterified cholesterol and the transfer of lipids to HDL, are altered in glucose-intolerant patients with normal plasma lipids. METHODS: Fourteen glucose-intolerant patients and 15 control patients were studied; none of the patients had cardiovascular disease manifestations, and they were paired for age, sex, race and co-morbidities. A nanoemulsion resembling a LDL lipid composition (LDE) labeled with 14C-cholesteryl ester and 3H-free cholesterol was intravenously injected, and blood samples were collected over a 24-h period to determine the fractional clearance rate of the labels by compartmental analysis. The transfer of free and esterified cholesterol, triglycerides and phospholipids from the LDE to HDL was measured by the incubation of the LDE with plasma and radioactivity counting of the supernatant after chemical precipitation of non-HDL fractions. RESULTS: The levels of LDL, non-HDL and HDL cholesterol, triglycerides, apo A1 and apo B were equal in both groups. The 14C-esterified cholesterol fractional clearance rate was not different between glucose-intolerant and control patients, but the 3H-free- cholesterol fractional clearance rate was greater in glucose-intolerant patients than in control patients. The lipid transfer to HDL was equal in both groups. CONCLUSION: In these glucose-intolerant patients with normal plasma lipids, a faster removal of LDE free cholesterol was the only lipid metabolic alteration detected in our study. This finding suggests that the dissociation of free cholesterol from lipoprotein particles occurs in normolipidemic glucose intolerance and may participate in atherogenic

  2. 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

  3. 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

  4. Presence of elevated non-HDL among patients with T2DM with CV events despite of optimal LDL-C - A report from South India.

    PubMed

    Kumpatla, Satyavani; Soni, Anju; Narasingan, S N; Viswanathan, Vijay

    2016-01-01

    Elevated non-high density lipoprotein cholesterol (non-HDL-C) was the commonest lipid abnormality among T2DM patients with cardiovascular events (CV) events. Prevalence of elevated non-HDL-C was 21.6% among patients who were on statin therapy and with optimal low density lipoprotein-cholesterol (LDL-C) levels. Despite an optimal LDL-C level, 47% of the T2DM patients with CV events had elevated non-HDL-C.

  5. 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.

  6. Direct detection of ABCA1-dependent HDL formation based on lipidation-induced hydrophobicity change in apoA-I[S

    PubMed Central

    Omura, Risa; Nagao, Kohjiro; Kobayashi, Norihiro; Ueda, Kazumitsu; Saito, Hiroyuki

    2014-01-01

    ABCA1 mediates the efflux of cholesterol and phospholipids into apoA-I to form HDL, which is important in the prevention of atherosclerosis. To develop a novel method for the evaluation of HDL formation, we prepared an apoA-I-POLARIC by labeling the specific residue of an apoA-I variant with a hydrophobicity-sensitive fluorescence probe that detects the environmental change around apoA-I during HDL formation. apoA-I-POLARIC possesses the intact ABCA1-dependent HDL formation activity and shows 4.0-fold higher fluorescence intensity in HDL particles than in the lipid-free state. Incubation of apoA-I-POLARIC with ABCA1-expressing cells, but not ABCA1-non-expressing cells, caused a 1.7-fold increase in fluorescence intensity. Gel filtration analysis demonstrated that the increase in fluorescence intensity of apoA-I-POLARIC represents the amount of apoA-I incorporated into the discoidal HDL particles rather than the amount of secreted cholesterol. THP-1 macrophage-mediated HDL formation and inhibition of HDL formation by cyclosporine A could also be measured using apoA-I-POLARIC. Furthermore, HDL formation-independent lipid release induced by microparticle formation or cell death was not detected by apoA-I-POLARIC. These results demonstrate that HDL formation by ABCA1-expressing cells can be specifically detected by sensing hydrophobicity change in apoA-I, thus providing a novel method for assessing HDL formation and screening of the HDL formation modulator. PMID:25214539

  7. 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

  8. 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.

  9. An isoenergetic very low carbohydrate diet improves serum HDL cholesterol and triacylglycerol concentrations, the total cholesterol to HDL cholesterol ratio and postprandial pipemic responses compared with a low fat diet in normal weight, normolipidemic women.

    PubMed

    Volek, Jeff S; Sharman, Matthew J; Gómez, Ana L; Scheett, Timothy P; Kraemer, William J

    2003-09-01

    Very low carbohydrate diets are popular, yet little is known about their effects on blood lipids and other cardiovascular disease risk factors. We reported previously that a very low carbohydrate diet favorably affected fasting and postprandial triacylglycerols, LDL subclasses and HDL cholesterol (HDL-C) in men but the effects in women are unclear. We compared the effects of a very low carbohydrate and a low fat diet on fasting lipids, postprandial lipemia and markers of inflammation in women. We conducted a balanced, randomized, two-period, crossover study in 10 healthy normolipidemic women who consumed both a low fat (<30% fat) and a very low carbohydrate (<10% carbohydrate) diet for 4 wk each. Two blood draws were performed on separate days at 0, 2 and 4 wk and an oral fat tolerance test was performed at baseline and after each diet period. Compared with the low fat diet, the very low carbohydrate diet increased (P HDL-C (33%) and decreased serum triacylglycerols (-30%), the total cholesterol to HDL ratio (-13%) and the area under the 8-h postprandial triacylglycerol curve (-31%). There were no significant changes in LDL size or markers of inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-alpha) after the very low carbohydrate diet. In normal weight, normolipidemic women, a short-term very low carbohydrate diet modestly increased LDL-C, yet there were favorable effects on cardiovascular disease risk status by virtue of a relatively larger increase in HDL-C and a decrease in fasting and postprandial triaclyglycerols.

  10. The Impact of Lipoproteins on Wound Healing: Topical HDL Therapy Corrects Delayed Wound Healing in Apolipoprotein E Deficient Mice

    PubMed Central

    Gordts, Stephanie C.; Muthuramu, Ilayaraja; Amin, Ruhul; Jacobs, Frank; Geest, Bart De

    2014-01-01

    Chronic non-healing wounds lead to considerable morbidity and mortality. Pleiotropic effects of high density lipoproteins (HDL) may beneficially affect wound healing. The objectives of this murine study were: (1) to investigate the hypothesis that hypercholesterolemia induces impaired wound healing and (2) to study the effect of topical HDL administration in a model of delayed wound healing. A circular full thickness wound was created on the back of each mouse. A silicone splint was used to counteract wound contraction. Coverage of the wound by granulation tissue and by epithelium was quantified every 2 days. Re-epithelialization from day 0 till day 10 was unexpectedly increased by 21.3% (p < 0.05) in C57BL/6 low density lipoprotein (LDLr) deficient mice with severe hypercholesterolemia (489 ± 14 mg/dL) compared to C57BL/6 mice and this effect was entirely abrogated following cholesterol lowering adenoviral LDLr gene transfer. In contrast, re-epithelialization in hypercholesterolemic (434 ± 16 mg/dL) C57BL/6 apolipoprotein (apo) E−/− mice was 22.6% (p < 0.0001) lower than in C57BL/6 mice. Topical HDL gel administered every 2 days increased re-epithelialization by 25.7% (p < 0.01) in apo E−/− mice. In conclusion, topical HDL application is an innovative therapeutic strategy that corrects impaired wound healing in apo E−/− mice. PMID:24705596

  11. 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...

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

    PubMed

    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

  13. Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol

    PubMed Central

    Heemskerk, Mattijs M.; Pieterman, Elsbet J.; van Klinken, Jan B.; van den Berg, Sjoerd A. A.; Smit, Johannes W. A.; Havekes, Louis M.; Rensen, Patrick C. N.; van der Hoorn, José W. A.; Princen, Hans M. G.; Jukema, J. Wouter

    2013-01-01

    Objective Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD). Approach and Results Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by −50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (−30%; −55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (−36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (−46%; −47%, P<0.01; −53%, P<0.001), atherosclerotic lesion area (−78%; −49%, P<0.01; −87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (−71%, P<0.01; −81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R2 = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R2 = 0.20, P<0.001). Conclusion Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL

  14. 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

  15. Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces diet-induced atherosclerosis[S

    PubMed Central

    Vaisman, Boris L.; Demosky, Stephen J.; Stonik, John A.; Ghias, Mona; Knapper, Cathy L.; Sampson, Maureen L.; Dai, Cuilian; Levine, Stewart J.; Remaley, Alan T.

    2012-01-01

    The role of endothelial ABCA1 expression in reverse cholesterol transport (RCT) was examined in transgenic mice, using the endothelial-specific Tie2 promoter. Human ABCA1 (hABCA1) was significantly expressed in endothelial cells (EC) of most tissues except the liver. Increased expression of ABCA1 was not observed in resident peritoneal macrophages. ApoA-I-mediated cholesterol efflux from aortic EC was 2.6-fold higher (P < 0.0001) for cells from transgenic versus control mice. On normal chow diet, Tie2 hABCA1 transgenic mice had a 25% (P < 0.0001) increase in HDL-cholesterol (HDL-C) and more than a 2-fold increase of eNOS mRNA in the aorta (P < 0.04). After 6 months on a high-fat, high-cholesterol (HFHC) diet, transgenic mice compared with controls had a 40% increase in plasma HDL-C (P < 0.003) and close to 40% decrease in aortic lesions (P < 0.02). Aortas from HFHC-fed transgenic mice also showed gene expression changes consistent with decreased inflammation and apoptosis. Beneficial effects of the ABCA1 transgene on HDL-C levels or on atherosclerosis were absent when the transgene was transferred onto ApoE or Abca1 knockout mice. In summary, expression of hABCA1 in EC appears to play a role in decreasing diet-induced atherosclerosis in mice and is associated with increased plasma HDL-C levels and beneficial gene expression changes in EC. PMID:22039582

  16. HDL Cholesterol Level Is Associated with Contrast Induced Acute Kidney Injury in Chronic Kidney Disease Patients Undergoing PCI

    PubMed Central

    Park, Hoon Suk; Kim, Chan Joon; Hwang, Byung-Hee; Kim, Tae-Hoon; Koh, Yoon Seok; Park, Hun-Jun; Her, Sung-Ho; Jang, Sung Won; Park, Chul-Soo; Lee, Jong Min; Kim, Hee-Yeol; Jeon, Doo Soo; Kim, Pum-Joon; Yoo, Ki-Dong; Chang, Kiyuk; Jin, Dong Chan; Seung, Ki-Bae

    2016-01-01

    Chronic kidney disease (CKD) is a significant risk factor for contrast induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI). This study included 1592 CKD patients extracted from a prospective multicenter, all comer-based registry of patients undergoing PCI. In multivariate logistic analysis for CI-AKI development, a significant linear trend was observed between the quartiles of HDL-C (quartile 1 vs. 2: odds ratio [OR], 0.716; 95% confidence interval [CI], 0.421–1.219; quartile 1 vs. 3: OR, 0.534; 95% CI, 0.301–0.947; quartile 1 vs. 4: OR, 0.173; 95% CI, 0.079–0.377; P for trend < 0.001). HDL-C quartiles were also negatively correlated with the incidence of CI-AKI; 19.0%, 12.1%, 8.7%, and 3.7% for quartile 1(Q1) (<34 mg/dL), Q2 (34–40 mg/dL), Q3 (40–48 mg/dL), and Q4 (>48 mg/dL) respectively (P < 0.001 overall and for the trend). Multivariate Cox regression analysis for the long term mortality, the highest HDL-C quartile was associated with decreased mortality compared with the lowest HDL-C quartile (hazard ratio [HR] 0.516, 95% CI, 0.320–0.832, P = 0.007). Our study suggests more intensive strategies should be considered for preventing CI-AKI in CKD patients with low serum HDL-C level who is planned for PCI. PMID:27775043

  17. 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...

  18. 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 ...

  19. High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C.

    PubMed

    Bochem, Andrea E; Holleboom, Adriaan G; Romijn, Johannes A; Hoekstra, Menno; Dallinga-Thie, Geesje M; Motazacker, Mahdi M; Hovingh, G Kees; Kuivenhoven, Jan A; Stroes, Erik S G

    2013-06-01

    Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans. PMID:23511897

  20. Will Lipidation of ApoA1 through Interaction with ABCA1 at the Intestinal Level Affect the Protective Functions of HDL?

    PubMed Central

    Niesor, Eric J.

    2015-01-01

    The relationship between levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) risk is well recognized; however, in recent years, large-scale phase III studies with HDL-C-raising or -mimicking agents have failed to demonstrate a clinical benefit on CV outcomes associated with raising HDL-C, casting doubt on the “HDL hypothesis.” This article reviews potential reasons for the observed negative findings with these pharmaceutical compounds, focusing on the paucity of translational models and relevant biomarkers related to HDL metabolism that may have confounded understanding of in vivo mechanisms. A unique function of HDL is its ability to interact with the ATP-binding cassette transporter (ABC) A1 via apolipoprotein (Apo) A1. Only recently, studies have shown that this process may be involved in the intestinal uptake of dietary sterols and antioxidants (vitamin E, lutein and zeaxanthin) at the basolateral surface of enterocytes. This parameter should be assessed for HDL-raising drugs in addition to the more documented reverse cholesterol transport (RCT) from peripheral tissues to the liver. Indeed, a single mechanism involving the same interaction between ApoA1 and ABCA1 may encompass two HDL functions previously considered as separate: antioxidant through the intestinal uptake of antioxidants and RCT through cholesterol efflux from loaded cells such as macrophages. PMID:25569858

  1. 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

  2. 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.

  3. Distal hemorrhoidectomy with ALTA injection: a new method for hemorrhoid surgery.

    PubMed

    Abe, Tatsuya; Hachiro, Yoshikazu; Ebisawa, Yoshiaki; Hishiyama, Houhei; Kunimoto, Masao

    2014-01-01

    Aluminum potassium sulfate and tannic acid injection (ALTA) is a useful and less-invasive treatment for internal hemorrhoids. However, it is not a treatment option for external hemorrhoidal diseases, including mixed hemorrhoids. Distal hemorrhoidectomy with ALTA injection involves surgical resection of external piles, followed by injection therapy on internal piles. We report technical details and the short-term results of this procedure in patients with mixed hemorrhoids. Seventy-two patients with mixed hemorrhoids treated between 2010 and 2011 were included. The main outcome measures were the short-term response and complication rates. At 28 days after surgery, the disappearance rate of prolapse was 100%. Three patients (4%) had postoperative complications, all minor in nature. No prolapse recurrence was observed within a median follow-up period of 6 months. Distal hemorrhoidectomy with ALTA injection appears to be a promising treatment option for patients with mixed hemorrhoids.

  4. Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency.

    PubMed

    Fasano, Tommaso; Zanoni, Paolo; Rabacchi, Claudio; Pisciotta, Livia; Favari, Elda; Adorni, Maria Pia; Deegan, Patrick B; Park, Adrian; Hlaing, Thinn; Feher, Michael D; Jones, Ben; Uzak, Asli Subasioglu; Kardas, Fatih; Dardis, Andrea; Sechi, Annalisa; Bembi, Bruno; Minuz, Pietro; Bertolini, Stefano; Bernini, Franco; Calandra, Sebastiano

    2012-11-01

    The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia. PMID:22959828

  5. Short term effects of a low-carbohydrate diet in overweight and obese subjects with low HDL-C levels

    PubMed Central

    2010-01-01

    Background The aim of this study was to evaluate short-term effects of a low-carbohydrate diet in overweight and obese subjects with low HDL-C levels. Methods Overweight (BMI between 25-30 kg/m2) or obese (BMI over 30 kg/m2) subjects with low HDL-C levels (men with HDL-C <1.03, women <1.29 mmol/l) were invited to the study. A 1400 kcal 75-gram carbohydrate (CHO) diet was given to women and an 1800 kcal 100-gram CHO diet was given to men for four weeks. The distribution of daily energy of the prescribed diet was 21-22% from CHO, 26-29% from protein and 49-53% from fat. Subjects completed a three-day dietary intake record before each visit. Anthropometric indices, body fat ratio, blood lipids, glucose and insulin were measured. Baseline and week-four results were compared with a Wilcoxon signed ranks test. Results Twenty-five women and 18 men participated. Basal median LDL-C level of men was 3.11 and basal median LDL-C level of women was 3.00 mmol/l. After four weeks of a low-carbohydrate diet, the median energy intake decreased from 1901 to 1307 kcal/day, daily energy from carbohydrate from 55% to 33%, body weight from 87.7 to 83.0 kg and HDL-C increased from 0.83 to 0.96 mmol/l in men (p < 0.002, for all). After four weeks of a low-carbohydrate diet, the median energy intake tended to decrease (from 1463 to 1243 kcal, p = 0.052), daily energy from carbohydrate decreased from 53% to 30% (p < 0.001) and body weight decreased from 73.2 to 70.8 kg (p < 0.001) in women, but HDL-C did not significantly change (from 1.03 to 1.01 mmol/l, p = 0.165). There were significant decreases in body mass index, waist circumference, body fat ratio, systolic blood pressure, total cholesterol, triglyceride and insulin levels in all subjects. Conclusions HDL-C levels increased significantly with energy restriction, carbohydrate restriction and weight loss in men. HDL-C levels didn't change in women in whom there was no significant energy restriction but a significant carbohydrate

  6. [A rapid method for continuous flow measurement of cholesterol contained in high density lipoproteins (HDL) (author's transl)].

    PubMed

    Ponsot, P; Yvert, J P; Chevrier, M; Bon, R

    1981-01-01

    The authors utilized a reagent containing concanavalin A, a vegetal lecithin, to selectively precipitate lipoproteins containing apoprotein B, a component of VLDL, LDL, and Lp (a) which are well known for their atherogenic risk. During this precipitation "true" high density lipoproteins remain in solution. HDL cholesterol determination which constitutes an indirect indication of HDL activity or concentrations is performed by an enzymatic method using an automated continuous flow technique carried out on an Auto Analyzer II (Technicon Corp.). This rapid, easy determination obtains results comparable to other methods, particularly those chosen by the Société Française de Biologie Clinique (French Society of Clinical Biology). This technique should permit all laboratories to confirm an atherogenic index.

  7. 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

  8. The Challenges of Genome-Wide Interaction Studies: Lessons to Learn from the Analysis of HDL Blood Levels

    PubMed Central

    van Leeuwen, Elisabeth M.; Smouter, Françoise A. S.; Kam-Thong, Tony; Karbalai, Nazanin; Smith, Albert V.; Harris, Tamara B.; Launer, Lenore J.; Sitlani, Colleen M.; Li, Guo; Brody, Jennifer A.; Bis, Joshua C.; White, Charles C.; Jaiswal, Alok; Oostra, Ben A.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Boerwinkle, Eric; Ballantyne, Christie M.; Gudnason, Vilmundur; Psaty, Bruce M.; Cupples, L. Adrienne; Järvelin, Marjo-Riitta; Ripatti, Samuli; Isaacs, Aaron; Müller-Myhsok, Bertram; Karssen, Lennart C.; van Duijn, Cornelia M.

    2014-01-01

    Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10−8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS. PMID:25329471

  9. 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

  10. 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

  11. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly.

    PubMed

    Curb, J D; Abbott, R D; Rodriguez, B L; Masaki, K; Chen, R; Sharp, D S; Tall, A R

    2004-05-01

    High density lipoprotein cholesterol (HDL-C) levels are inversely associated with the incidence of coronary heart disease (CHD) in middle-aged individuals; in the elderly, the association is less clear. Genetic factors, including variations in the cholesteryl ester transfer protein (CETP) gene, play a role in determining HDL-C levels. Controversy remains about whether CETP deficiency and the resultant rise in HDL-C are antiatherogenic, or whether CETP has the opposite effect due to its role in reverse cholesterol transport. In a seven-year follow-up of 2340 men aged 71-93 in the Honolulu Heart Program, the age-adjusted CHD incidence rates were significantly lower in men with high versus low HDL-C levels. After adjustment for age, hypertension, smoking, and total cholesterol, the relative risk of CHD for those with HDL-C levels >or=60 mg/dl, compared with those with HDL-C levels <40 mg/dl, was 0.6. Men with a CETP mutation had the lowest rates of CHD, although this was not statistically significant. These data indicate that HDL-C remains an important risk factor for CHD in the elderly. Whether a CETP mutation offers additional protection against CHD warrants further investigation.

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

    PubMed Central

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

    2014-01-01

    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

  13. 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

  14. Serum HDL-C level of Iranian adults: results from sixth national Surveillance of Risk Factors of Non-Communicable Disease

    PubMed Central

    2014-01-01

    Background Reduced level of high-density lipoprotein-cholesterol (HDL-C) is shown to be in association with the risk of coronary artery disease (CAD), metabolic syndrome, and chronic renal disease. Lack of a national representative research for assessing the level of HDL-C among Iranian adults, which is essential for health policy makers, was the motivation for this study. Methods HDL-C levels of 4,803 Iranian adults aged 25–64 years old were measured by sixth national Surveillance of Risk Factors of Non-Communicable Disease (SuRFNCD) in 2011. Data were entered into STATA 12 software and were analyzed using fractional polynomial model and other statistical methods. Results In average, Iranian adult women had 5.8 ± 0.3 mg/dL higher HDL-C level than men. The analysis showed that the HDL-C levels will be changed at most 3 mg/dL from the age of 25 to 64 years. Furthermore, it was shown that approximately half of the men and one third of the women had HDL-C level less than 40 mg/DL. Also HDL-C level of more than 60% of the women was less than 50 mg/dL. Conclusions High level of HDL-C among Iranian adults was shown in this study which can be a major reason of increasing incidence of heart diseases in Iran. Hence, formulating policy regulations and interventions in Iranian lifestyle to reduce HDL-C levels should be among top priorities for health politicians. PMID:25028645

  15. Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

    PubMed Central

    Kühnast, Susan; van der Tuin, Sam J.L.; van der Hoorn, José W.A.; van Klinken, Jan B.; Simic, Branko; Pieterman, Elsbet; Havekes, Louis M.; Landmesser, Ulf; Lüscher, Thomas F.; Willems van Dijk, Ko; Rensen, Patrick C.N.; Jukema, J. Wouter; Princen, Hans M.G.

    2015-01-01

    Background The residual risk that remains after statin treatment supports the addition of other LDL-C-lowering agents and has stimulated the search for secondary treatment targets. Epidemiological studies propose HDL-C as a possible candidate. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from atheroprotective HDL to atherogenic (V)LDL. The CETP inhibitor anacetrapib decreases (V)LDL-C by ∼15–40% and increases HDL-C by ∼40–140% in clinical trials. We evaluated the effects of a broad dose range of anacetrapib on atherosclerosis and HDL function, and examined possible additive/synergistic effects of anacetrapib on top of atorvastatin in APOE*3Leiden.CETP mice. Methods and results Mice were fed a diet without or with ascending dosages of anacetrapib (0.03; 0.3; 3; 30 mg/kg/day), atorvastatin (2.4 mg/kg/day) alone or in combination with anacetrapib (0.3 mg/kg/day) for 21 weeks. Anacetrapib dose-dependently reduced CETP activity (−59 to −100%, P < 0.001), thereby decreasing non-HDL-C (−24 to −45%, P < 0.001) and increasing HDL-C (+30 to +86%, P < 0.001). Anacetrapib dose-dependently reduced the atherosclerotic lesion area (−41 to −92%, P < 0.01) and severity, increased plaque stability index and added to the effects of atorvastatin by further decreasing lesion size (−95%, P < 0.001) and severity. Analysis of covariance showed that both anacetrapib (P < 0.05) and non-HDL-C (P < 0.001), but not HDL-C (P = 0.76), independently determined lesion size. Conclusion Anacetrapib dose-dependently reduces atherosclerosis, and adds to the anti-atherogenic effects of atorvastatin, which is mainly ascribed to a reduction in non-HDL-C. In addition, anacetrapib improves lesion stability. PMID:25142968

  16. Dysfunctional HDL Containing L159R ApoA-I Leads to Exacerbation of Atherosclerosis in Hyperlipidemic Mice

    PubMed Central

    Sorci-Thomas, Mary G.; Zabalawi, Manal; Bharadwaj, Manish S.; Wilhelm, Ashley J.; Owen, John S.; Asztalos, Bela F.; Bhat, Shaila; Thomas, Michael J.

    2013-01-01

    The mutation L159R apoA-I or apoA-IL159R (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL−/−, apoA-I−/−) (double knockout or DKO) were crossed > 9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr−/−, ApoA-I−/− (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12 weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α3-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-IL159R contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. PMID:21944998

  17. 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.

  18. 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...

  19. 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...

  20. 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

  1. 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

  2. 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

  3. 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

  4. Role of the hydrophobic and charged residues in the 218-226 region of apoA-I in the biogenesis of HDL.

    PubMed

    Fotakis, Panagiotis; Kateifides, Andreas K; Gkolfinopoulou, Christina; Georgiadou, Dimitra; Beck, Melissa; Gründler, Katharina; Chroni, Angeliki; Stratikos, Efstratios; Kardassis, Dimitris; Zannis, Vassilis I

    2013-12-01

    We investigated the significance of hydrophobic and charged residues 218-226 on the structure and functions of apoA-I and their contribution to the biogenesis of HDL. Adenovirus-mediated gene transfer of apoA-I[L218A/L219A/V221A/L222A] in apoA-I⁻/⁻ mice decreased plasma cholesterol and apoA-I levels to 15% of wild-type (WT) control mice and generated pre-β- and α4-HDL particles. In apoA-I⁻/⁻ × apoE⁻/⁻ mice, the same mutant formed few discoidal and pre-β-HDL particles that could not be converted to mature α-HDL particles by excess LCAT. Expression of the apoA-I[E223A/K226A] mutant in apoA-I⁻/⁻ mice caused lesser but discrete alterations in the HDL phenotype. The apoA-I[218-222] and apoA-I[E223A/K226A] mutants had 20% and normal capacity, respectively, to promote ABCA1-mediated cholesterol efflux. Both mutants had ∼65% of normal capacity to activate LCAT in vitro. Biophysical analyses suggested that both mutants affected in a distinct manner the structural integrity and plasticity of apoA-I that is necessary for normal functions. We conclude that the alteration of the hydrophobic 218-222 residues of apoA-I disrupts apoA-I/ABCA1 interactions and promotes the generation of defective pre-β particles that fail to mature into α-HDL subpopulations, thus resulting in low plasma apoA-I and HDL. Alterations of the charged 223, 226 residues caused milder but discrete changes in HDL phenotype. PMID:23990662

  5. [Comparative study of the consumption of virgin olive oil or seje on lipid profile and oxidation resistance of high density lipoprotein (HDL) of rat plasma].

    PubMed

    Isabel Giacopini, María; Guerrero, Omaira; Moya, Manuel; Bosch, Virgilio

    2011-06-01

    We compared the effect of the consumption of seje oil (Oenocarpus bataua), with that of olive oil, on plasma lipids and susceptibility in vitro to oxidation of high density lipoprotein (HDL) in the rat. Two groups often male Sprague Dawley rats were fed ad libitum, for a lapse of eight week, with a purified diets with 10g de seje oil or olive oil/100 g of diet (GS y GO respectively). The animals were exsanguinated at the end of the experimental after a 14 hour fast. Plasma was isolated by centrifugation, and the fractions of lipoproteins were separated from the plasma by sequential ultracentrifugation. Rats of GO had a statistically significant lower in concentration of TG (p < 0.05) compared with GS group. HDL fractions in both groups were oxidatively modified by incubation with copper ions. Differences in the fractions susceptibilities to peroxidation were studied by measuring the formation of thiobarbituric acid reactive substance (TBARS) for 3 hours. HDL in GS had a statistically significant decrease in TBARS formation (p < 0.05) relative to HDL of GO. This may be explained by the lower concentration of polyunsaturated fatty acids of HDL in GS compared with HDL in GO.

  6. 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

  7. 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

  8. The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties[S

    PubMed Central

    Schwendeman, Anna; Sviridov, Denis O.; Yuan, Wenmin; Guo, Yanhong; Morin, Emily E.; Yuan, Yue; Stonik, John; Freeman, Lita; Ossoli, Alice; Thacker, Seth; Killion, Salena; Pryor, Milton; Chen, Y. Eugene; Turner, Scott; Remaley, Alan T.

    2015-01-01

    The goal of this study was to understand how the reconstituted HDL (rHDL) phospholipid (PL) composition affects its cholesterol efflux and anti-inflammatory properties. An ApoA-I mimetic peptide, 5A, was combined with either SM or POPC. Both lipid formulations exhibited similar in vitro cholesterol efflux by ABCA1, but 5A-SM exhibited higher ABCG1- and SR-BI-mediated efflux relative to 5A-POPC (P < 0.05). Injection of both rHDLs in rats resulted in mobilization of plasma cholesterol, although the relative potency was 3-fold higher for the same doses of 5A-SM than for 5A-POPC. Formation of preβ HDL was observed following incubation of rHDLs with both human and rat plasma in vitro, with 5A-SM inducing a higher extent of preβ formation relative to 5A-POPC. Both rHDLs exhibited anti-inflammatory properties, but 5A-SM showed higher inhibition of TNF-α, IL-6, and IL-1β release than did 5A-POPC (P < 0.05). Both 5A-SM and 5A-POPC showed reduction in total plaque area in ApoE−/− mice, but only 5A-SM showed a statistically significant reduction over placebo control and baseline (P < 0.01). The type of PL used to reconstitute peptide has significant influence on rHDL’s anti-inflammatory and anti-atherosclerosis properties. PMID:26117661

  9. 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.

  10. 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

  11. Plasma lipids, lipoprotein metabolism and HDL lipid transfers are equally altered in metabolic syndrome and in type 2 diabetes.

    PubMed

    Silva, Vanessa M; Vinagre, Carmen G C; Dallan, Luis A O; Chacra, Ana P M; Maranhão, Raul C

    2014-07-01

    Metabolic syndrome (MetS) refers to states of insulin resistance that predispose to development of cardiovascular disease and type 2 diabetes (T2DM). The aim was to investigate whether plasma lipids and lipid metabolism differ in MetS patients compared to those with T2DM with poor glycemic control (glycated hemoglobin > 7.0). Eighteen patients with T2DM, 18 with MetS and 14 controls, paired for age (40-70 years) and body mass index (BMI), were studied. Plasma lipids and the kinetics of a triacylglycerol-rich emulsion labeled with [(3)H]-triolein ([(3)H]-TAG) and [(14)C]-cholesteryl esters ([(14)C]-CE) injected intravenously followed by one-hour blood sampling were determined. Lipid transfers from an artificial nanoemulsion donor to high-density lipoprotien (HDL) were assayed in vitro. Low-density lipoprotein (LDL) and HDL cholesterol (mg/dl) were not different in T2DM (128 ± 7; 42 ± 7) and MetS (142 ± 6; 39 ± 3), but triacylglycerols were even higher in MetS (215 ± 13) than in T2DM (161 ±11, p < 0.05). Fractional clearance rate (FCR, in min(1)) of [(3)H]-TAG and [(14)C]-CE were equal in T2DM (0.008 ± 0.018; 0.005 ± 0.024) and MetS (0.010 ± 0.016; 0.006 ± 0.013), and both were reduced compared to controls. The transfer of non-esterified cholesterol, phospholipids and triacylglycerols to HDL was higher in MetS and T2DM than in controls (p < 0.01). Cholesteryl ester transfer and HDL size were equal in all groups. Results imply that MetS is equal to poorly controlled T2DM concerning the disturbances of plasma lipid metabolism examined here, and suggest that there are different thresholds for the insulin action on glucose and lipids. These findings highlight the magnitude of the lipid disturbances in MetS, and may have implications in the prevention of cardiovascular diseases. PMID:24719245

  12. Plasma lipids, lipoprotein metabolism and HDL lipid transfers are equally altered in metabolic syndrome and in type 2 diabetes.

    PubMed

    Silva, Vanessa M; Vinagre, Carmen G C; Dallan, Luis A O; Chacra, Ana P M; Maranhão, Raul C

    2014-07-01

    Metabolic syndrome (MetS) refers to states of insulin resistance that predispose to development of cardiovascular disease and type 2 diabetes (T2DM). The aim was to investigate whether plasma lipids and lipid metabolism differ in MetS patients compared to those with T2DM with poor glycemic control (glycated hemoglobin > 7.0). Eighteen patients with T2DM, 18 with MetS and 14 controls, paired for age (40-70 years) and body mass index (BMI), were studied. Plasma lipids and the kinetics of a triacylglycerol-rich emulsion labeled with [(3)H]-triolein ([(3)H]-TAG) and [(14)C]-cholesteryl esters ([(14)C]-CE) injected intravenously followed by one-hour blood sampling were determined. Lipid transfers from an artificial nanoemulsion donor to high-density lipoprotien (HDL) were assayed in vitro. Low-density lipoprotein (LDL) and HDL cholesterol (mg/dl) were not different in T2DM (128 ± 7; 42 ± 7) and MetS (142 ± 6; 39 ± 3), but triacylglycerols were even higher in MetS (215 ± 13) than in T2DM (161 ±11, p < 0.05). Fractional clearance rate (FCR, in min(1)) of [(3)H]-TAG and [(14)C]-CE were equal in T2DM (0.008 ± 0.018; 0.005 ± 0.024) and MetS (0.010 ± 0.016; 0.006 ± 0.013), and both were reduced compared to controls. The transfer of non-esterified cholesterol, phospholipids and triacylglycerols to HDL was higher in MetS and T2DM than in controls (p < 0.01). Cholesteryl ester transfer and HDL size were equal in all groups. Results imply that MetS is equal to poorly controlled T2DM concerning the disturbances of plasma lipid metabolism examined here, and suggest that there are different thresholds for the insulin action on glucose and lipids. These findings highlight the magnitude of the lipid disturbances in MetS, and may have implications in the prevention of cardiovascular diseases.

  13. The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study

    PubMed Central

    2013-01-01

    Background Low levels of high-density lipoproteins (HDL) are considered an important risk factor for cardiovascular disease and constitute one of the criteria for the Metabolic Syndrome (MetS). Lifestyle interventions promoting a low-fat, plant-based eating pattern appear to paradoxically reduce cardiovascular risk but also HDL levels. This study examined the changes in MetS risk factors, in particular HDL, in a large cohort participating in a 30-day lifestyle intervention that promoted a low-fat, plant-based eating pattern. Methods Individuals (n = 5,046; mean age = 57.3 ± 12.9 years; 33.5% men, 66.5% women) participating in a in a Complete Health Improvement Program (CHIP) lifestyle intervention within the United States were assessed at baseline and 30 days for changes in body mass index (BMI), blood pressure (BP), lipid profile and fasting plasma glucose (FPG). Results HDL levels decreased by 8.7% (p<0.001) despite significant reductions (p<0.001) in BMI (-3.2%), systolic BP (-5.2%), diastolic BP (-5.2%), triglycerides (TG; -7.7%), FPG (-6.3%), LDL (-13.0%), total cholesterol (TC, -11.1%), TC: HDL ratio (-3.2%), and LDL: HDL ratio (-5.3%). While 323 participants classified as having MetS at program entry no longer had this status after the 30 days, 112 participants acquired the MetS classification as a result of reduction in their HDL levels. Conclusions When people move towards a low-fat, plant-based diet, HDL levels decrease while other indicators of cardiovascular risk improve. This observation raises questions regarding the value of using HDL levels as a predictor of cardiovascular risk in populations who do not consume a typical western diet. As HDL is part of the assemblage of risk factors that constitute MetS, classifying individuals with MetS may not be appropriate in clinical practice or research when applying lifestyle interventions that promote a plant-based eating pattern. PMID:24283215

  14. Poland and United States Collaborative Study on Cardiovascular Epidemiology. A comparison of HDL cholesterol and its subfractions in populations covered by the United States Atherosclerosis Risk in Communities Study and the Pol-MONICA Project.

    PubMed

    Broda, G; Davis, C E; Pajak, A; Williams, O D; Rywik, S L; Baczyńska, E; Folsom, A R; Szklo, M

    1996-02-01

    HDL cholesterol (HDL-C) levels are inversely related to coronary heart disease (CHD) risk, and HDL-C distributions vary among countries. Poland is one of the few developed countries in which CHD rates are increasing at the same time that US rates have been falling, but whether these differences are explained by differences in risk factors such as HDL-C has not been determined. To examine this possibility, levels of HDL-C and its subfractions were compared in US and Polish urban and rural men and women aged 45 to 64 years. Age-adjusted HDL-C means were 0.20 mmol/L higher in urban Polish men and 0.37 mmol/L higher in rural Polish men than in their US counterparts (P < .0001); means in urban Polish women were 0.06 mmol/L higher (P < .05) and in rural Polish women 0.09 mmol/L higher (P < .001) than in their US counterparts. Adjustment for age, education, alcohol intake, smoking, BMI, heart rate, and menopause status (in women) had little effect on differences. Means of HDL2 and HDL3 levels showed similar between-country differences, although differences were minimal for HDL2 in urban men and women, and HDL3 means did not differ between rural women. BMI was inversely related to HDL-C and both subfractions in all gender-country-site strata (P < .001), and alcohol was directly related to HDL-C (P < .001) in all strata except Polish women. Cigarette smoking was negatively related to HDL-C and both subfractions in all US samples except HDL2 in urban men, whereas in Polish samples, significant associations were found only in urban women for HDL-C and in rural and urban women for HDL3. Age, heart rate, and education showed inconsistent or no association with HDL-C and its subfractions in either country. This profile of HDL-C and its subfractions in Polish samples contrasts sharply with the opposite trend in CHD mortality rates, which suggests either that other risk factors may account for the trends or that the relationship between HDL-C and CHD may differ between the two

  15. 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

  16. [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.

  17. [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

  18. Modification of LCAT activity and HDL structure. New links between cigarette smoke and coronary heart disease risk.

    PubMed

    McCall, M R; van den Berg, J J; Kuypers, F A; Tribble, D L; Krauss, R M; Knoff, L J; Forte, T M

    1994-02-01

    The mechanism(s) through which smoking influences the progression of atherosclerosis is poorly understood. Recent evidence suggests that oxidants present in the gas phase of cigarette smoke are involved. We exposed human plasma to the filtered gas phase of cigarette smoke to assess its effects on plasma components involved in the antiatherogenic reverse cholesterol transport pathway. In our model, freshly isolated plasma (24 mL) was exposed to filtered air or gas-phase cigarette smoke for up to 6 hours at 37 degrees C. Lecithin-cholesterol acyltransferase (LCAT) activity was dramatically inhibited by cigarette smoke. A single 15-minute exposure to the smoke from an eighth of a cigarette was sufficient to reduce LCAT activity by 7%; additional exposures resulted in further decreases in activity. At 6 hours, only 22% of control LCAT activity remained in plasma exposed to smoke. Compared with control, gas-phase cigarette smoke-exposed plasma possessed high-density lipoprotein (HDL) with increased (16%) negative charge and with cross-linked apolipoproteins AI and AII. These data demonstrate that gas-phase cigarette smoke can inhibit a key enzyme (LCAT) and modify an integral lipid transport particle (HDL) that are essential components for the normal function of the reverse cholesterol transport pathway. Gas-phase cigarette smoke-induced modification of the reverse cholesterol transport pathway may provide a new mechanistic link between cigarette smoke and coronary heart disease risk.

  19. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome

    PubMed Central

    Song, Guohua; Li, Min; Sang, Hui; Zhang, Liying; Li, Xiuhong; Yao, Shutong; Yu, Yang; Zong, Chuanlong; Xue, Yazhuo; Qin, Shucun

    2013-01-01

    We have found that hydrogen (dihydrogen; H2) has beneficial lipid-lowering effects in high-fat diet-fed Syrian golden hamsters. The objective of this study was to characterize the effects of H2-rich water (0.9–1.0 l/day) on the content, composition, and biological activities of serum lipoproteins on 20 patients with potential metabolic syndrome. Serum analysis showed that consumption of H2-rich water for 10 weeks resulted in decreased serum total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels. Western blot analysis revealed a marked decrease of apolipoprotein (apo)B100 and apoE in serum. In addition, we found H2 significantly improved HDL functionality assessed in four independent ways, namely, i) protection against LDL oxidation, ii) inhibition of tumor necrosis factor (TNF)-α-induced monocyte adhesion to endothelial cells, iii) stimulation of cholesterol efflux from macrophage foam cells, and iv) protection of endothelial cells from TNF-α-induced apoptosis. Further, we found consumption of H2-rich water resulted in an increase in antioxidant enzyme superoxide dismutase and a decrease in thiobarbituric acid-reactive substances in whole serum and LDL. In conclusion, supplementation with H2-rich water seems to decrease serum LDL-C and apoB levels, improve dyslipidemia-injured HDL functions, and reduce oxidative stress, and it may have a beneficial role in prevention of potential metabolic syndrome. PMID:23610159

  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. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome.

    PubMed

    Song, Guohua; Li, Min; Sang, Hui; Zhang, Liying; Li, Xiuhong; Yao, Shutong; Yu, Yang; Zong, Chuanlong; Xue, Yazhuo; Qin, Shucun

    2013-07-01

    We have found that hydrogen (dihydrogen; H2) has beneficial lipid-lowering effects in high-fat diet-fed Syrian golden hamsters. The objective of this study was to characterize the effects of H2-rich water (0.9-1.0 l/day) on the content, composition, and biological activities of serum lipoproteins on 20 patients with potential metabolic syndrome. Serum analysis showed that consumption of H2-rich water for 10 weeks resulted in decreased serum total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels. Western blot analysis revealed a marked decrease of apolipoprotein (apo)B100 and apoE in serum. In addition, we found H2 significantly improved HDL functionality assessed in four independent ways, namely, i) protection against LDL oxidation, ii) inhibition of tumor necrosis factor (TNF)-α-induced monocyte adhesion to endothelial cells, iii) stimulation of cholesterol efflux from macrophage foam cells, and iv) protection of endothelial cells from TNF-α-induced apoptosis. Further, we found consumption of H2-rich water resulted in an increase in antioxidant enzyme superoxide dismutase and a decrease in thiobarbituric acid-reactive substances in whole serum and LDL. In conclusion, supplementation with H2-rich water seems to decrease serum LDL-C and apoB levels, improve dyslipidemia-injured HDL functions, and reduce oxidative stress, and it may have a beneficial role in prevention of potential metabolic syndrome.

  2. 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.

  3. 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

  4. Disruption of the murine procollagen C-proteinase enhancer 2 gene causes accumulation of pro-apoA-I and increased HDL levels

    PubMed Central

    Francone, Omar L.; Ishida, Brian Y.; de la Llera-Moya, Margarita; Royer, Lori; Happe, Christiane; Zhu, Jian; Chalkey, Robert J.; Schaefer, Peter; Cox, Cheryl; Burlingame, Al; Kane, John P.; Rothblat, George H.

    2011-01-01

    Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered. PMID:21771977

  5. 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

  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. Anacetrapib and dalcetrapib differentially alters HDL metabolism and macrophage-to-feces reverse cholesterol transport at similar levels of CETP inhibition in hamsters.

    PubMed

    Briand, François; Thieblemont, Quentin; Muzotte, Elodie; Burr, Noémie; Urbain, Isabelle; Sulpice, Thierry; Johns, Douglas G

    2014-10-01

    Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters.

  8. Effect of compounds affecting ABCA1 expression and CETP activity on the HDL pathway involved in intestinal absorption of lutein and zeaxanthin.

    PubMed

    Niesor, Eric J; Chaput, Evelyne; Mary, Jean-Luc; Staempfli, Andreas; Topp, Andreas; Stauffer, Andrea; Wang, Haiyan; Durrwell, Alexandre

    2014-12-01

    The antioxidant xanthophylls lutein and zeaxanthin are absorbed from the diet in a process involving lipoprotein formation. Selective mechanisms exist for their intestinal uptake and tissue-selective distribution, but these are poorly understood. We investigated the role of high-density lipoprotein (HDL), apolipoprotein (apo) A1 and ATP-binding cassette transporter (ABC) A1 in intestinal uptake of lutein in a human polarized intestinal cell culture and a hamster model. Animals received dietary lutein and zeaxanthin and either a liver X receptor (LXR) agonist or statin, which up- or down-regulate intestinal ABCA1 expression, respectively. The role of HDL was studied following treatment with the cholesteryl ester transfer protein (CETP) modulator dalcetrapib or the CETP inhibitor anacetrapib. In vitro, intestinal ABCA1 at the basolateral surface of enterocytes transferred lutein and zeaxanthin to apoA1, not to mature HDL. In hamsters, plasma lutein and zeaxanthin levels were markedly increased with the LXR agonist and decreased with simvastatin. Dalcetrapib, but not anacetrapib, increased plasma and liver lutein and zeaxanthin levels. ABCA1 expression and apoA1 acceptor activity are important initial steps in intestinal uptake and maintenance of lutein and zeaxanthin levels by an HDL-dependent pathway. Their absorption may be improved by physiological and pharmacological interventions affecting HDL metabolism.

  9. Leukocyte-derived hepatic lipase increases HDL and decreases en face aortic atherosclerosis in LDLr−/− mice expressing CETP*s⃞

    PubMed Central

    Hime, Neil J.; Black, Audrey S.; Bulgrien, Josh J.; Curtiss, Linda K.

    2008-01-01

    In addition to hepatic expression, cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are expressed by human macrophages. The combined actions of these proteins have profound effects on HDL structure and function. It is not known how these HDL changes influence atherosclerosis. To elucidate the role of leukocyte-derived HL on atherosclerosis in a background of CETP expression, we studied low density lipoprotein receptor-deficient mice expressing human CETP (CETPtgLDLr−/−) with a leukocyte-derived HL deficiency (HL−/− BM). HL−/− bone marrow (BM), CETPtgLDLr−/− mice were generated via bone marrow transplantation. Wild-type bone marrow was transplanted into CETPtgLDLr−/− mice to generate HL+/+ BM, CETPtgLDLr−/− controls. The chimeras were fed a high-fat, high-cholesterol diet for 14 weeks to promote atherosclerosis. In female HL−/− BM, CETPtgLDLr−/− mice plasma HDL-cholesterol concentration during high-fat feeding was decreased 27% when compared with HL+/+ BM, CETPtgLDLr−/− mice (P < 0.05), and this was associated with a 96% increase in en face aortic atherosclerosis (P < 0.05). In male CETPtgLDLr−/− mice, leukocyte-derived HL deficiency was associated with a 16% decrease in plasma HDL-cholesterol concentration and a 25% increase in aortic atherosclerosis. Thus, leukocyte-derived HL in CETPtgLDLr−/− mice has an atheroprotective role that may involve increased HDL levels. PMID:18599739

  10. 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.

  11. 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

  12. The atherogenic dyslipidemia ratio [log(TG)/HDL-C] is associated with residual vascular risk, beta-cell function loss and microangiopathy in type 2 diabetes females

    PubMed Central

    2012-01-01

    Background Atherogenic dyslipidemia (AD), defined as low HDL-C plus elevated triglycerides (TG), comorbid to T2DM, increases cardiometabolic risk for CAD even when LDL-C is at target. In T2DM males, AD was shown to correlate with β-cell function loss, yet it is not established whether this applies across gender. Aim To establish the prevalence and severity of AD in T2DM females, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year absolute CV risk (UKPDS Risk Engine). Methods 340 T2DM females were ranked according to quintiles (Q) of the continuous variable log(TG)/HDL-C, with AD prevalence defined as HDL-C <50 mg.dL-1 plus TG ≥150 mg.dL-1, and β-cell function assessed with HOMA. Results AD prevalence was 35%; mean HDL-C and TG were 52 (15) and 160 (105) mg.dL-1. AD was significantly related to central fat, metabolic syndrome, sedentarity and skeletal sarcopenia, as well as to hsCRP, fibrinogen, uric acid, cystatin-C, Big ET-1, and 10-year UKPDS CV risk. AD correlated stepwise with lower β-cell function and hyperbolic product, and with accelerated loss of residual insulin secretion, higher HbA1c and prevalent microangiopathy. Conclusions log(TG)/HDL-C is a simple means to grade AD and residual macrovascular risk in T2DM females. This ratio associates with major non-LDL cardiometabolic variables and ranks predicted CAD risk. In addition, log(TG)/HDL-C identifies worsening glucose homeostasis, poorer glycemic control, and prevalent microangiopathy. PMID:23046637

  13. log(TG)/HDL-C is related to both residual cardiometabolic risk and β-cell function loss in type 2 diabetes males

    PubMed Central

    2010-01-01

    Background T2DM is associated with atherogenic dyslipidemia (AD), defined as decreased HDL-C plus raised triglycerides (TG). AD confers increased risk for CAD, even when LDL-C is at target. AD is rarely assessed due to lack of screening methods consensus. Aim To establish the prevalence and severity of AD from log(TG)/HDL-C in T2DM males, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year UKPDS CV risk. Methods 585 T2DM males divided according to quintiles (Q) of log(TG)/HDL-C. AD prevalence defined as HDL-C <40 mg.dL-1 plus TG ≥150 mg.dL-1. β-cell function assessed with HOMA. Results Mean HDL-C and TG were 44 (13) and 204 (155) mg.dL-1. AD prevalence was 35%. AD correlated with lower β-cell function, with accelerated loss of insulin secretion, and with poorer HbA1c levels. AD was related to a high prevalence of CAD, and also to 10-year absolute CAD risk. Conclusions log(TG)/HDL-C is a simple means to estimate AD and the residual CV risk it confers in T2DM. AD closely associates with major cardiometabolic and glucose homeostasis determinants and poorer metabolic control. The ratio also relates to macroangiopathy prevalence and ranks future CAD risk, and is well-suited to capture non-LDL-related macrovascular residual risk and major glycemic determinants. PMID:21156040

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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).

  19. 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...

  20. 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

  1. 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.

  2. Higher prevalence of elevated LDL-C than non-HDL-C and low statin treatment rate in elderly community-dwelling Chinese with high cardiovascular risk

    PubMed Central

    Kuang, YaShu; Li, Xiaolin; Chen, Xiaoli; Sun, Huimin; Tomlinson, Brian; Chan, Paul; Zheng, Liang; Pi, Jinjiang; Peng, Sheng; Wu, Hong; Ding, Xugang; Qian, Dingguang; Shen, Yixin; Yu, Zuoren; Fan, Lieying; Chen, Ming; Fan, Huimin; Liu, Zhongmin; Zhang, Yuzhen

    2016-01-01

    Lipid levels are increasing in all age groups in the Chinese population, but the use of statin treatment in the elderly is not well documented. We examined serum lipids, statin usage and achievement of lipid goals in 3950 subjects aged ≥65 years. Established CVD was present in 7.77% of participants and increased CVD risk was common. Elevated LDL-C according to CVD risk level was present in 46.70% of all subjects and was more frequent (p < 0.01) than elevated non-HDL-C at 32.58%. With increasing age, LDL-C was unchanged but triglycerides and non-HDL-C decreased and HDL-C increased. Individuals at moderate risk for CVD had higher TC, LDL-C, and non-HDL-C than low-risk subjects, but the values were lower in high- and very-high-risk individuals, probably because of the use of statin which was 28.57% in high-risk subjects with established CVD and 37.60% in very-high-risk individuals, but only 2.62% in those with estimated high-risk and 3.75% in those with high-risk from diabetes. More subjects in each risk group reached the non-HDL-C goal than the LDL-C goal because of the relatively low triglycerides and VLDL-C levels. These findings demonstrate a high prevalence of elevated LDL-C but low rate of statin treatment in elderly community-dwelling Chinese. PMID:27686151

  3. Associations of Cholesteryl Ester Transfer Protein TaqIB Polymorphism with the Composite Ischemic Cardiovascular Disease Risk and HDL-C Concentrations: A Meta-Analysis

    PubMed Central

    Guo, Shu-xia; Yao, Ming-hong; Ding, Yu-song; Zhang, Jing-yu; Yan, Yi-zhong; Liu, Jia-ming; Zhang, Mei; Rui, Dong-sheng; Niu, Qiang; He, Jia; Guo, Heng; Ma, Ru-lin

    2016-01-01

    Background: Previous studies have evaluated the associations between the cholesteryl ester transfer protein (CETP) TaqIB polymorphism (rs708272), the risk of developing composite ischemic cardiovascular disease (CVD) and the concentration of high-density lipoprotein cholesterol (HDL-C), but results remain controversial. The objective of this study was to investigate whether a relationship exists between these factors. Methods: We conducted a meta-analysis of available studies to clarify the associations of the CETP TaqIB polymorphism with HDL-C concentration and the composite ischemic CVD risk in both Asians and Caucasians. All statistical analyses were done with Stata 12.0. Results: Through utilization of the Cochrane Library, Embase, PubMed, Web of Science, Springer, China Science and Technology Journal Database, China National Knowledge Infrastructure, Google Scholar, and Baidu Library, a total of 45 studies from 44 papers with 20,866 cases and 21,298 controls were combined showing a significant association between the CETP TaqIB variant and composite ischemic CVD risk. Carriers of allele TaqIB-B1 were found to have a higher risk of composite ischemic CVD than non-carriers: OR = 1.15, 95% CI = 1.09–1.21, p < 0.001. Meanwhile, 28 studies with 23,959 subjects were included in the association between the CETP TaqIB polymorphism and the concentration of HDL-C. Results suggested that carriers of the B1B1 genotype had lower concentrations of HDL-C than those of the B2B2 genotype: SMD = 0.50, 95% CI = 0.36–0.65, p < 0.001. Conclusions: The synthesis of available evidence demonstrates that the CETP TaqIB polymorphism protects against composite ischemic CVD risk and is associated with a higher HDL-C concentration in both Asians and Caucasians. PMID:27608031

  4. Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes

    PubMed Central

    2013-01-01

    Background Qualitative alterations of lipoproteins underlie the high incidence of atherosclerosis in diabetes. The objective of this study was to assess the impact of low-density lipoprotein (LDL) subfraction phenotype on the qualitative characteristics of LDL and high-density lipoprotein (HDL) in patients with type 2 diabetes. Methods One hundred twenty two patients with type 2 diabetes in poor glycemic control and 54 healthy subjects were included in the study. Patients were classified according to their LDL subfraction phenotype. Seventy-seven patients presented phenotype A whereas 45 had phenotype B. All control subjects showed phenotype A. Several forms of modified LDL, HDL composition and the activity and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) were analyzed. Results Oxidized LDL, glycated LDL and electronegative LDL were increased in both groups of patients compared with the control group. Patients with phenotype B had increased oxidized LDL and glycated LDL concentration than patients with phenotype A. HDL composition was abnormal in patients with diabetes, being these abnormalities more marked in patients with phenotype B. Total Lp-PLA2 activity was higher in phenotype B than in phenotype A or in control subjects. The distribution of Lp-PLA2 between HDL and apoB-containing lipoproteins differed in patients with phenotype A and phenotype B, with higher activity associated to apoB-containing lipoproteins in the latter. Conclusions The presence of LDL subfraction phenotype B is associated with increased oxidized LDL, glycated LDL and Lp-PLA2 activity associated to apoB-containing lipoproteins, as well as with abnormal HDL composition. PMID:23915379

  5. 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

  6. 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

  7. 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

  8. 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...

  9. 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.

  10. First record of Hesperolabops nigriceps Reuter (Hemiptera: Miridae) on Opuntia ficus-indica in Milpa Alta, Mexico City.

    PubMed

    Palomares-Pérez, Martín; Rodríguez-Leyva, Esteban; Brailovsky, Harry; Ramírez-Alarcón, Samuel

    2010-01-01

    In recent years a species of Hesperolabops has become a problem as a pest of nopalitos, Opuntia ficus-indica, in Milpa Alta, in the south of Mexico City, which is the most important production region of this vegetable in the country. A survey of Hesperolabops in Milpa Alta has resulted in the first report of Hesperolabops nigriceps Reuter. This occurrence should be monitored and considered in future studies in order to avoid misidentification of Hesperolabops spp. Kirkaldy native populations there, and to avoid the confusion of the damage that may be caused on O. ficus-indica.

  11. Photoelectrochemical evidence of nitrogen incorporation during anodizing sputtering--deposited Al-Ta alloys.

    PubMed

    Zaffora, A; Santamaria, M; Di Franco, F; Habazaki, H; Di Quarto, F

    2016-01-01

    Anodic films were grown to 20 V on sputtering-deposited Al-Ta alloys in ammonium biborate and borate buffer solutions. According to glow discharge optical emission spectroscopy, anodizing in ammonium containing solution leads to the formation of N containing anodic layers. Impedance measurements did not evidence significant differences between the dielectric properties of the anodic films as a function of the anodizing electrolyte. Photoelectrochemical investigation allowed evidencing that N incorporation induces a red-shift in the light absorption threshold of the films due to the formation of allowed localized states inside their mobility gap. The estimated Fowler threshold for the internal photoemission processes of electrons resulted to be independent of the anodizing electrolyte confirming that N incorporation does not appreciably affect the density of states distribution close to the conduction band mobility edge. The transport of photogenerated carriers has been rationalized according to the Pai-Enck model of geminate recombination.

  12. 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.

  13. 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.

  14. 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

  15. The serum LDL/HDL cholesterol ratio is influenced more favorably by exchanging saturated with unsaturated fat than by reducing saturated fat in the diet of women.

    PubMed

    Müller, Hanne; Lindman, Anja S; Brantsaeter, Anne Lise; Pedersen, Jan I

    2003-01-01

    We compared the effects of a high fat diet [38.4% of energy (E%) from fat; HSAFA diet, polyunsaturated/saturated fatty acid (P/S) ratio = 0.14], a low fat diet (19.7 E% from fat; LSAFA diet, P/S = 0.17), both based on coconut oil, and a diet with a high content of mono- and polyunsaturated fatty acids (PUFA; 38.2 E% from fat; HUFA diet, P/S = 1.9) on serum lipoproteins. The 25 women studied consumed each diet for 3-wk periods in a crossover design. The two high fat diets were identical except for the quality of the test fat. The LSAFA diet was identical to the HSAFA diet except that half the fat was replaced by carbohydrates. Serum total cholesterol, LDL cholesterol and apoB concentrations did not differ between the HSAFA and the LSAFA diet periods. Total cholesterol, LDL cholesterol and apoB were lower when women consumed the HUFA diet than when they consumed the other two diets. HDL cholesterol and apoA-I were 15 and 11%, respectively, higher when women consumed the HSAFA diet than when they consumed the LSAFA diet; HDL cholesterol and apoA-I were lower when women consumed the HUFA diet than when they consumed the HSAFA diet, but not the LSAFA diet. The LDL cholesterol/HDL cholesterol and apoB/apoA-I ratios were higher when women consumed the LSAFA diet than when they consumed the HSAFA diet. The LDL/HDL cholesterol ratio was higher when women consumed either the LSAFA or the HSAFA diet than when they consumed the HUFA diet, whereas apoB/apoA-I was higher when women consumed the LSAFA diet than when they consumed the HUFA diet. Triacylglycerol and VLDL cholesterol were higher when women consumed the LSAFA diet than when they consumed either the HSAFA or the HUFA diet. We conclude that, to influence the LDL/HDL cholesterol ratio, changing the proportions of dietary fatty acids may be more important than restricting the percentage of total or saturated fat energy, at least when derived mainly from lauric and myristic acids, both of which increase HDL cholesterol.

  16. Physical Activity Modifies the Effect of LPL, LIPC and CETP polymorphisms on HDL-C Levels and the Risk of Myocardial Infarction in Caucasian Women

    PubMed Central

    Ahmad, Tariq; Chasman, Daniel I.; Buring, Julie E.; Lee, I-Min; Ridker, Paul M; Everett, Brendan M.

    2010-01-01

    Background Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease (CVD), is uncertain. Methods and Results In a prospective cohort study of 22,939 apparently healthy Caucasian US women, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5×10−8) with HDL-C levels and sought evidence of effect modification according to levels of physical activity (PA). PA modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at LPL, rs1800588 at LIPC and rs1532624 at CETP (each P-interaction <0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of MI in active (Hazard Ratio [HR] 0.42, 95% Confidence Interval [CI] 0.23–0.76) but not amongst inactive women (HR 1.10, 95% CI 0.83–1.44; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of MI regardless of activity level (HR 0.72, 95% CI 0.57–0.92; P-interaction=0.71). No association between LIPC SNP carrier status and MI risk was noted Conclusions The effects of common variants in the LPL, LIPC and CETP genes on HDL-C levels are modified by PA. For a common variant in LPL, the impact on MI varied by activity level, while the effects of a common variant in CETP on MI risk did not. PMID:21252145

  17. 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

  18. 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…

  19. 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

    ...-referenced proceeding, of Alta Wind XI, LLC's application for market-based rate authority, with an accompanying rate schedule, noting that such application includes a request for blanket authorization, under 18 CFR part 34, of future issuances of securities and assumptions of liability. Any person desiring...

  20. 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

    ...-referenced proceeding, of Alta Wind X, LLC's application for market-based rate authority, with an accompanying rate schedule, noting that such application includes a request for blanket authorization, under 18 CFR part 34, of future issuances of securities and assumptions of liability. Any person desiring...

  1. Comparison of NCEP performance specifications for triglycerides, HDL-, and LDL-cholesterol with operating specifications based on NCEP clinical and analytical goals.

    PubMed

    Fallest-Strobl, P C; Olafsdottir, E; Wiebe, D A; Westgard, J O

    1997-11-01

    The National Cholesterol Education Program (NCEP) performance specifications for methods that measure triglycerides, HDL-cholesterol, and LDL-cholesterol have been evaluated by deriving operating specifications from the NCEP analytical total error requirements and the clinical requirements for interpretation of the tests. We determined the maximum imprecision and inaccuracy that would be allowable to control routine methods with commonly used single and multirule quality-control procedures having 2 and 4 control measurements per run, and then compared these estimates with the NCEP guidelines. The NCEP imprecision specifications meet the operating imprecision necessary to assure meeting the NCEP clinical quality requirements for triglycerides and HDL-cholesterol but not for LDL-cholesterol. More importantly, the NCEP imprecision specifications are not adequate to assure meeting the NCEP analytical total error requirements for any of these three tests. Our findings indicate that the NCEP recommendations fail to adequately consider the quality-control requirements necessary to detect medically important systematic errors.

  2. 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

  3. 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

  4. The low-resolution structure of nHDL reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion[S

    PubMed Central

    Gogonea, Valentin; Gerstenecker, Gary S.; Wu, Zhiping; Lee, Xavier; Topbas, Celalettin; Wagner, Matthew A.; Tallant, Thomas C.; Smith, Jonathan D.; Callow, Philip; Pipich, Vitaliy; Malet, Hélène; Schoehn, Guy; DiDonato, Joseph A.; Hazen, Stanley L.

    2013-01-01

    Small-angle neutron scattering (SANS) with contrast variation was used to obtain the low-resolution structure of nascent HDL (nHDL) reconstituted with dimyristoyl phosphatidylcholine (DMPC) in the absence and presence of cholesterol, [apoA1:DMPC (1:80, mol:mol) and apoA1:DMPC:cholesterol (1:86:9, mol:mol:mol)]. The overall shape of both particles is discoidal with the low-resolution structure of apoA1 visualized as an open, contorted, and out of plane conformation with three arms in nascent HDL/dimyristoyl phosphatidylcholine without cholesterol (nHDLDMPC) and two arms in nascent HDL/dimyristoyl phosphatidylcholine with cholesterol (nHDLDMPC+Chol). The low-resolution shape of the lipid phase in both nHDLDMPC and nHDLDMPC+Chol were oblate ellipsoids, and fit well within their respective protein shapes. Modeling studies indicate that apoA1 is folded onto itself in nHDLDMPC, making a large hairpin, which was also confirmed independently by both cross-linking mass spectrometry and hydrogen-deuterium exchange (HDX) mass spectrometry analyses. In nHDLDMPC+Chol, the lipid was expanded and no hairpin was visible. Importantly, despite the overall discoidal shape of the whole particle in both nHDLDMPC and nHDLDMPC+Chol, an open conformation (i.e., not a closed belt) of apoA1 is observed. Collectively, these data show that full length apoA1 retains an open architecture that is dictated by its lipid cargo. The lipid is likely predominantly organized as a bilayer with a micelle domain between the open apoA1 arms. The apoA1 configuration observed suggests a mechanism for accommodating changing lipid cargo by quantized expansion of hairpin structures. PMID:23349207

  5. 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

  6. 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

  7. 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

  8. Effects of dietary zinc and copper supplementation on serum triglyceride, total-cholesterol and HDL-cholesterol concentrations on young Sprague Dawley male rats

    SciTech Connect

    Frimpong, N.A.; Magee, A.C.

    1986-03-01

    To determine the effects of the level of zinc (Zn) and copper (Cu) supplementation and of Zn/Cu ratio on serum triglycerides (TG), total-cholesterol (TC), and HDL-cholesterol (HDL-C) concentrations, groups of weanling male Sprague Dawley rats were fed diets containing 4 levels of Cu (0, 0.56, 1.68, and 5.04 ppm) and 4 levels of Zn (0, 5, 10 and 20 ppm) for 6 weeks (Low supplementation, Expt I), or a high Zn and Cu supplements each at 4 levels (0, 5.6, 16.8, and 50.4 ppm Cu, plus 0, 50, 100, and 200 ppm Zn) for 6 weeks (Expt II). The effects of Zn/Cu ratios on the parameters were evaluated by combining data from Expt I and Expt II treatments with the same Zn/Cu ratios but different levels of Zn and Cu. Results of the combined data indicated that an increase in dietary Zn was associated with significant (p less than or equal to 0.01) increase in serum triglyceride concentrations, while an increase in dietary Cu was associated with significant (p less than or equal to 0.01) decrease in serum TC and HDL-C concentrations. Dietary Zn/Cu ratios had no significant effect on serum lipids. There is the indication that the absolute levels of the minerals in the diet may be more important in lipid metabolism. These results are in agreement with previous reports.

  9. Association of Serum Cholesterol, Triglyceride, High and Low Density Lipoprotein (HDL and LDL) Levels in Chronic Periodontitis Subjects with Risk for Cardiovascular Disease (CVD): A Cross Sectional Study

    PubMed Central

    Sandi, R.M.; Pol, K.G.; Basavaraj, P.; Khuller, Nitin; Singh, Shilpi

    2014-01-01

    Purpose: To assess serum cholesterol, triglycerides, high and low density lipoprotein (HDL and LDL) levels (serum lipid profile) in subjects with chronic periodontitis and the possible association for risk of cardiovascular disease (CVD). Materials and Methods: Total of 80 participants (42 males and 38 females) who were in the age range of 30-65 years were divided into test group (group I- 40 subjects with chronic periodontitis) and control group (group II- 40 subjects with healthy periodontium), based on their periodontal disease statuses. Three ml of venous blood samples were taken for measurement of parameters of lipid metabolism [serum cholesterol (chol); triglycerides (Tg); HDL and LDL. Results: Significant increase in serum cholesterol and LDL (P<0.05) were observed in test group (group I), whereas serum triglycerides and HDL (P>0.66) showed no significant increase in test group (group I) as compared to their values in the control group (group II). A P-value of < 0.05 was considered for statistical significance. Conclusions: Subjects with chronic periodontitis showed increased serum cholesterol and LDL levels. This may suggest that these subjects are potentially at a risk of getting CVD. PMID:24596778

  10. 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

  11. 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

  12. The TG/HDL-C ratio does not predict insulin resistance in overweight women of African descent: a study of South African, African American and West African women.

    PubMed

    Knight, Michael G; Goedecke, Julia H; Ricks, Madia; Evans, Juliet; Levitt, Naomi S; Tulloch-Reid, Marshall K; Sumner, Anne E

    2011-01-01

    Women of African descent have a high prevalence of diseases caused by insulin resistance. To positively impact cardiometabolic health in Black women, effective screening tests for insulin resistance must be identified. Recently, the TG/HDL-C ratio has been recommended as a tool to predict insulin resistance in overweight people. While the ratio predicts insulin resistance in White women, it is ineffective in African American women. As there are no data for African women, we tested the ability of the TG/HDL-C ratio to predict insulin resistance in Black women from South Africa, West Africa and the United States. For comparison, the ratio was also tested in White women from South Africa. Participants were 801 women (157 Black South African, 382 African American, 119 West African, 143 White South African, age 36 +/- 9y [mean +/- SD]). Standardized scores were created from log-transformed homeostasis model assessment-insulin resistance values from each population. Participants in the upper third of their population distribution were classified as insulin-resistant. To predict insulin resistance by the TC/HDL-C ratio, area under the receiver operating characteristic (AUC-ROC) curve was used and criteria were: 0.50 for no discrimination and > or = 0.70 for acceptable. Seventy-one percent of the Black women were overweight vs 51% of White women (P<.01). In overweight White women, AUC-ROC curve for prediction of insulin resistance by TG/HDL-C was 0.76 +/- 0.06, but below the 0.70 threshold in each group of overweight Black women (Black South African: 0.64 +/- 0.06, African American: 0.66 +/- 0.03, and West African: 0.63 +/- 0.07). Therefore, TG/HDL-C does not predict insulin resistance in overweight African American women and this investigation extends that finding to overweight Black South African and West African women. Resources to identify effective markers of insulin resistance are needed to improve cardiometabolic health in women of African descent.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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 Central

    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.

    2015-01-01

    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

  18. Levels of Cholesterol in Small LDL Particles Predict Atherosclerosis Progression and Incident CHD in the HDL-Atherosclerosis Treatment Study (HATS)

    PubMed Central

    Williams, Paul T.; Zhao, Xue-Qiao; Marcovina, Santica M.; Brown, B. Greg; Krauss, Ronald M.

    2013-01-01

    Objective Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses. Methods Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments. Results The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2–24.6 nm) and LDL-IVa (23.3–24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values. Conclusions Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol. Trial Registration ClinicalTrials.gov NCT00000553 PMID:23460815

  19. 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.

  20. 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

  1. APOA1-75 G to A Substitution Associated with Severe Forms of CAD, Lower Levels of HDL and apoA-I among Northern Indians

    PubMed Central

    Chhabra, S.; Narang, R.; Lakshmy, R.; Das, N.

    2005-01-01

    Apolipoprotein A-I (APOA1 gene, apoA-I protein) is the major protein for plasma high density lipoprotein (HDL). The relationship of APOA1-75G/A polymorphism with lipid profile and coronary artery disease (CAD) is unclear. Out of 370 individuals initially recruited, 164 angiographically proven CAD patients (≥ 70% stenosis) and 36 individuals with normal coronaries or insignificant CAD (NCAD, ≤ 50% stenosis) from Delhi and adjoining areas were selected for analysis based on the set criteria. Polymorphism was determined by PCR followed by MspI restriction digestion. Lipid profile was estimated by enzymatic kit and apoA-I levels by immunoturbidimetry. A highly significant increasing trend in ‘A’ allele frequency was observed with the rise in severity of CAD: NCAD (0.097) < SVD (single vessel disease) (0.117) < DVD (double vessel disease) (0.223) < TVD (triple vessel disease) (0.291). In comparison to GG individuals, the OR of ‘A’ allele carriers to develop SVD, DVD, TVD was 1.3, 2.8 and 4.2 respectively (ptrend = 0.007). Analysis of intergenotypic variations in the lipid profile revealed significantly lower levels of HDL and apoA-I among ‘A’ allele carriers as compared to GG (patients). Our study, first of its kind from India, suggests that ‘A’ allele may contribute to severity of CAD and low levels of HDL & apoA-I. However, an in depth study with a larger set of sample is necessary. PMID:16403951

  2. 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.

  3. [Evaluation of heart rate and blood pressure in residents of Milpa Alta, D.F].

    PubMed

    Sánchez-Girón, C; Brust-Mascher, E; De Icaza-Herrera, M; Vidrio-Amor, H; Brust-Carmona, H

    1992-01-01

    Both the altitude of Mexico City (D.F.) and the increase in atmospheric pollutants make it important to establish parameters of comparison for cardiovascular variables, such as heart rate (HR) and blood pressure (BP). The epidemiological transition occurring in Mexico is increasing the need for human and physical resources at the first level of health care in order to perform early diagnoses of cardiovascular disorders among the population. Heart rate, systolic and diastolic blood pressures (SBP, DBP) were recorded under diverse conditions (seated, standing, performing 30 sit-ups, and then standing and seated after the sit-ups) in 235 inhabitants of Milpa Alta (a suburb of Mexico City). The procedures and equipment used were designed and produced at the Center for Development and Technological Applications, Ministry of Health. The following results were found: HR decreases with age and body surface. Likewise, the HR increase due to exercise is lower with increasing age and larger body surface and its return to resting levels is slower. SBP and DBP magnitude is directly related to body surface. In women an increase of body weight was found to be significantly related to a higher SBP. The orthostatic reflex (OR) decreases with age and body surface. The descending slope is higher in women than in men. We propose that the study of OR could provide better information for predicting cardiovascular changes. The described procedures can be performed with the physical and human resources available at the Health Centers. The extension of this type of applied research to first level health care centers would allow the country to respond efficiently to the epidemiological transition.

  4. 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.

  5. 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

  6. 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

  7. Pretreatment TG/HDL-C Ratio Is Superior to Triacylglycerol Level as an Independent Prognostic Factor for the Survival of Triple Negative Breast Cancer Patients

    PubMed Central

    Dai, Danian; Chen, Bo; Wang, Bin; Tang, Hailin; Li, Xing; Zhao, Zhiping; Li, Xuan; Xie, Xiaoming; Wei, Weidong

    2016-01-01

    Purpose: Previous studies have reported that the triacylglycerol (TG) level and high-density lipoprotein cholesterol (HDL-C) are connected with breast cancer. However, the prognostic utility of the TG level and the TG/HDL-C ratio (THR) as conventional biomarkers in patients with triple negative breast cancer (TNBC) has not been elucidated. In this research, we investigate and compare the predictive value of the pretreatment serum TG level and THR in TNBC patients. Methods: We evaluated 221 patients with TNBC who had pretreatment conventional blood biochemical examinations and calculated the THR. Univariate and multivariate logistic regression analyses were used to assess the effect of the TG level and the THR on overall survival (OS) and disease-free survival (DFS). Results: The optimal cutoff values of the TG level and the THR were determined to be 0.935 mmol/L and 0.600, respectively. As shown in a Kaplan-Meier analysis, TNBC patients with a high TG level and THR had shorter OS and DFS than patients in the low-level groups (p < 0.05). The multivariate analysis suggested that the pretreatment THR level is an independent prognostic factor of OS (HR: 1.935; 95%CI: 1.032-3.629; p = 0.040) in TNBC patients. Conclusions: In conclusion, our data indicate that a high THR is an independent predictor and is superior to the TG level for predicting poor clinical outcomes in TNBC patients.

  8. 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

  9. 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

  10. 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

  11. 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

  12. Sedimentation survey of Lago La Plata, Toa Alta, Puerto Rico, March–April 2015

    USGS Publications Warehouse

    Gómez-Fragoso, Julieta

    2016-10-31

    IntroductionLago La Plata is operated by the Puerto Rico Aqueduct and Sewer Authority (PRASA) and is part of the San Juan Metropolitan Water District. The reservoir serves a population of about 425,000 people. During 2013 the reservoir provided 0.307 million cubic meters (Mm3 ) of water per day (about 81 million gallons per day), which is equivalent to 31 percent of the total water demand for the metropolitan area (Wanda L. Molina, U.S. Geological Survey, written commun., 2015). The dam was constructed in 1974 and is located about 5 kilometers (km) south of the town of Toa Alta and 5 km north of the town of Naranjito (fig. 1). The drainage area upstream from the Lago La Plata dam is about 469 square kilometers (km2 ). The storage capacity at construction in 1974 was 26.84 Mm3 with a spillway elevation of 47.12 meters (m) above mean sea level (msl). Storage capacity was increased to 40.21 Mm3 in 1989 after the installation of bascule gates to provide a normal dam pool elevation at 52 m above msl (Puerto Rico Electric and Power Authority, 1979). The maximum height of the dam is about 40 m above the river bottom near the dam, and the intake structure consists of six 1.82-m-diameter ports facing upstream, with 6-m vertical spacing that begins at an elevation of 19 m above msl. The U.S. Geological Survey (USGS), in cooperation with the PRASA, conducted a bathymetric survey of the Lago La Plata reservoir during March and April 2015. The hydrographic survey was designed to provide an update of the reservoir storage capacity and sedimentation rate. Areas with substantial sediment accumulation are also discussed in this report. The results of the survey were used to prepare a bathymetric map showing the reservoir bottom (fig. 2) referenced with respect to the spillway elevation. This report also includes a summary of a previous bathymetric survey conducted in 2006 (Soler-López, 2008).

  13. CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells.

    PubMed

    Sun, Run-Lu; Huang, Can-Xia; Bao, Jin-Lan; Jiang, Jie-Yu; Zhang, Bo; Zhou, Shu-Xian; Cai, Wei-Bin; Wang, Hong; Wang, Jing-Feng; Zhang, Yu-Ling

    2016-09-01

    High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.

  14. CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells *

    PubMed Central

    Sun, Run-Lu; Huang, Can-Xia; Bao, Jin-Lan; Jiang, Jie-Yu; Zhang, Bo; Zhou, Shu-Xian; Cai, Wei-Bin; Wang, Hong; Wang, Jing-Feng; Zhang, Yu-Ling

    2016-01-01

    High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [3H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD. PMID:27458015

  15. 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

  16. 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.

  17. In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide

    PubMed Central

    Vaziri, Nosratola D; Moradi, Hamid; Pahl, Madeleine V; Fogelman, Alan M; Navab, Mohamad

    2010-01-01

    Features of end-stage renal disease such as oxidative stress, inflammation, hypertension, and dyslipidemia are associated with accelerated atherosclerosis and increased risk of death from cardiovascular disease. By inhibiting the formation and increasing the disposal of oxidized lipids, HDL exerts potent antioxidant and anti-inflammatory actions. Given that apolipoproteinA-1 can limit atherosclerosis, we hypothesized that an apolipoproteinA-1 mimetic peptide, 4F, may reduce the proinflammatory properties of LDL and enhance the anti-inflammatory properties of HDL in uremic plasma. To test this, plasma from each of 12 stable hemodialysis patients and age-matched control subjects was incubated with 4F or vehicle. The isolated HDL and LDL fractions were added to cultured human aortic endothelial cells to quantify monocyte chemotactic activity, thus measuring their pro- or anti-inflammatory index. The LDL from the hemodialysis patients was more pro-inflammatory and their HDL was less anti-inflammatory than those of the control subjects. Pre-incubation of the plasma from the hemodialysis patients with 4F decreased LDL pro-inflammatory activity and enhanced HDL anti-inflammatory activity. Whether 4F or other apolipoproteinA-1 mimetic peptides will have any therapeutic benefit in end-stage renal disease will have to be examined directly in clinical studies. PMID:19471321

  18. 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

  19. 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

  20. 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

  1. 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

  2. Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene.

    PubMed

    Priore Oliva, C; Carubbi, F; Schaap, F G; Bertolini, S; Calandra, S

    2008-04-01

    APOA5 encodes a novel apolipoprotein (apo A-V) which appears to be a modulator of plasma triglyceride (TG). In apoA5 knock out mice plasma TG level increases almost fourfold, whereas in human APOA5 transgenic mice it decreases by 70%. Some SNPs in the APOA5 gene have been associated with variations in plasma TG in humans. In addition, hypertriglyceridaemic (HTG) patients have been identified who carried rare nonsense mutations in the APOA5 gene (Q139X and Q148X), predicted to result in apo A-V deficiency. In this study we report a 17-year-old male with high TG and low high density lipoprotein cholesterol (HDL-C), who at the age of two had been found to have severe HTG and eruptive xanthomas suggesting a chylomicronaemia syndrome. Plasma postheparin LPL activity, however, was normal and no mutations were found in LPL and APOC2 genes. The sequence of APOA5 gene revealed that the patient was homozygous for a point mutation (c.289 C>T) in exon 4, converting glutamine codon at position 97 into a termination codon (Q97X). Apo A-V was not detected in patient's plasma, indicating that he had complete apo A-V deficiency. The administration of a low-fat and low-oligosaccharide diet, either alone or supplemented with omega-3 fatty acids, started early in life, reduced plasma TG to a great extent but had a negligible effect on plasma HDL-C. Loss of function mutations of APOA5 gene may be the cause of severe HTG in patients without mutations in LPL and APOC2 genes. PMID:18324930

  3. Plasma triacylglycerol and HDL cholesterol concentrations confirm self-reported changes in carbohydrate and fat intakes in women in a diet intervention trial.

    PubMed

    Rock, Cheryl L; Flatt, Shirley W; Thomson, Cynthia A; Stefanick, Marcia L; Newman, Vicky A; Jones, Lovell; Natarajan, Loki; Pierce, John P; Chang, R Jeffrey; Witztum, Joseph L

    2004-02-01

    Diet intervention trials are currently testing whether reduced fat intake can reduce the risk and progression of breast cancer. Energy from dietary fat is generally replaced by energy from carbohydrate in these studies, and altering the proportion of energy from dietary carbohydrate and fat has been shown to affect plasma lipid concentrations in controlled feeding studies. The purpose of this study was to examine the effect of increased carbohydrate and reduced fat intakes on plasma lipids in a randomized, controlled trial that is testing the effect of diet modification on risk for recurrence and survival in women previously treated for breast cancer. Plasma concentrations of lipids and related factors were measured at enrollment and 1-y follow-up in 393 women enrolled in the trial. Dietary goals for the intervention group focused on an increase in vegetable, fruit and fiber intakes, and reduced fat intake. Women assigned to the intervention group significantly reduced fat intake (from 28.1 to 21.0% of energy), and significantly increased intakes of carbohydrate (from 56.9 to 65.3% of energy) and fiber (from 21.0 to 29.6 g/d) (P < 0.05). Body weight did not change significantly in either study group. A small but significant increase in fasting plasma triacylglycerol concentration, and decreases in HDL cholesterol and apoprotein-A1 concentrations, were observed in the intervention group (P < 0.05) but not in the comparison group. Changes in total cholesterol, LDL cholesterol, apoprotein-B, lipoprotein (a), and insulin concentrations, and in the LDL cholesterol/HDL cholesterol ratio, were not observed in either group. The lipid responses that were observed in this study provide biological evidence that validates the self-reported change in dietary intakes of fat and carbohydrate in response to the intervention efforts. The degree of change in these lipid concentrations was small and does not suggest increased cardiovascular disease risk.

  4. Integration and optimization of the DUV ALTA pattern generation system using a CAR process with the Tetra photomask etch system

    NASA Astrophysics Data System (ADS)

    Buxbaum, Alex H.; Fuller, Scott E.; Montgomery, Warren; Ungureit, Michael E.

    2003-12-01

    Etec Systems, the Mask Business Group of Applied Materials, is in a unique position within the mask making industry - Etec has the opportunity to integrate individual parts of the overall mask manufacturing process to provide a more complete solution. Here we present the integration of the DUV ALTA laser pattern generator and the TetraTM photomask etch system with advanced CAR resist processes. Dry etch process effects of flow, overetch, and oxygen content (in a Cl2/O2/He plasma) are discussed for the baseline POR resist in terms of etch rate, selectivity, etch bias, CD uniformity and micro-loading; the optimized etch process space was then implemented for advanced CAR resists. Iso-dense bias, football pattern loading and other pattern transfer results influencing mask manufactureability are also presented. Within the synthesis and optimization of the pattern generation system, process, and dry etch sub 13 nm range process uniformity has been achieved. The integrated ALTA / Tetra / Advanced-CAR solution set is characterized on both Etec test patterns and customer demonstrations.

  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. 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 ...

  7. [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

  8. Cis-9, trans-11 and trans-10, cis-12 CLA mixture does not change body composition, induces insulin resistance and increases serum HDL cholesterol level in rats.

    PubMed

    de Almeida, Mariana Macedo; de Souza, Yamara Oliveira; Dutra Luquetti, Sheila Cristina Potente; Sabarense, Céphora Maria; do Amaral Corrêa, José Otávio; da Conceição, Ellen Paula Santos; Lisboa, Patrícia Cristina; de Moura, Egberto Gaspar; Andrade Soares, Sara Malaguti; Moura Gualberto, Ana Cristina; Gameiro, Jacy; da Gama, Marco Antônio Sundfeld; Ferraz Lopes, Fernando César; González Garcia, Raúl Marcel

    2015-01-01

    Synthetic supplements of conjugated linoleic acid (CLA) containing 50:50 mixture of cis-9, trans-11 and trans-10, cis-12 CLA isomers have been commercialized in some places for reducing body fat. However the safety of this CLA mixture is controversial and in some countries the CLA usage as food supplement is not authorized. Changes in insulinemic control and serum lipids profile are potential negative effects related to consumption of CLA mixture. The present study aimed to evaluate the effects of a diet containing mixture of cis-9, trans-11 and trans-10, cis-12 CLA on prevention of obesity risk as well as on potential side effects such as insulin resistance and dyslipidemia in Wistar rats. Thirty male Wistar rats were randomly assigned to the following dietary treatments (n=10/group), for 60 days: Normolipidic Control (NC), diet containing 4.0% soybean oil (SO); High Fat-Control (HF-C), diet containing 24.0% SO; High Fat-synthetic CLA (HF-CLA), diet containing 1.5% of an isomeric CLA mixture (Luta-CLA 60) and 22.5% SO. Luta-CLA 60 (BASF) contained nearly 60% of CLA (cis-9, trans-11 and trans-10, cis-12 CLA at 50:50 ratio). The HF-CLA diet contained 0.3% of each CLA isomer. HF-CLA diet had no effect on dietary intake and body composition. HF-CLA-fed rats had lower levels of PPARγ protein in retroperitoneal adipose tissue, hyperinsulinemia compared to HF-C-fed rats, hyperglycemia compared to NC-fed rats while no differences in glycemia were observed between NC and HF-C groups, increased HOMA index and higher levels of serum HDL cholesterol. Thus, feeding rats with a high fat diet containing equal parts of cis-9, trans-11 and trans-10, cis-12 CLA isomers had no effect on body composition and induced insulin resistance. Despite HF-CLA-fed rats had increased serum HDL cholesterol levels, caution should be taken before synthetic supplements containing cis-9, trans-11 and trans-10, cis-12 CLA are recommended as a nutritional strategy for weight management.

  9. Coffee intake can promote activity of antioxidant enzymes with increasing MDA level and decreasing HDL-cholesterol in physically trained rats.

    PubMed

    Choi, Eun-Young; Jang, Jin-Young; Cho, Youn-Ok

    2010-08-01

    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.

  10. 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

  11. Acute Cocoa Supplementation Increases Postprandial HDL Cholesterol and Insulin in Obese Adults with Type 2 Diabetes after Consumption of a High-Fat Breakfast123

    PubMed Central

    Basu, Arpita; Betts, Nancy M; Leyva, Misti J; Fu, Dongxu; Aston, Christopher E; Lyons, Timothy J

    2015-01-01

    Background: Dietary cocoa is an important source of flavonoids and is associated with favorable cardiovascular disease effects, such as improvements in vascular function and lipid profiles, in nondiabetic adults. Type 2 diabetes (T2D) is associated with adverse effects on postprandial serum glucose, lipids, inflammation, and vascular function. Objective: We examined the hypothesis that cocoa reduces metabolic stress in obese T2D adults after a high-fat fast-food–style meal. Methods: Adults with T2D [n = 18; age (mean ± SE): 56 ± 3 y; BMI (in kg/m2): 35.3 ± 2.0; 14 women; 4 men] were randomly assigned to receive cocoa beverage (960 mg total polyphenols; 480 mg flavanols) or flavanol-free placebo (110 mg total polyphenols; <0.1 mg flavanols) with a high-fat fast-food–style breakfast [766 kcal, 50 g fat (59% energy)] in a crossover trial. After an overnight fast (10–12 h), participants consumed the breakfast with cocoa or placebo, and blood sample collection [glucose, insulin, lipids, and high-sensitivity C-reactive protein (hsCRP)] and vascular measurements were conducted at 0.5, 1, 2, 4, and 6 h postprandially on each study day. Insulin resistance was evaluated by homeostasis model assessment. Results: Over the 6-h study, and specifically at 1 and 4 h, cocoa increased HDL cholesterol vs. placebo (overall Δ: 1.5 ± 0.8 mg/dL; P ≤ 0.01) but had no effect on total and LDL cholesterol, triglycerides, glucose, and hsCRP. Cocoa increased serum insulin concentrations overall (Δ: 5.2 ± 3.2 mU/L; P < 0.05) and specifically at 4 h but had no overall effects on insulin resistance (except at 4 h, P < 0.05), systolic or diastolic blood pressure, or small artery elasticity. However, large artery elasticity was overall lower after cocoa vs. placebo (Δ: −1.6 ± 0.7 mL/mm Hg; P < 0.05), with the difference significant only at 2 h. Conclusion: Acute cocoa supplementation showed no clear overall benefit in T2D patients after a high-fat fast-food–style meal challenge

  12. 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

  13. Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss.

    PubMed

    Kuo, Kung-Kai; Wu, Bin-Nan; Liu, Chung-Pin; Yang, Tzu-Yang; Kao, Li-Pin; Wu, Jiunn-Ren; Lai, Wen-Ter; Chen, Ing-Jun

    2015-11-01

    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 (14)C 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.

  14. Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss.

    PubMed

    Kuo, Kung-Kai; Wu, Bin-Nan; Liu, Chung-Pin; Yang, Tzu-Yang; Kao, Li-Pin; Wu, Jiunn-Ren; Lai, Wen-Ter; Chen, Ing-Jun

    2015-11-01

    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 (14)C 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

  15. 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

    2014-09-01

    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.

  16. Superfund Record of Decision (EPA Region 2): Vega Alta Public Supply Wells, Puerto Rico (first remedial action), September 1987. Final report

    SciTech Connect

    Not Available

    1987-09-29

    The Vega Alta Public Supply Wells site is a public water supply well field located in the municipality of Vega Alta, Puerto Rico, approximately 32 km west of San Juan where ground water is the primary source of water. The well field consists of eight active wells. It currently supplies about 3.8 million gallons per day of water to Vega Alta and surrounding residential areas. The Puerto Rico Aqueduct and Sewer Authority (PRASA) is responsible for operation and maintenance of the public water-supply system. The first indication of contamination was discovered in June 1983, when a survey of public water wells made by the U.S. Geological Survey detected 574 ug/1 of trichloroethylene (TCE) in the Ponderosa public supply well. Other VOCs were detected at lower concentrations in non-public wells in the well field system and ground water contamination was suspected. In June and August of 1983 Ponderosa and well GE 1 were shut down by PRASA because of contamination, respectively. This shutdown caused a potential water supply shortage in Vega Alta. PRASA constructed well Bajura 3 to eliminate the shortage. In 1984 an air stripper was constructed at the Ponderosa well and operated until May 1985 when technical problems arose with the air stripper. Currently, ground water is contaminated with 1,1,1-trichloroethene, tetrachloroethene, 1,2-dichloroethene, 1,1-dichloroethene and other VOCs.

  17. 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

  18. 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.

  19. Reduced glomerular filtration rate, inflammation and HDL cholesterol as main determinants of superoxide production in non-dialysis chronic kidney disease patients.

    PubMed

    Morena, Marion; Patrier, Laure; Jaussent, Isabelle; Bargnoux, Anne-Sophie; Dupuy, Anne-Marie; Badiou, Stéphanie; Leray-Moragues, Hélène; Klouche, Kada; Canaud, Bernard; Cristol, Jean-Paul

    2011-06-01

    Enhanced oxidative stress partly resulting from an over-production of superoxide anion (O(2)(•-)) represents a novel and particular risk factor in chronic kidney disease (CKD) patients. This study was therefore designed to evaluate O(2)(•-) determinants in this population. O(2)(•-) production was evaluated using chemiluminescence method in 136 CKD patients (79M/57F, median age: 69.5 [27.4-94.6]). Renal function (evaluated by the glomerular filtration rate using modification of diet in renal disease (MDRD)), inflammation, lipids, nutritional and bone mineral as well as clinical parameters were evaluated. Potential relationships between O(2)(•-) and these clinico-biological parameters were investigated to identify main determinants of such a pathological process. Enhanced O(2)(•-) production has been observed at the pre-dialysis phase: stages 4 and 5 of CKD (p = 0.0065). In multivariate analysis, low eGFR (MDRD <30 mL/min/1.73 m(2); p = 0.046), high fibrinogen (≥3.7 g/L; p = 0.044) and abnormal HDL cholesterol (<1.42 mmol/L and ≥ 1.75 mmol/L; p = 0.042) were the main determinants of O(2)(•-) production in CKD patients.

  20. 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

  1. 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

  2. Endurance exercise training effects on body fatness, VO2max, HDL-C subfractions, and glucose tolerance are influenced by a PLIN haplotype in older Caucasians.

    PubMed

    Jenkins, Nathan T; McKenzie, Jennifer A; Damcott, Coleen M; Witkowski, Sarah; Hagberg, James M

    2010-03-01

    Perilipins are lipid droplet-coating proteins that regulate intracellular lipolysis in adipocytes. A haplotype of two perilipin gene (PLIN) single nucleotide polymorphisms, 13041A>G and 14995A>T, has been previously associated with obesity risk. Furthermore, the available data indicate that this association may be modified by sex. We hypothesized that this haplotype would associate with body fatness, aerobic fitness, and a number of cardiovascular (CV) risk factor phenotypes before and after a 6-mo endurance exercise training program in sedentary older Caucasians. The major haplotype group (13041A/14995A; n = 57) had significantly lower body mass index (BMI) and body fatness compared with noncarriers of the AA haplotype (n = 44) before the training intervention. Training improved body composition in both groups, but fatness remained higher in noncarriers than AA carriers after training. This fat retention in noncarriers blunted their maximal oxygen uptake (Vo(2 max)) adaptation to training. Female noncarriers had substantially higher concentrations of several conventionally and NMR-measured HDL-C subfractions than male noncarriers before and after training, but only minimal differences were found between the sexes in the AA haplotype group. Haplotype group differences in baseline and after-training responses to an oral glucose tolerance test (OGTT) also differed by sex, as noncarrier men had the highest baseline area under the insulin curve (insulin AUC), but were the only group to significantly improve insulin AUC with training. The insulin sensitivity index and plasma glucose responses to the OGTT were more favorable in AA carriers than noncarriers before and after training. Overall, our findings suggest that PLIN variation explains some of the interindividual differences in the response of obesity and CV phenotypes to exercise training. Furthermore, these data contribute to the growing understanding of PLIN as a candidate gene for human obesity and the

  3. Estudio fotométrico de estrellas tardías de alta luminosidad en 23 cúmulos abiertos

    NASA Astrophysics Data System (ADS)

    Clariá, J. J.; Piatti, A. E.; Osborn, W.

    Se presentan resultados obtenidos en los Observatorios de Cerro Tololo, Kitt Peak, Lowell y Las Campanas, a partir de fotometría UBV y DDO de 54 estrellas tardías de alta luminosidad en 23 cúmulos abiertos. La aplicación de dos criterios fotométricos independientes permite asignar a cada estrella probabilidades de pertenencia a cada agregado. Se encuentra que 32 estrellas son muy probablemente miembros de los cúmulos, mientras que las restantes son objetos del campo. En todos los casos se determinan excesos de color E(B-V) a través de procedimientos fotométricos y espectroscópicos tradicionales. Recientes calibraciones del sistema DDO permiten, además, derivar tipos espectrales MK, temperaturas efectivas, y abundancias superficiales de la muestra examinada. Las metalicidades DDO derivadas se distribuyen entre valores típicos de cúmulos moderadamente pobres en metales ([Fe/H]~=-0.3) y moderadamente ricos ([Fe/H]~=0.2), en tanto que las masas calculadas para las gigantes rojas oscilan entre 1 y 4 masas solares, con una dispersión dentro de cada cúmulo menor que 1 Msolar.

  4. Biodiversity of Saccharomyces cerevisiae populations in Malbec vineyards from the "Zona Alta del Río Mendoza" region in Argentina.

    PubMed

    Mercado, Laura; Sturm, María Elena; Rojo, María Cecilia; Ciklic, Iván; Martínez, Claudio; Combina, Mariana

    2011-12-15

    The "Zona Alta del Río Mendoza" (ZARM) is the major Malbec grape viticulture region of Argentina. The aim of the present study was to explore Saccharomyces cerevisiae biodiversity in ZARM vineyards. Interdelta PCR and RFLP mtDNA molecular markers were applied to differentiate S. cerevisiae strains. The presence of commercial strains on ZARM vineyards was also assessed. Our results reveal a highly diverse, but genetically closely related, S. cerevisiae population (containing more than 190 molecular patterns among 590 S. cerevisiae isolates). According to the S. cerevisiae strain diversity found in vineyards, they were classified as vineyards with high and low polymorphic S. cerevisiae populations. Six vineyards showed a high polymorphic population, with more than 20 different S. cerevisiae molecular patterns. S. cerevisiae populations in these vineyards were diverse and irregularly distributed, with different strains in each vineyard site. Low polymorphic S. cerevisiae population vineyards displayed very low yeast diversity, with only 9 to 10 different S. cerevisiae strains and presence of two commercial strains widely distributed. Population diversity estimators were calculated to determine the population structure of S. cerevisiae in the ZARM vineyards. The obtained values support the hypothesis that the eight sampled subpopulations come indeed from a larger population.

  5. Impact of Virgin Olive Oil and Phenol-Enriched Virgin Olive Oils on the HDL Proteome in Hypercholesterolemic Subjects: A Double Blind, Randomized, Controlled, Cross-Over Clinical Trial (VOHF Study)

    PubMed Central

    Pedret, Anna; Catalán, Úrsula; Fernández-Castillejo, Sara; Farràs, Marta; Valls, Rosa-M; Rubió, Laura; Canela, Núria; Aragonés, Gerard; Romeu, Marta; Castañer, Olga; de la Torre, Rafael; Covas, Maria-Isabel; Fitó, Montse; Motilva, Maria-José; Solà, Rosa

    2015-01-01

    The effects of olive oil phenolic compounds (PCs) on HDL proteome, with respect to new aspects of cardioprotective properties, are still unknown. The aim of this study was to assess the impact on the HDL protein cargo of the intake of virgin olive oil (VOO) and two functional VOOs, enriched with their own PCs (FVOO) or complemented with thyme PCs (FVOOT), in hypercholesterolemic subjects. Eligible volunteers were recruited from the IMIM-Hospital del Mar Medical Research Institute (Spain) from April 2012 to September 2012. Thirty-three hypercholesterolemic participants (total cholesterol >200mg/dL; 19 men and 14 women; aged 35 to 80 years) were randomized in the double-blind, controlled, cross-over VOHF clinical trial. The subjects received for 3 weeks 25 mL/day of: VOO, FVOO, or FVOOT. Using a quantitative proteomics approach, 127 HDL-associated proteins were identified. Among these, 15 were commonly differently expressed after the three VOO interventions compared to baseline, with specific changes observed for each intervention. The 15 common proteins were mainly involved in the following pathways: LXR/RXR activation, acute phase response, and atherosclerosis. The three VOOs were well tolerated by all participants. Consumption of VOO, or phenol-enriched VOOs, has an impact on the HDL proteome in a cardioprotective mode by up-regulating proteins related to cholesterol homeostasis, protection against oxidation and blood coagulation while down-regulating proteins implicated in acute-phase response, lipid transport, and immune response. The common observed protein expression modifications after the three VOOs indicate a major matrix effect. Trial Registration International Standard Randomized Controlled Trials ISRCTN77500181. PMID:26061039

  6. Conversion of α-linolenic acid to long-chain omega-3 fatty acid derivatives and alterations of HDL density subfractions and plasma lipids with dietary polyunsaturated fatty acids in Monk parrots (Myiopsitta monachus).

    PubMed

    Petzinger, C; Larner, C; Heatley, J J; Bailey, C A; MacFarlane, R D; Bauer, J E

    2014-04-01

    The effect of α-linolenic acid from a flaxseed (FLX)-enriched diet on plasma lipid and fatty acid metabolism and possible atherosclerosis risk factors was studied in Monk parrots (Myiopsitta monachus). Twenty-four Monk parrots were randomly assigned to diets containing either 10% ground SUNs or 10% ground FLXs. Feed intake was calculated daily. Blood samples, body condition scores and body weights were obtained at -5 weeks, day 0, 7, 14, 28, 42 and 70. Plasma samples were analysed for total cholesterol, free cholesterol, triacylglycerols and lipoproteins. Phospholipid subfraction fatty acid profiles were determined. By day 70, the FLX group had significantly higher plasma phospholipid fatty acids including 18:3n-3 (α-linolenic acid), 20:5n-3 (eicosapentaenoic acid) and 22:6n-3 (docosahexaenoic acid). The sunflower group had significantly higher plasma phospholipid levels of 20:4n-6 (arachidonic acid). By day 70, the high-density lipoprotein (HDL) peak shifted resulting in significantly different HDL peak densities between the two experimental groups (1.097 g/ml FLX group and 1.095 g/ml SUN group, p = 0.028). The plasma fatty acid results indicate that Monk parrots can readily convert α-linolenic acid to the long-chain omega-3 derivatives including docosahexaenoic acid and reduce 20:4n-6 accumulation in plasma phospholipids. The reason for a shift in the HDL peak density is unknown at this time. PMID:23600588

  7. Conversion of α-linolenic acid to long-chain omega-3 fatty acid derivatives and alterations of HDL density subfractions and plasma lipids with dietary polyunsaturated fatty acids in Monk parrots (Myiopsitta monachus).

    PubMed

    Petzinger, C; Larner, C; Heatley, J J; Bailey, C A; MacFarlane, R D; Bauer, J E

    2014-04-01

    The effect of α-linolenic acid from a flaxseed (FLX)-enriched diet on plasma lipid and fatty acid metabolism and possible atherosclerosis risk factors was studied in Monk parrots (Myiopsitta monachus). Twenty-four Monk parrots were randomly assigned to diets containing either 10% ground SUNs or 10% ground FLXs. Feed intake was calculated daily. Blood samples, body condition scores and body weights were obtained at -5 weeks, day 0, 7, 14, 28, 42 and 70. Plasma samples were analysed for total cholesterol, free cholesterol, triacylglycerols and lipoproteins. Phospholipid subfraction fatty acid profiles were determined. By day 70, the FLX group had significantly higher plasma phospholipid fatty acids including 18:3n-3 (α-linolenic acid), 20:5n-3 (eicosapentaenoic acid) and 22:6n-3 (docosahexaenoic acid). The sunflower group had significantly higher plasma phospholipid levels of 20:4n-6 (arachidonic acid). By day 70, the high-density lipoprotein (HDL) peak shifted resulting in significantly different HDL peak densities between the two experimental groups (1.097 g/ml FLX group and 1.095 g/ml SUN group, p = 0.028). The plasma fatty acid results indicate that Monk parrots can readily convert α-linolenic acid to the long-chain omega-3 derivatives including docosahexaenoic acid and reduce 20:4n-6 accumulation in plasma phospholipids. The reason for a shift in the HDL peak density is unknown at this time.

  8. 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.

  9. Role of ApoA1 on high-density lipoprotein: an intervention with plant sterols in patients with hypercholesterolemia.

    PubMed

    San Mauro Martín, Ismael; Collado Yurrita, Luis; Cuadrado Cenzual, María Ángeles; Ciudad Cabañas, María José; Mendive Dubourdieu, Paula

    2014-10-03

    Antecedentes: Numerosos estudios han demostrado una asociación inversa entre la concentración de colesterol asociado a lipoproteínas de alta densidad de colesterol (HDL-c) y el riesgo cardiovascular. El presente estudio investigo la posible relación entre la apolipoproteína A (ApoA1) y el HDL-C como una nueva estrategia para reducir el riesgo cardiovascular. Objetivo: determinar el efecto de ApoA1 en el metabolismo del colesterol a través de su influencia sobre el HDL-c en la población adulta joven. Métodos: ensayo clínico, controlado, aleatorizado, doble ciego, proporcionando una leche comercial con esteroles, “Naturcol”, durante 3 semanas (n = 19) y placebo (n = 16). Se diseñó un cuestionario Ad Hoc y se realizó un estudio antropométrico completo. Se utilizó el programa SPSS 21.0 para analizar los datos estadísticos. Resultados: Se observaron diferencias significativas entre la leche de esterol y el placebo únicamente en un solo marcador, en las lipoproteínas de baja densidad del colesterol (LDL-c). Se encontró una dispersión lineal de datos entre HDL-C y ApoA1, tanto al principio y al final de la intervención (correlación de Person = 0,846 y 0,903, respectivamente). Se observó alta dependencia en la regresión lineal (R2 = 0,715 y 0,816, respectivamente). Conclusión: Una relación significativa entre el HDL-c y ApoA1 fue comprobada. Teniendo en cuenta la importancia que los niveles de HDL-c parecen tener en la salud cardiovascular, la ApoA1 se presenta como un importante marcador clínico para mejorar la función del corazón, así como para reducir el riesgo cardiovascular.

  10. 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.

  11. 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.

  12. MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo.

    PubMed

    Horie, Takahiro; Nishino, Tomohiro; Baba, Osamu; Kuwabara, Yasuhide; Nakao, Tetsushi; Nishiga, Masataka; Usami, Shunsuke; Izuhara, Masayasu; Nakazeki, Fumiko; Ide, Yuya; Koyama, Satoshi; Sowa, Naoya; Yahagi, Naoya; Shimano, Hitoshi; Nakamura, Tomoyuki; Hasegawa, Koji; Kume, Noriaki; Yokode, Masayuki; Kita, Toru; Kimura, Takeshi; Ono, Koh

    2014-01-01

    MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models. PMID:24931346

  13. 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]).

  14. Substitution of whole cows' milk with defatted milk for 4 months reduced serum total cholesterol, HDL-cholesterol and total apoB in a sample of Mexican school-age children (6-16 years of age).

    PubMed

    Villalpando, Salvador; Lara Zamudio, Yaveth; Shamah-Levy, Teresa; Mundo-Rosas, Verónica; Manzano, Alejandra Contreras; Lamadrid-Figueroa, Héctor

    2015-09-14

    We carried out this study to compare the effect of consuming whole, partially defatted and defatted cows' milk for 4 months on serum concentrations of blood indicators of cardiovascular risk (CVR) in Mexican children and adolescents. Children aged between 6 and 16 years living in indigenous boarding schools in Mexico and who were usual consumers of whole milk were recruited to this study. Totally, thirteen boarding schools were randomly selected to receive full supplies of whole, partially defatted and defatted cows' milk for 4 months. Serum total cholesterol (TC), TAG, HDL-cholesterol, apoA and total apoB, and Lp(a) concentrations were measured before and after the intervention. Comparisons were made with multi-level mixed-effects linear regression models using the difference in differences approach. Compared with the whole milk group, TC, LDL-cholesterol, HDL-cholesterol and total apoB were lower in defatted milk consumers by -0·43, -0·28, -0·16 mmol/l and -0·05 g/l, respectively (all P<0·001). Compared with the whole milk group, the group that consumed partially defatted milk showed a significant decrease in the concentrations of LDL-cholesterol (-0·12, P=0·01), apoA (-0·05 g/l, P=0·01) and total apoB (-0·05 g/l, P=0·001). Defatted milk intake for 4 months reduced some of the serum indicators of CVR.

  15. 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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. Genetic loci associated with plasma concentration of LDL-C, HDL-C, triglycerides, ApoA1, and ApoB among 6382 Caucasian women in genome-wide analysis with replication

    PubMed Central

    Chasman, Daniel I.; Paré, Guillaume; Zee, Robert Y. L.; Parker, Alex N.; Cook, Nancy R.; Buring, Julie E.; Kwiatkowski, David J.; Rose, Lynda M.; Smith, Joshua D.; Williams, Paul T.; Rieder, Mark J.; Rotter, Jerome I.; Nickerson, Deborah A.; Krauss, Ronald M.; Miletich, Joseph P.; Ridker, Paul M

    2009-01-01

    Background Genome-wide genetic association analysis represents an opportunity for comprehensive survey of genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders. Methods and Results We have performed large-scale, genome-wide genetic analysis among 6382 Caucasian women with replication in two cohorts of 970 additional Caucasian men and women for associations between common SNPs and LDL-C, HDL-C, triglycerides, apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). Genome-wide associations (P<5×10−8) were found at the PCSK9 gene, the APOB gene, the LPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition, genome-wide associations with triglycerides at the GCKR gene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at five novel loci with LDL-C, HDL-C, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB. Conclusions Genome-wide associations at the GCKR gene and near the SORT1 gene as well as confirmatory associations at five additional novel loci suggest emerging biological pathways for lipid metabolism among Caucasian women. PMID:19802338

  1. 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.

  2. Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials.

    PubMed

    Michos, Erin D; Sibley, Christopher T; Baer, Jefferson T; Blaha, Michael J; Blumenthal, Roger S

    2012-06-01

    Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values <70 mg/dl, but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C-increasing hypothesis.

  3. 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, ...

  4. Lacustrine Records of Forest Fire Indicators and Trace Elements Deposition in an Land Use Change Region in the Brazilian Amazonia (Alta Floresta, MT)

    NASA Astrophysics Data System (ADS)

    Rodrigues, R. R.; Conceicão, M. G.; Cordeiro, R. C.; Turcq, B. J.; Seoane, J. S.; Sifeddine, A.

    2009-05-01

    The dynamics of terrestrial ecosystems depend on interactions between the carbon cycle, nutrient cycles, and the hydrological cycle, all of which may be modified by climate and human actions. Terrestrial ecological systems, in which carbon is retained in live biomass, decomposing organic matter, and soil, play an important role in the global carbon cycle. Human activities change carbon stocks in these pools and exchanges between them and the atmosphere through land-use change and other activities. From 1850 to 1998 about 136 (+55) Gt C has been emitted as a result of land-use change, predominantly from forest ecosystems. Amazonia's carbon storage potential gives great importance to land-use changes in this region because disturbances of the natural landscape can increase atmospheric carbon and affect global biogeochemical cycles. Mercury release from gold mining activities and deforestation are the two most important environmental issues in the Amazon Basin. Gold mining activities in Amazonia have been responsible for the release of about 2000-3000 t of Hg over the last 20 y. In Alta Floresta region (southern Amazonia), concurrent with the deforestation, an intense gold rush occurred with the exploration of riverbed sediments. This region was a significant gold mining site from 1980 to 1996. This study aims to understand the atmospheric deposition rates of charcoal particles, mercury and other trace elements and discuss the environmental changes caused by man activities in an area of an intense land use change. Accordingly to the fact that in Brazilian Amazonia the colonization process generally takes place after the building of a road, an 82 cm core (AF SSW 150) was collected in a lake formed by the barrier effect of a road embankment and distant 150 km of the center of Alta Floresta city. The ages of the sedimentary sections in the core were calculated by the activity of 210Pb. The grain size profile showed a huge change from 1985, with the dominance of fine

  5. Geometrical and geochemical properties of isotope exchange and reaction fronts in the Alta aureole, Utah: evidence for scale-dependent heterogeneity and anisotropy in permeability of marbles

    NASA Astrophysics Data System (ADS)

    Bowman, J. R.

    2012-12-01

    A carbon isotope exchange front, periclase reaction front and an oxygen isotope exchange front are developed with increasing distance from the igneous contact in dolomitic marbles of the south Alta aureole, Utah in response to infiltration-driven metamorphism of the marbles. Their relative distances from the igneous contact, approx. 100, 200 and 350 m, respectively, are consistent with down-temperature infiltration of water-rich fluid that was equilibrated isotopically with the adjacent Alta stock. At the aureole scale both the C and O isotope exchange fronts exhibit significant dispersion: there is significant variation in both δ18O and δ13C values at any given position for >100m to either side of the geometric centers of both fronts. Applications of one-dimensional models of advection-dispersion to these aureole-scale dispersed fronts yield a minimum dispersion coefficient of 2E-8 m2/sec. However at outcrop and bedding scale, steep, coherent gradients in both δ18O and δ13C exist at or near bedding boundaries between marble layers of contrasting lithology and isotopic compositions; modeling of these profiles requires much lower diffusion/dispersion coefficients in the range of 7E-12 to 1E-14 m2/sec. The periclase reaction front (isograd) can be mapped as a fairly regular surface at the aureole scale, located an average 200 m from the igneous contact, and normally of narrow width (<10 m). However at two locations, lenses of dolomite and periclase marble interfinger for distances up to 40-50 m closer to, and farther from, the igneous contact, compared to the average location of the reaction front. This intermixing can be interpreted to result from dispersion of the reaction front owing to heterogeneity in permeability rather than to reaction kinetics, because at outcrop and bedding scales where exposed, the boundary separating dolomite- from periclase-marble is sharp (<1 cm width). Additionally, at the two locations where measurements have been made, steep δ18O

  6. In vitro and in vivo Analysis of the Binding of the C Terminus of the HDL Receptor Scavenger Receptor Class B type I (SR-BI) to the PDZ1 Domain of its Cytoplasmic Adaptor Protein PDZK1

    SciTech Connect

    O Kocher; G Birrane; K Tsukamoto; S Fenske; A Yesilaltay; R Pal; K Daniels; J Ladias; M Krieger

    2011-12-31

    The PDZ1 domain of the four PDZ domain-containing protein PDZK1 has been reported to bind the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), and to control hepatic SR-BI expression and function. We generated wild-type (WT) and mutant murine PDZ1 domains, the mutants bearing single amino acid substitutions in their carboxylate binding loop (Lys(14)-Xaa(4)-Asn(19)-Tyr-Gly-Phe-Phe-Leu(24)), and measured their binding affinity for a 7-residue peptide corresponding to the C terminus of SR-BI ((503)VLQEAKL(509)). The Y20A and G21Y substitutions abrogated all binding activity. Surprisingly, binding affinities (K(d)) of the K14A and F22A mutants were 3.2 and 4.0 ?M, respectively, similar to 2.6 ?M measured for the WT PDZ1. To understand these findings, we determined the high resolution structure of WT PDZ1 bound to a 5-residue sequence from the C-terminal SR-BI ((505)QEAKL(509)) using x-ray crystallography. In addition, we incorporated the K14A and Y20A substitutions into full-length PDZK1 liver-specific transgenes and expressed them in WT and PDZK1 knock-out mice. In WT mice, the transgenes did not alter endogenous hepatic SR-BI protein expression (intracellular distribution or amount) or lipoprotein metabolism (total plasma cholesterol, lipoprotein size distribution). In PDZK1 knock-out mice, as expected, the K14A mutant behaved like wild-type PDZK1 and completely corrected their hepatic SR-BI and plasma lipoprotein abnormalities. Unexpectedly, the 10-20-fold overexpressed Y20A mutant also substantially, but not completely, corrected these abnormalities. The results suggest that there may be an additional site(s) within PDZK1 that bind(s) SR-BI and mediate(s) productive SR-BI-PDZK1 interaction previously attributed exclusively to the canonical binding of the C-terminal SR-BI to PDZ1.

  7. [ACCURACY PARAMETERS AS INDICATORS OF ANTHROPOMETRIC ADIPOSITY VISCERAL SCHEDULED FOR TWO-DIMENSIONAL EQUATION].

    PubMed

    Lira Santos, Andréia; Araújo Tavares de Sá, Cristiane Maria; Calado Brito, Daniel; Lourenço Batista, Camila; Kétteryn Maior Evangelista da Costa, Meury; Araújo Gomes de Lima, Kamilla Brianne; Magalhães Souza, Jaqueline; Tenório Ramos, Irya Laryssa

    2015-11-01

    Introducción: los indicadores antropométricos son fáciles de aplicar y pueden ayudar en la identificación de la acumulación de grasa visceral, lo que favorece la aparición de eventos cardiovasculares, así como, el aumento de la morbilidad y mortalidad por enfermedades crónicas. Objetivo: evaluar la exactitud de los indicadores antropométricos de distribución de la grasa abdominal para determinar la adiposidad visceral. Sujetos/Métodos: estudio transversal realizado con pacientes ambulatorios, de ambos sexos, mayores de 20 años. Fueron evaluados: circunferencia de la cintura (CC); relación cintura-cadera (WHR); cintura-altura (CER); índice Taper (CI); diámetro abdominal sagital (DAS); (DC) de diámetro coronal; índice de masa corporal (IMC); porcentaje de grasa corporal (% GC); adiposidad visceral (AV/AS) predicha por la fórmula; glucosa en sangre en ayunas; colesterol total (TC); lipoproteína de baja densidad (LDL); lipoproteína de alta densidad (HDL); lipoproteínas de muy baja densidad (VLDL) y triglicéridos (TG). Resultados: se evaluaron 129 pacientes, edad media 51, 06 + 14,02 años y una mayor prevalencia de adultos (72,9%) y mujeres (75,2%). CC 102,9 (+ 10,82), HF 2,08 (± 0,13) y AV/AS 1,03 (+ 0,16), mostraron valores altos con significación estadística entre los hombres, p < 0,001. Lo mismo ocurrió con la CT (+ 46,4 212,41), HDL (50,15 + 13,24) y LDL (135,62 + 40,16) entre las mujeres, p < 0,05. DC, RCE, DAS y DC mostraron una correlación inversa y significativa con la AV/AS: r = -0,364; -0.457; -0.403; -0.296; -0.475, respectivamente, p < 0,001. Sin embargo, que mejor explicó la varianza de la obesidad visceral fueron el DC (R² = 0,77), CQ (R² = 0,64) y RCE (R² = 0,59). Discusión/Conclusión: la DC y el CER fueron los mejores predictores para las mediciones antropométricas de la obesidad visceral.

  8. Blood lipid profile and glucose of university students (China).

    PubMed

    Liang, Wei; Wang, Linghong; Guo, Daoxia; Nie, Zhognhua; Chen, Yan; Jin, Yuelong; He, Lianping; Yao, Yingshui

    2015-05-01

    Objetivo: El objetivo principal de este estudio fue estimar la glucosa de la sangre y el perfil lípido de la sangre de estudio en una universidad en China. Métodos: Estudio descriptivo basado en la revision de salud; datos para estudiantes universitarios en 2013. La glucosa en la sangre (GLU), perfiles de lípidos (colesterol total (CT), triglicéridos (Tg) y lipoproteína de alta densidad (HDL - c) se midió utilizando Hitachi modelo 747 Analizador automático. Los valores de colesterol LDL se calculan según la fórmula: C - LDL HDL - C = TC Ching Ching TG / 5. Resultados: La media de HDL fueron 51,31 y 56.30 mg / dl para varón y mujer, respectivamente (p < 0,05) y LDL (p < 0.05). La mayoría de los estudiantes tienen nivel normal de Glu (65-110mgl / dl). TC y LDL elevados fueron observados en 6.92% y el 5,82% de varones, asimismo, 5,91% y el 3,57% de mujeres. Altos niveles de TC, LDL y TG fueron detectados en estudiantes universitarios masculinos; 1.02% 0,71% y un 1,41%, respectivamente; en mujeres estudiantes de la Universidad were1.26%, 1.04 y 0,68%, respectivamente. La reducción de los niveles de HDL fueron observados en 5.59% de hombres y el 2,62% de mujeres. Conclusión: El estudio demostró que la prevalencia de la glucosa de la sangre y de lípidos en sangre en los estudiantes universitarios, especialmente la reducción de los niveles de HDL y LDL elevados de TC y en estudiantes universitarios, se ha convertido en un problema de salud crítico. Colegios, escuelas y el Gobierno deben prestar más atención a la salud física de los estudiantes.

  9. 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

  10. Investigação dos perfís temporais de alta resolução de explosões solares tipo-III decimétricas

    NASA Astrophysics Data System (ADS)

    Cecatto, J. R.; Fernandes, F. C. R.; Sawant, H. S.; Madsen, F. R. H.

    2003-08-01

    Explosões solares tipo-III indicam a presença de feixes de elétrons acelerados durante "flares" solares. Sua investigação fornece informações tanto sobre os processos de aceleração de partículas quanto das características do agente causador e do local de aceleração. Explosões tipo-III decimétricas são geradas por feixes de elétrons viajando através de arcos magnéticos densos da baixa coroa solar. Os perfís temporais destes fenômenos, quando tomados com alta resolução, informam sobre os mecanismos de aceleração de partículas do feixe e o meio de transporte da energia liberada a partir da região de aceleração. Usando o Brazilian Solar Spectroscope (BSS), em operação no INPE, foram registradas dezenas de explosões tipo-III decimétricas, dentro da faixa de 2050-2250 MHz com alta resolução temporal (20 ms), em 13 de setembro de 2001, entre 13:00 e 16:10 UT. Foram selecionadas 10 explosões isoladas para uma investigação estatística detalhada de seus perfís temporais, em todos os cerca de 50 canais de freqüência. Os resultados indicam que cerca de 70% dos perfís temporais são complexos tanto durante a subida quanto descida. Os 30% restantes indicam que os perfís da subida podem ser bem representados, na maioria dos casos, por um processo não-linear e uma parcela significativa por processos lineares. Os perfís temporais da descida são dominados por um decaimento não-linear. Neste trabalho, será efetuada uma análise dos perfís temporais, tanto durante a subida quanto descida do fluxo, para as explosões selecionadas, em termos dos prováveis mecanismos de aceleração e relaxamento. 2

  11. Líneas UV como indicadores de temperatura y densidad

    NASA Astrophysics Data System (ADS)

    Brusasco, M. A.; Cidale, L. S.

    In order to investigate the behavior of Fe II lines in Be stars, we carry out a statistical analysis over a sample of IUE images. We found that only 4 of the 39 studied stars (with spectral types B2, B5 and B8) show Fe II lines. Synthetic spectra of Fe II lines were computed by means of a rigorous treatment of the line transfer equation for moving flows, considering different effective temperature, velocity and temperature structure. Preliminary results show that the shape of the profiles depends mainly on the velocity structure, while the intensity changes with both the temperature and the density structure.

  12. [Prevalence of metabolic syndrome and insulin resistance in system sclerosis].

    PubMed

    Peralta-Amaro, Ana Lilia; Cruz-Domínguez, María del Pilar; Olvera-Acevedo, Arturo; Vera-Lastra, Olga Lidia

    2015-01-01

    Introducción: el síndrome metabólico (SM) es un conjunto de factores de riesgo cardiovascular cuya prevalencia se encuentra incrementada en enfermedades reumáticas. El objetivo de este estudio fue estimar la prevalencia de SM y resistencia a la insulina (RI) en esclerosis sistémica (ES). Métodos: se incluyeron 55 pacientes con ES. Se evaluó SM utilizando los criterios de la OMS. Se registraron datos demográficos, antropométricos y presión arterial. Se midieron valores de glucosa, colesterol de lipoproteínas de alta densidad (c-HDL), triglicéridos e insulina. Se realizó una curva de tolerancia oral a la glucosa para identificar intolerancia a la glucosa y diabetes mellitus en pacientes con glucosa normal en ayuno. Se calculó el índice HOMA y se cuantificó proteinuria en orina de 24 horas. Resultados: la prevalencia del SM fue del 36.4 %. El 70 % de los pacientes con SM correspondió a ES limitada y 30 % a ES difusa. Se observó mayor resistencia a la insulina (RI) en la ES limitada frente a ES difusa. Se encontró asociación entre RI y el SM en la forma limitada. Del resto de los criterios de SM, la hipertrigliceridemia y el índice cintura/cadera anormal fueron las variables más frecuentes, 95 % y 85 % respectivamente. El 50 % de los pacientes con SM tuvo niveles bajos de c-HDL, e hipertensión arterial sistémica 40 %. En ningún paciente hubo proteinuria. Conclusiones: la prevalencia de SM en ES fue del 36.4 %, similar a la encontrada en otras enfermedades reumáticas, pero mayor en comparación con la población mexicana.

  13. [The prevalence of obesity and metabolic syndrome in paediatric patients with epilepsy treated in monotherapy with valproic acid].

    PubMed

    Carmona-Vazquez, C R; Ruiz-Garcia, M; Pena-Landin, D M; Diaz-Garcia, L; Greenawalt, S R

    2015-09-01

    Introduccion. El acido valproico (VPA) es un antiepileptico util para controlar diferentes tipos de epilepsia. Tiene efectos colaterales y se asocia a incremento del peso corporal y a alteraciones metabolicas y endocrinas, entre ellas sindrome metabolico. Objetivo. Conocer la prevalencia de la obesidad y el sindrome metabolico en pacientes pediatricos con epilepsia tratados en monoterapia con VPA. Pacientes y metodos. Estudio transversal, observacional, analitico. Se estudiaron pacientes tratados con VPA entre 2010-2014, y se midio el indice de masa corporal (IMC), el perimetro abdominal, la presion arterial, la glucosa, los trigliceridos y las lipoproteinas de alta densidad (HDL), en busqueda de obesidad y sindrome metabolico. La obesidad se definio con un IMC mayor del percentil 95; el sindrome metabolico, con al menos tres de los siguientes criterios: perimetro abdominal mayor del percentil 90, presion arterial sistemica mayor del percentil 90, trigliceridos mayores de 110 mg/dL y HDL menor de 40 mg/dL. Resultados. Se estudiaron 47 pacientes con una edad media de 10,1 ± 4 años; el 51,06% eran varones. Ocho (17%) desarrollaron obesidad y, de ellos, dos (25%), sindrome metabolico. Tres pacientes desarrollaron sobrepeso (6%). Observamos diferencias estadisticamente significativas de media de edad comparados con los grupos de IMC, donde los pacientes obesos eran adolescentes (ANOVA; p = 0,0001), y aquellos que tomaban mas VPA al dia eran los obesos (ANOVA; p = 0,024). Conclusiones. Los pacientes tratados con VPA que se convierten en obesos pueden desarrollar sindrome metabolico. Requieren una monitorizacion cuidadosa y, ante la presencia de ganancia de peso, se debera valorar la retirada del farmaco.

  14. THE EFFECT OF DIETARY WHEAT BRAN ON SUCROSE-INDUCED CHANGES OF SERUM GLUCOSE AND LIPIDS IN RATS.

    PubMed

    Numan Ahmad, Mousa; Rabah Takruri, Hamid

    2015-10-01

    Introducción: son conocidos los muchos beneficios del salvado de trigo para la salud, pero su glucosa y la actividad hipolipemiante aún sigue sin resolverse. Objetivos: investigar los efectos de cantidades variables de salvado de trigo en la alimentación sobre la glucosa en suero y los lípidos en ratas alimentadas con sacarosa. Métodos: se asignaron a ochenta ratas Sprague-Dawley macho cuatro dietas a base de sacarosa que contenían 0, 5, 10 o 20% de salvado de trigo (WB) dadas ad libitum a las ratas durante 4, 8, 12 o 16 semanas. Glucosa sérica, colesterol total (CT), colesterol de baja y alta densidad de lipoproteínas (LDL -C y HDL -C), los triglicéridos (TG), fosfolípidos (PL) y lípidos totales (TL) se cuantificaron al final de cada período de alimentación y otros parámetros biológicos se evaluaron. Resultados: en todos los períodos de alimentación, la ingesta de alimentos mostró una tendencia lineal ascendente (p < 0,05), mientras que el peso corporal no respondió a WB. En comparación con 0%, 10% o 20 inducida WB disminución (p < 0.05) en TC (16 semanas) y HDL-C (12 o 16 semanas), mientras que 5, 10 o 20% WB inducida disminución similar en PL (4 o 12 semanas), TL (todos los períodos) y glucosa (4 u 8 semanas). Este efecto de glucosa y lípidos bajar se justificó descendiendo respuestas lineales (p < 0.05) a WB. PL y TL descendente respuestas a WB se observaron en todos los períodos de alimentación. TG exhibió ningún cambio con WB, pero respondió linealmente (4 u 8 semanas). Las diferencias en la glucosa o lípidos variables de ratas alimentadas con dietas WB para todos los períodos de alimentación fueron menos evidentes. Conclusiones: los resultados sugieren que el salvado de trigo reduce la glucosa y los lípidos en suero, principalmente fosfolípidos, en ratas alimentadas con sacarosa en una interacción que puede tener implicaciones clínicas en condiciones cardiometabólicas.

  15. 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].

  16. 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...

  17. 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.

  18. Formación de Estrellas de Alta Masa

    NASA Astrophysics Data System (ADS)

    Saldaño, Hugo Pablo

    2011-03-01

    En este Trabajo Especial se presenta un estudio en el infrarrojo cercano de las regiones de formacíon estelar asociadas con las fuentes IRAS 12272-6240 y IRAS 17149-3916. En un an álisis fotométrico sobre las imágenes de las regiones en los filtros J(1.25 μm), H(1.65 μm) y Ks (2.16 μm), obtenidas con el telescopio Baade (Las Campanas, Chile), se identificaron potenciales cúmulos jóvenes asociados con cada una de las fuentes IRAS y se detectaron estrellas jóvenes en formación en un amplio rango de masas (desde 0.5 a 40 M⊙). También se analizan imágenes en Bγ y H2 obtenidas con el mismo telescopio. Este Trabajo Especial contribuye a una mejor comprensión de la formación de las estrellas de gran masa.

  19. 78 FR 67349 - AltaGas Facilities (U.S.), Inc. (AltaGas); Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-12

    ... extending from the international boundary in Toole County, Montana to Alberta, Canada. This filing is available for review at the Commission in the Public Reference Room or may be viewed on the Commission's Web... feet of six-inch diameter natural gas pipeline extending from the international boundary with Canada...

  20. Musings on "Densidades, Potenciales y Funciones Asociadas a una Galaxia Reducida" by Poveda et al. (1960)

    NASA Astrophysics Data System (ADS)

    López-Cruz, O.; Aguilar, L. A.; Añorve, C.

    2011-04-01

    We present a critical review on the paper "Densities, Potentials and related functions for a spherical reduced galaxy" by A. Poveda, R. Iturriaga, and I. Orozco published in 1960 in the Boletín de los Observatorios de Tonantzintla y Tacubaya (BOTT), 2, 20, 3.

  1. 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.

  2. 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

  3. 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...

  4. SUITABILITY OF VISCERAL ADIPOSITY INDEX AS A MARKER FOR CARDIOMETABOLIC RISKS IN JORDANIAN ADULTS.

    PubMed

    Numan Ahmad, Mousa; Halim Haddad, Fares

    2015-12-01

    Introducción: el índice de adiposidad visceral (VAI) ha sido propuesto recientemente como predictor de riesgo cardiometabólico, pero su utilidad no ha sido confirmada. Objetivos: evaluar la asociación entre VAI y los índices de adiposidad y riesgo cardiometabólico convencionales y examinar la capacidad predictiva del riesgo VAI en comparación con otros índices de adiposidad. Métodos: en este estudio se incluyeron un total de 1.622 adultos de Jordania, 686 hombres y 936 mujeres, de edad entre 20 y 80 años. Fueron examinados el VAI, el índice de masa corporal (BMI), la circunferencia de la cintura (WC), la relación cintura-cadera (WHR) y la relación cintura-estatura (WHtR) y se determinaron el colesterol de lipoproteínas de alta densidad (HDL-C), los triglicéridos (TG), la glucosa sérica en ayunas (FSG), y la presión arterial sistólica (SBP) y diastólica (DBP). Se evaluaron las asociaciones, la distribución por edad y género y las diferencias. El receptor de funcionamiento característico (ROC) y el área bajo la curva (AUC) se utilizaron para comparar la capacidad de predicción del riesgo. Resultados: el VAI de las mujeres (6,82 ± 6,43) fue mayor que el de los hombres (4,15 ± 4,62). El VAI severidad aumenta con la edad en una tendencia dosis-respuesta (p < 0,001) en ambos sexos. Las mujeres tuvieron mayor prevalencia que los hombres de alto riesgo de VAI y todos los índices de adiposidad y cardiometabólicos. VAI marcadamente asociado con TG, HDL-C, FSG, SBP y DBP o WHR, WC, WHtR y el BMI en orden respectivo de la potencia de correlación para los índices de riesgo cardiometabólico o adiposidad. En hombres y mujeres, respectivamente, el AUC era más grande para VAI (0,79 vs. 0,77), seguido por WHR (0,73 vs. 0,75), aseo (0,69 vs. 0,74), WHtR (0,65 vs. 0,71) y el BMI (0,53 vs. 0,51). Conclusiones: los hallazgos sugieren que el VAI potencialmente se asocia con riesgos cardiometabólicos y demuestra que es superior a otros índices de

  5. 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...

  6. Serum lipid levels and M/L55 allele distribution of HDL paraoxonase gene in Saami and Finnish men.

    PubMed

    Malin, R; Lehtinen, S; Luoma, P; Näyhä, S; Hassi, J; Koivula, T; Lehtimäki, T

    2001-01-01

    Paraoxonase (PON) is an antioxidative enzyme, which eliminates lipid peroxides. The mutation in codon 55 of PON1 gene causes a change of methionine (M-allele) to leucine (L-allele) and influences PON activity. The Saami are a population living in the northern part of Fennoscandia. In previous studies their death rate from coronary artery disease (CAD) was found to be low. We compared PON M/L55 allele frequencies of 68 Saami and 68 Finnish men and related the PON genotypes to plasma lipid levels and to the levels of autoantibodies against oxidized LDL. The M/L55 genotypes were determined by PCR and restriction enzyme digestion. ELISA was used to measure antibodies against oxidized LDL. The L- and M-allele frequencies were 64% and 36% in Saami population and 64% and 36% in Finnish men, respectively (p = NS, Fisher's exact test). There were also no significant differences in plasma lipid levels or in antibody levels against oxidized LDL between PON genotypes or between Saami and Finnish men. Our results indicate that the PON M/L55 genotype is not associated with plasma lipid levels or the levels of autoantibodies against oxidized LDL in these populations. The Saami men have the same PON M/L55 allele distribution as the Finnish men and the PON genotype might thus not be one factor protecting Saami against CAD.

  7. Sex-specific HDL Cholesterol Changes with Weight Loss and Their Association with Anthropometric variables: the LIFE Study

    PubMed Central

    Yatsuya, Hiroshi; Jeffery, Robert W; Erickson, Darin J; Welsh, Ericka M; Flood, Andrew P; Jaeb, Melanie A; Laqua, Patricia S; Mitchell, Nathan; Langer, Shelby L; Levy, Rona L

    2010-01-01

    Decrease in the level of high density lipoprotein cholesterol (HDLC) has been observed in women who start dieting, but not in men. Patterns of HDLC change during intentional weight loss through 30-months of follow-up, and their association with changes in anthropometric measurements were examined in obese women (N=112) and men (N=100). Missing HDLC values at 6-, 12-, 18-, and 30-month follow-up (N=16, 34, 55, and 50, respectively) due to drop-out were imputed by multiple imputation. Mean ages and body mass indices (BMIs) of subjects at baseline were 47.2 years and 34.8 kg/m2 for women, and 50.4 years and 35.0 kg/m2 for men. On average, participants lost weight steadily for 12 months, followed by slow regain. During the first six months, HDLC decreased significantly in women (−4.1 mg/dl, P=0.0007), but not in men. Significant HDLC increases were observed in both men and women from 6- to 12-month follow-up. HDLC changes in women were positively associated with changes in hip circumference from baseline to 12-month independent of changes in triglycerides, glucose and insulin. Rapid decrease of predominantly subcutaneous fat in the femoral and gluteal area might be associated with HDLC decrease in women during initial weight loss. PMID:20885387

  8. Modeling biology with HDL languages: a first step toward a genetic design automation tool inspired from microelectronics.

    PubMed

    Gendrault, Yves; Madec, Morgan; Lallement, Christophe; Haiech, Jacques

    2014-04-01

    Nowadays, synthetic biology is a hot research topic. Each day, progresses are made to improve the complexity of artificial biological functions in order to tend to complex biodevices and biosystems. Up to now, these systems are handmade by bioengineers, which require strong technical skills and leads to nonreusable development. Besides, scientific fields that share the same design approach, such as microelectronics, have already overcome several issues and designers succeed in building extremely complex systems with many evolved functions. On the other hand, in systems engineering and more specifically in microelectronics, the development of the domain has been promoted by both the improvement of technological processes and electronic design automation tools. The work presented in this paper paves the way for the adaptation of microelectronics design tools to synthetic biology. Considering the similarities and differences between the synthetic biology and microelectronics, the milestones of this adaptation are described. The first one concerns the modeling of biological mechanisms. To do so, a new formalism is proposed, based on an extension of the generalized Kirchhoff laws to biology. This way, a description of all biological mechanisms can be made with languages widely used in microelectronics. Our approach is therefore successfully validated on specific examples drawn from the literature.

  9. Metabolic syndrome and associated factors in children and adolescents of a Brazilian municipality.

    PubMed

    Dias Pitangueira, Jacqueline Costa; Rodrigues Silva, Luciana; Portela de Santana, Mônica Leila; Monteiro da Silva, Maria da Conceição; de Farias Costa, Priscila Ribas; D'Almeida, Vânia; de Oliveira Assis, Ana Marlúcia

    2014-04-01

    Introducción: Los factores asociados al Síndrome metabólico (SM) han sido ampliamente estudiados en adultos, pero aún son poco explorado en niños y adolescentes Objetivo: Identificar la superioridad de SM y los factores asociados en niños y adolescentes. Métodos: Se trata de estudio transversal, con 540 niños de 7 a 14 años de edad. Los datos socioeconómicos, demográficos, estilo de vida e historia familiar de enfermedades crónicas fueron informados por la persona y/o responsable y registrados en cuestionario estructurado. Fueron realizadas dosificaciones bioquímicas (glicemia en ayuno, triglicérides, lipoproteína de alta densidad reducida, lipoproteína de muy baja densidad, homocisteina y cisteina), evaluación antropométrica y verificación de la presión arterial. La SM fue definida de acuerdo con los criterios del The National Cholesterol Education Program Adult Treatment Panel III adaptado por Ferranti. Se utilizó regresión de Poisson como técnica estadística para identificar los factores asociados a la SM. Resultados: La superioridad de la SM fue del 12,8%, siendo a lipoproteína de alta densidad reducida (58,2%) el componente más frecuente, seguido por la hipertrigliceridemia (41,8%), presión arterial aumentada (29,1%), circunferencia de la cintura aumentada (26,7%) e hiperglicemia (7,2%). Fue observada asociación entre SM y exceso de peso (RP: 2,2 [1,22-3,95]), escolaridad paterna (RP: 2,19 [1,10-4,37]), concentración sérica de la lipoproteína de muy baja densidad (RP: 1,08 [1,04-1,11]) y concentraciones séricas simultáneamente aumentadas de homocisteina y cisteina (RP: 2,58 [1,32-5,04]). Conclusiones: La superioridad de SM es elevada en niños y adolescentes y se encuentra aumentada en paciente con exceso de peso, mayor escolaridad paterna, concentraciones séricas aumentadas de la lipoproteína de muy baja densidad, y elevación simultánea de los niveles séricos de homocisteína y cisteína.

  10. [Ectoparasites of the zokor Myospalax myospalax (Rodentia) in northern Altaĭ].

    PubMed

    Litvinov, Iu N; Sapegina, V F

    2003-01-01

    Following ectoparasites have been recorded on the zokor in the Northern Altay: specific fleas--Ctenophthalmus dilatatus, Rhadinopsylla ioffi, Brachyctenonotus myospalacis; a flea distributed on various rodents; ixodid ticks--Ixodes crenulatus, I. persulcatus; gamasid mites--Hirstionyssus myosplalacis. The C. dilatatus carried hypopi of acaroid mites.

  11. Astrofísica de altas energías de objetos compactos

    NASA Astrophysics Data System (ADS)

    Combi, J. A.

    2015-08-01

    This paper summarizes the different aspects related to phenomenology derived from the evolution and activity of compact objects (white dwarfs, neutron stars and black holes) that emit at high energies. The fundamental questions regarding compact objects are how they form, and how material behaves in their extreme gravitational, magnetic and radiation fields. The answers to these questions lie in the study of isolated and/or accreting neutron stars and black holes in binary systems. In the last decade, the new generation of X/Gamma-ray satellites has boosted research in high energy astrophysics of objects of this type, to unprecedented levels. Other issues related to instrumental and future developments of orbital X-ray/gamma missions are also described at the end of the article.

  12. Pediatric liver transplantation: preliminary results at Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione.

    PubMed

    Cintorino, D; Spada, M; Clarizia, S; Vasta, F; Mandalà, L; Aricò, M; Traverso, G; Luca, A; Panarello, G; Minervini, M; Gruttadauria, S; Verzaro, R; Volpes, R; Scotti Foglieni, C; Gridelli, B

    2005-01-01

    Between July 2003 and November 2004 14 pediatric liver transplantations (LTx) have been performed in 12 children using cadaveric donors. The primary diseases were as follows biliary atresia in 9 cases, whereas the other 3 children were affected by cystic fibrosis, Langherans cells histiocytosis, and hepatoblastoma, respectively. Median patient waiting time was 103 days (range, 2-158); no patient died while on the waiting list. Patients who underwent transplantation included 7 boys and 5 girls, ranging in age from 6 months to 14 years (median age, 5 years). Recipient median weight was 16 kg (range, 6-38). Donor median age was 19 years (range, 3-47), whereas donor median weight was 74 kg (range, 15-90). All children who underwent primary LTx were United Network for Organ Sharing (UNOS) status 2B. Of the 12 transplanted patients, 9 received a left lateral segment (LLS) from an in situ split liver, whereas 3 received a whole graft. Two children developed an episode of acute cellular rejection on the seventh postoperative day, which was treated successfully with a course of intravenous steroids for 3 days. After a median follow-up of 245 days, 10 children are alive but 2 children died due to primary nonfunction (PNF) on the second postoperative day and septic shock on the fifth postoperative day after retransplantation for acute hepatic artery thrombosis, respectively. One child who underwent retransplantation for hepatic artery thrombosis on the 31st postoperative day after primary LTx is currently alive. Evaluation of our initial data suggests that the split liver technique has the potential to meet the needs of pediatric LTx allowing grafting early in the course of the original disease and reducing waiting time. PMID:16182756

  13. 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...

  14. 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 .

  15. Proceedings of the Summer Conference on Argumentation (Alta, Utah, July 26-29, 1979).

    ERIC Educational Resources Information Center

    Rhodes, Jack, Ed.; Newell, Sara, Ed.

    This collection represents most of the papers and programs presented at the 1979 Summer Conference on Argumentation sponsored by the Speech Communication Association and the American Forensic Association. Two keynote addresses are included along with a distributed paper on argumentation as a communication process. The other 23 papers and programs…

  16. [HIGH-INTENSITY INTERVAL EXERCISE THERAPY TO REDUCE CARDIOVASCULAR RISK FACTORS IN PEOPLE WITH THE METABOLIC SYNDROME; SYSTEMATIC REVIEW WITH META-ANALYSIS].

    PubMed

    Aguilera Eguía, Raúl; Vergara Miranda, Camila; Quezada Donoso, Romina; Sepúlveda Silva, Mabel; Coccio, Nicol; Cortés, Patricio; Delarze, Carlos; Flores, Cherie

    2015-12-01

    El síndrome metabólico es una agrupación de factores de riesgo cardiovascular que incluyen obesidad central, presión sanguínea elevada, resistencia a la insulina y dislipidemias. Objetivo: determinar el efecto del ejercicio intervalado de alta intensidad sobre los factores de riesgo cardiovascular en personas con síndrome metabólico. Materiales y métodos: se buscó en la base de datos WOS, Medline, Lilacs, PEDro y en los metabuscadores Epistemonikos y Trip Database. Se realizó una búsqueda manual, se hizo seguimiento de referencias relevantes, se buscaron protocolos de ECAs y se contactó con expertos en esta área. Resultados: la búsqueda preliminar arrojó un total de 239 artículos potencialmente elegibles; según los criterios de elegibilidad solo incluimos tres revisiones sistemáticas. Conclusión: no hay grandes diferencias en relación al índice de masa corporal, circunferencia de cintura, glucosa en ayunas, lipoproteínas de alta densidad y triglicéridos. En relación a la presión arterial, fue superior el ejercicio continuo de moderada intensidad. Al comparar el ejercicio intervalado de alta intensidad versus control, el primero resultó ser superior en todos los resultados analizados.

  17. 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 fru