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Sample records for elevated high-density lipoprotein

  1. Elevated High-Density Lipoprotein Cholesterol and Age-Related Macular Degeneration: The Alienor Study

    PubMed Central

    Cougnard-Grégoire, Audrey; Delyfer, Marie-Noëlle; Korobelnik, Jean-François; Rougier, Marie-Bénédicte; Le Goff, Mélanie; Dartigues, Jean-François; Barberger-Gateau, Pascale; Delcourt, Cécile

    2014-01-01

    Background Lipid metabolism and particularly high-density lipoprotein (HDL) may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with plasma HDL and other lipids, which may be confounded by the recently reported associations of AMD with HDL-related genes. We explored the association of AMD with plasma lipid levels and lipid-lowering medication use, taking into account most of HDL-related genes associated with AMD. Methods The Alienor study is a population-based study on age-related eye diseases performed in 963 elderly residents of Bordeaux (France). AMD was graded from non mydriatic color retinal photographs in three exclusive stages: no AMD (n = 430 subjects, 938 eyes); large soft distinct drusen and/or large soft indistinct drusen and/or reticular drusen and/or pigmentary abnormalities (early AMD, n = 176, 247); late AMD (n = 40, 61). Associations of AMD with plasma lipids (HDL, total cholesterol (TC), Low-density lipoprotein (LDL), and triglycerides (TG)) were estimated using Generalized Estimating Equation logistic regressions. Statistical analyses included 646 subjects with complete data. Results After multivariate adjustment for age, sex, educational level, smoking, BMI, lipid-lowering medication use, cardiovascular disease and diabetes, and for all relevant genetic polymorphisms (ApoE2, ApoE4, CFH Y402H, ARMS2 A69S, LIPC rs10468017, LIPC rs493258, LPL rs12678919, ABCA1 rs1883025 and CETP rs3764261), higher HDL was significantly associated with an increased risk of early (OR = 2.45, 95%CI: 1.54–3.90; P = 0.0002) and any AMD (OR = 2.29, 95%CI: 1.46–3.59; P = 0.0003). Association with late AMD was far from statistical significance (OR = 1.58, 95%CI: 0.48–5.17; p = 0.45). No associations were found for any stage of AMD with TC, LDL and TG levels, statin or fibrate drug use. Conclusions This study suggests that

  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. Females with angina pectoris have altered lipoprotein metabolism with elevated cholesteryl ester transfer protein activity and impaired high-density lipoproteins-associated antioxidant enzymes

    PubMed Central

    PARK, JUNGHO; KIM, JAE-RYONG; SHIN, DONG-GU; CHO, KYUNG-HYUN

    2012-01-01

    In order to investigate non-invasive biomarkers for angina pectoris (AP), we analyzed the lipid and protein composition in individual lipoproteins from females with angina pectoris (n=22) and age- and gender-matched controls (n=20). In the low-density lipoprotein (LDL) fraction, the triglycerides (TG) and protein content increased in the AP group compared to the control group. The AP group had lower total cholesterol (TC) and elevated TG in the high-density lipoprotein (HDL) fraction. In the AP group, cholesteryl ester transfer protein (CETP) activity was enhanced in HDL and LDL, while lecithin:cholesterol acyltransferase (LCAT) activity in HDL3 was almost depleted. Antioxidant activity was significantly decreased in the HDL3 fraction, with a decrease in the HDL2 particle size. In the HDL3 fraction, paraoxonase and platelet activating factor-acetylhydrolase (PAF-AH) activity were much lower and the levels of CETP and apoC-III were elevated in the AP group. The LDL from the AP group was more sensitive to cupric ion-mediated oxidation with faster mobility. In conclusion, the lipoprotein fractions in the AP group had impaired antioxidant activity and increased TG and apoC-III with structural and functional changes. PMID:22211242

  4. Elevated hepatic lipase activity and low levels of high density lipoprotein in a normotriglyceridemic, nonobese Turkish population.

    PubMed

    Bersot, T P; Vega, G L; Grundy, S M; Palaoglu, K E; Atagündüz, P; Ozbayrakçi, S; Gökdemir, O; Mahley, R W

    1999-03-01

    Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease and, in the United States, are often associated with hypertriglyceridemia and obesity. In Turkey, low HDL-C levels are highly prevalent, 53% of men and 26% of women having HDL-C levels <35 mg/dl, in the absence of hypertriglyceridemia and obesity. In this study to investigate the cause of low HDL-C levels in Turks, various factors affecting HDL metabolism were assessed in normotriglyceridemic Turkish men and women living in Istanbul and in non-Turkish men and women living in San Francisco. Turkish men and women had significantly lower HDL-C levels than the San Francisco men and women, as well as markedly lower apolipoprotein A-I levels (25 and 39 mg/dl lower, respectively). In both Turkish and non-Turkish subjects, the mean body mass index was <27 kg/m2, the mean triglyceride level was <120 mg/dl, and the mean total cholesterol was 170-180 mg/dl. The mean hepatic triglyceride lipase activity was 21% and 31% higher in Turkish men and women, respectively, than in non-Turkish men and women, and remained higher even after subjects with a body mass index >50th percentile for men and women in the United States were excluded from the analysis. As no dietary or behavioral factors have been identified in the Turkish population that account for increased hepatic triglyceride lipase activity, the elevation most likely has a genetic basis. high density lipoprotein in a normotriglyceridemic, nonobese Turkish population. PMID:10064731

  5. Elevated triglyceride and decreased high density lipoprotein level in carbon disulfide workers in Taiwan.

    PubMed

    Luo, Jiin-Chyuan John; Chang, Ho-Yuan; Chang, Shu-Ju; Chou, Tzu-Chieh; Chen, Chiou-Jong; Shih, Tung-Sheng; Huang, Chin-Chang

    2003-01-01

    Carbon disulfide (CS2) is a man-made product utilized primarily in the manufacture of viscose rayon. Overexposure to CS2 has been associated with an increase in coronary heart disease. The aims of this study were to examine the dose-response relationship of CS2 exposure and elevated lipid profile tests among CS2-exposed workers in Taiwan. A total of 132 workers were recruited from two viscose rayon plants. Air sampling was performed to determine the CS2 exposure of workers. Demographic data and work history were gathered by a standard self-administered questionnaire. Lipid profile tests were also performed by routine methods. The average CS2 exposure concentration was 50.6 +/- 25.6 ppm (range: 24-127 ppm) in the high-exposure group, 12.9 +/- 5 ppm (range: 5.2-22.3 ppm) in the mid-exposure group, and 3.5 +/- 1.2 ppm (range 0.97-5.2 ppm) in the low-exposure group. There were 21 out of 33 (63.7%) elevated triglyceride levels among high-CS2-exposure workers, 27 out of 64 (42.2%) among the middle-CS2-exposure, and 14 out of 35 (40%) among low-CS2-exposure workers, respectively. Compared to the low-CS2-exposure workers, the age- and weight-adjusted odds ratios (and 95% confidence intervals) of the prevalence of elevated triglyceride value were 1.12 (0.5, 2.7) for middle-CS2-exposure workers, and 2.81 (1.02, 7.8) for high-CS2-exposure workers. There was a significant linear trend between CS2 exposure and the prevalence of elevated triglyceride value (P = 0.046) after adjusting for other factors. There was also a lower prevalence of elevated HDL level in high-CS2-exposure workers than low-CS2-exposure workers (15.2% versus 31.4%). Compared to the low-CS2-exposure workers, the age- and weight-adjusted odds ratio (and 95% confidence intervals) of elevated HDL level were 0.34 (0.1, 1.18) for high-CS2-exposure workers, which was borderline significant. In conclusion, this study suggests that elevated triglyceride level and decreased HDL level are associated with CS2 exposure

  6. Osbpl8 Deficiency in Mouse Causes an Elevation of High-Density Lipoproteins and Gender-Specific Alterations of Lipid Metabolism

    PubMed Central

    Béaslas, Olivier; Metso, Jari; Nissilä, Eija; Laurila, Pirkka-Pekka; Kaiharju, Essi; Batchu, Krishna Chaithanya; Kaipiainen, Leena; Mäyränpää, Mikko I.; Yan, Daoguang; Gylling, Helena; Jauhiainen, Matti; Olkkonen, Vesa M.

    2013-01-01

    OSBP-related protein 8 (ORP8) encoded by Osbpl8 is an endoplasmic reticulum sterol sensor implicated in cellular lipid metabolism. We generated an Osbpl8−/− (KO) C57Bl/6 mouse strain. Wild-type and Osbpl8KO animals at the age of 13-weeks were fed for 5 weeks either chow or high-fat diet, and their plasma lipids/lipoproteins and hepatic lipids were analyzed. The chow-fed Osbpl8KO male mice showed a marked elevation of high-density lipoprotein (HDL) cholesterol (+79%) and phospholipids (+35%), while only minor increase of apolipoprotein A-I (apoA-I) was detected. In chow-fed female KO mice a less prominent increase of HDL cholesterol (+27%) was observed, while on western diet the HDL increment was prominent in both genders. The HDL increase was accompanied by an elevated level of HDL-associated apolipoprotein E in male, but not female KO animals. No differences between genotypes were observed in lecithin:cholesterol acyltransferase (LCAT) or hepatic lipase (HL) activity, or in the fractional catabolic rate of fluorescently labeled mouse HDL injected in chow-diet fed animals. The Osbpl8KO mice of both genders displayed reduced phospholipid transfer protein (PLTP) activity, but only on chow diet. These findings are consistent with a model in which Osbpl8 deficiency results in altered biosynthesis of HDL. Consistent with this hypothesis, ORP8 depleted mouse hepatocytes secreted an increased amount of nascent HDL into the culture medium. In addition to the HDL phenotype, distinct gender-specific alterations in lipid metabolism were detected: Female KO animals on chow diet showed reduced lipoprotein lipase (LPL) activity and increased plasma triglycerides, while the male KO mice displayed elevated plasma cholesterol biosynthetic markers cholestenol, desmosterol, and lathosterol. Moreover, modest gender-specific alterations in the hepatic expression of lipid homeostatic genes were observed. In conclusion, we report the first viable OsbplKO mouse model, demonstrating a

  7. Regulation of high density lipoprotein levels

    SciTech Connect

    Krauss, R.M.

    1982-03-01

    An increasing awareness of the physiologic and pathologic importance of serum high density lipoproteins (HDL) has led to a large number of observations regarding factors which influence their concentrations. HDL consists of a heterogeneous collection of macromolecules with diverse physical properties and chemical constituents. While laboratory techniques have made it possible to measure HDL and their individual components, there are as yet large gaps in our knowledge of the biochemical mechanisms and clinical significance of changes in these laboratory parameters. In this review, current concepts of the structure and metabolism of HDL will be briefly summarized, and the factors influencing their levels in humans will be surveyed. 313 references.

  8. Abnormal high density lipoproteins in cerebrotendinous xanthomatosis

    SciTech Connect

    Shore, V.; Salen, G.; Cheng, F.W.; Forte, T.; Shefer, S.; Tint, G.S.

    1981-11-01

    The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The adnormalities in lipoprotein distribution profiles and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.

  9. Regulation of high-density lipoprotein metabolism.

    PubMed

    Rye, Kerry-Anne; Barter, Philip J

    2014-01-01

    There is compelling evidence from human population studies that plasma levels of high-density lipoprotein (HDL) cholesterol correlate inversely with cardiovascular risk. Identification of this relationship has stimulated research designed to understand how HDL metabolism is regulated. The ultimate goal of these studies has been to develop HDL-raising therapies that have the potential to decrease the morbidity and mortality associated with atherosclerotic cardiovascular disease. However, the situation has turned out to be much more complex than originally envisaged. This is partly because the HDL fraction consists of multiple subpopulations of particles that vary in terms of shape, size, composition, and surface charge, as well as in their potential cardioprotective properties. This heterogeneity is a consequence of the continual remodeling and interconversion of HDL subpopulations by multiple plasma factors. Evidence that the remodeling of HDLs may impact on their cardioprotective properties is beginning to emerge. This serves to highlight the importance of understanding not only how the remodeling and interconversion of HDL subpopulations is regulated but also how these processes are affected by agents that increase HDL levels. This review provides an overview of what is currently understood about HDL metabolism and how the subpopulation distribution of these lipoproteins is regulated. PMID:24385508

  10. Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component.

    PubMed

    Herzog, Eva; Pragst, Ingo; Waelchli, Marcel; Gille, Andreas; Schenk, Sabrina; Mueller-Cohrs, Jochen; Diditchenko, Svetlana; Zanoni, Paolo; Cuchel, Marina; Seubert, Andreas; Rader, Daniel J; Wright, Samuel D

    2016-08-01

    Human apolipoprotein A-I preparations reconstituted with phospholipids (reconstituted high-density lipoprotein [HDL]) have been used in a large number of animal and human studies to investigate the physiological role of apolipoprotein A-I. Several of these studies observed that intravenous infusion of reconstituted HDL might cause transient elevations in plasma levels of hepatic enzymes. Here we describe the mechanism of this enzyme release. Observations from several animal models and in vitro studies suggest that the extent of hepatic transaminase release (alanine aminotransferase [ALT]) correlates with the movement of hepatic cholesterol into the blood after infusion. Both the amount of ALT release and cholesterol movement were dependent on the amount and type of phospholipid present in the reconstituted HDL. As cholesterol is known to dissolve readily in phospholipid, an HDL preparation was loaded with cholesterol before infusion into rats to assess the role of diffusion of cholesterol out of the liver and into the reconstituted HDL. Cholesterol-loaded HDL failed to withdraw cholesterol from tissues and subsequently failed to cause ALT release. To investigate further the role of cholesterol diffusion, we employed mice deficient in SR-BI, a transporter that facilitates spontaneous movement of cholesterol between cell membranes and HDL. These mice showed substantially lower movement of cholesterol into the blood and markedly lower ALT release. We conclude that initial depletion of hepatic cholesterol initiates transient ALT release in response to infusion of reconstituted HDL. This effect may be controlled by appropriate choice of the type and amount of phospholipid in reconstituted HDL. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26651060

  11. Increased serum triglyceride clearance and elevated high-density lipoprotein 2 and 3 cholesterol during treatment of primary hypertriglyceridemia with bezafibrate☆

    PubMed Central

    Sakuma, Nagahiko; Ikeuchi, Reiko; Hibino, Takeshi; Yoshida, Takayuki; Mukai, Seiji; Akita, Sachie; Yajima, Kazuhiro; Miyabe, Hiromichi; Goto, Toshihiko; Takada, Norio; Ohte, Nobuyuki; Kunimatu, Mitoshi; Kimura, Genjiro

    2003-01-01

    Background Hypertriglyceridemia accompanied by low levels of high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. High-density lipoprotein 2 (HDL2) and 3 (HDL3) are believed to suppress the progress of atherosclerosis through reverse cholesterol transport. As a result, peripheral tissues can be protected against excessive accumulation of cholesterol. Although bezafibrate is known to accelerate the increase of HDL-C, results are not standardized regarding increases of HDL3 and HDL2 subfractions. Objective This study assessed the effects of bezafibrate on serum triglyceride (TG) fractional clearance rate (K2) and HDL2 and HDL3 cholesterol (HDL2-C and HDL3-C, respectively) levels in patients with primary hypertriglyceridemia (serum TG ≥150 mg/dL). Methods Outpatients with primary hypertriglyceridemia were enrolled in this 8-week study conducted at the Third Department of Internal Medicine, Nagoya City University Hospital (Nagoya, Japan). Oral bezafibrate was administered at a dose of 400 mg/d (200-mg tablet BID, morning and evening) for 8 weeks. After 8 weeks, serum levels of total cholesterol (TC), TG, HDL-C, HDL2-C, and HDL3-C were measured. A fat emulsion tolerance test to assess K2 and measurements of plasma lipoprotein lipase (LPL) mass, LPL activity, and hepatic triglyceride lipase (HTGL) activity in postheparin plasma were performed before bezafibrate administration and after the course of treatment. Results Sixteen patients (10 men, 6 women; mean [SD] age, 54 [12] years [range, 30–69 years]; mean [SD] body mass index, 23 [2] kg/m2) entered the study. The following findings were observed in male and female patients after 8 weeks of treatment. A statistically significant reduction was observed in mean serum TG level (P<0.01). Significant increases were seen in HDL-C, HDL2-C, and HDL3-C (all P<0.01), K2 (P<0.01), and in plasma LPL mass (P<0.01) and LPL activity (P<0.05). TC level and HTGL activity did not change

  12. Excessive centrifugal fields damage high density lipoprotein[S

    PubMed Central

    Munroe, William H.; Phillips, Martin L.; Schumaker, Verne N.

    2015-01-01

    HDL is typically isolated ultracentrifugally at 40,000 rpm or greater, however, such high centrifugal forces are responsible for altering the recovered HDL particle. We demonstrate that this damage to HDL begins at approximately 30,000 rpm and the magnitude of loss increases in a rotor speed-dependent manner. The HDL is affected by elevated ultracentrifugal fields resulting in a lower particle density due to the shedding of associated proteins. To circumvent the alteration of the recovered HDL, we utilize a KBr-containing density gradient and a lowered rotor speed of 15,000 rpm to separate the lipoproteins using a single 96 h centrifugation step. This recovers the HDL at two density ranges; the bulk of the material has a density of about 1.115 g/ml, while lessor amounts of material are recovered at >1.2 g/ml. Thus, demonstrating the isolation of intact HDL is possible utilizing lower centrifuge rotor speeds. PMID:25910941

  13. High-density lipoprotein prevents organ damage in endotoxemia.

    PubMed

    Lee, Ru-Ping; Lin, Nien-Tsung; Chao, Yann-Fen Chiou; Lin, Chia-Chin; Harn, Horng-Jyh; Chen, Hsing-I

    2007-06-01

    High-density lipoprotein (HDL) may decrease organ injury in sepsis. This study was designed using an animal model to mimic people who had a high HDL level and to test HDL effects on preventing organ damage in endotoxemia. Endotoxemia was induced by an infusion of lipopolysac-charide (LPS) after HDL or LDL administration. Levels of blood biochemical substances, nitrate/nitrite, and TNF-alpha in sera were measured. Pathological examinations were performed 72 hours after LPS infusion. HDL decreased the endotoxin-induced elevation of AST, ALT, BUN, creatinine, LDH, CPK, nitrate/nitrite, and TNF-alpha. On histological examination, neutrophil infiltration was lower in the HDL group. HDL had a significant effect in preventing endotoxin-induced organ damage. PMID:17514720

  14. A Novel Anti-Inflammatory Effect for High Density Lipoprotein

    PubMed Central

    Cameron, Scott J.; Morrell, Craig N.; Bao, Clare; Swaim, AnneMarie F.; Rodriguez, Annabelle; Lowenstein, Charles J.

    2015-01-01

    High density lipoprotein has anti-inflammatory effects in addition to mediating reverse cholesterol transport. While many of the chronic anti-inflammatory effects of high density lipoprotein (HDL) are attributed to changes in cell adhesion molecules, little is known about acute signal transduction events elicited by HDL in endothelial cells. We now show that high density lipoprotein decreases endothelial cell exocytosis, the first step in leukocyte trafficking. ApoA-I, a major apolipoprotein of HDL, mediates inhibition of endothelial cell exocytosis by interacting with endothelial scavenger receptor-BI which triggers an intracellular protective signaling cascade involving protein kinase C (PKC). Other apolipoproteins within the HDL particle have only modest effects upon endothelial exocytosis. Using a human primary culture of endothelial cells and murine apo-AI knockout mice, we show that apo-AI prevents endothelial cell exocytosis which limits leukocyte recruitment. These data suggest that high density lipoprotein may inhibit diseases associated with vascular inflammation in part by blocking endothelial exocytosis. PMID:26680360

  15. A Novel Anti-Inflammatory Effect for High Density Lipoprotein.

    PubMed

    Cameron, Scott J; Morrell, Craig N; Bao, Clare; Swaim, AnneMarie F; Rodriguez, Annabelle; Lowenstein, Charles J

    2015-01-01

    High density lipoprotein has anti-inflammatory effects in addition to mediating reverse cholesterol transport. While many of the chronic anti-inflammatory effects of high density lipoprotein (HDL) are attributed to changes in cell adhesion molecules, little is known about acute signal transduction events elicited by HDL in endothelial cells. We now show that high density lipoprotein decreases endothelial cell exocytosis, the first step in leukocyte trafficking. ApoA-I, a major apolipoprotein of HDL, mediates inhibition of endothelial cell exocytosis by interacting with endothelial scavenger receptor-BI which triggers an intracellular protective signaling cascade involving protein kinase C (PKC). Other apolipoproteins within the HDL particle have only modest effects upon endothelial exocytosis. Using a human primary culture of endothelial cells and murine apo-AI knockout mice, we show that apo-AI prevents endothelial cell exocytosis which limits leukocyte recruitment. These data suggest that high density lipoprotein may inhibit diseases associated with vascular inflammation in part by blocking endothelial exocytosis. PMID:26680360

  16. Ethanol enhances de novo synthesis of high density lipoprotein cholesterol

    SciTech Connect

    Cluette, J.E.; Mulligan, J.J.; Noring, R.; Doyle, K.; Hojnacki, J.

    1984-05-01

    Male squirrel monkeys fed ethanol at variable doses were used to assess whether alcohol enhances de novo synthesis of high density lipoprotein (HDL) cholesterol in vivo. Monkeys were divided into three groups: 1) controls fed isocaloric liquid diet; 2) low ethanol monkeys fed liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) High Ethanol animals fed diet plus vodka at 24% of calories. High Ethanol primates had significantly higher levels of HDL nonesterified cholesterol than Control and Low Ethanol animals while serum glutamate oxaloacetate transaminase was similar for the three treatments. There were no significant differences between the groups in HDL cholesteryl ester mass or specific activity following intravenous injection of labeled mevalonolactone. By contrast, High Ethanol monkeys had significantly greater HDL nonesterified cholesterol specific activity with approximately 60% of the radioactivity distributed in the HDL/sub 3/ subfraction. This report provides the first experimental evidence that ethanol at 24% of calories induces elevations in HDL cholesterol in primates through enhanced de novo synthesis without adverse effects on liver function.

  17. In vivo protection against endotoxin by plasma high density lipoprotein.

    PubMed Central

    Levine, D M; Parker, T S; Donnelly, T M; Walsh, A; Rubin, A L

    1993-01-01

    Overwhelming bacterial infection is accompanied by fever, hypotension, disseminated intravascular coagulation, and multiple organ failure leading to death in 30-80% of cases. These classical symptoms of septic shock are caused by potent cytokines that are produced in response to endotoxin released from Gram-negative bacteria. Treatments with antibodies and receptor antagonists to block endotoxin or cytokine mediators have given mixed results in clinical trials. High density lipoprotein (HDL) is a natural component of plasma that is known to neutralize endotoxin in vitro. We report here that raising the plasma HDL concentration protects mice against endotoxin in vivo. Transgenic mice with 2-fold-elevated plasma HDL levels had more endotoxin bound to HDL, lower plasma cytokine levels, and improved survival rates compared with low-HDL mice. Intravenous infusion of HDL also protected mice, but only when given as reconstituted HDL prepared from phospholipid and either HDL apoprotein or an 18-amino acid peptide synthesized to mimic the structure of apolipoprotein A-I of HDL. Intact plasma HDL was mildly toxic, and HDL apoprotein was ineffective. The effectiveness of the reconstituted peptide renders very unlikely any significant contribution to protection by trace proteins in apo-HDL. These data suggest a simple leaflet insertion model for binding and neutralization of lipopolysaccharide by phospholipid on the surface of HDL. Plasma HDL may normally act to protect against endotoxin; this protection may be augmented by administration of reconstituted HDL or reconstituted peptides. Images Fig. 1 Fig. 2 Fig. 3 PMID:8265667

  18. Structural stability and functional remodeling of high-density lipoproteins.

    PubMed

    Gursky, Olga

    2015-09-14

    Lipoproteins are protein-lipid nanoparticles that transport lipids in circulation and are central in atherosclerosis and other disorders of lipid metabolism. Apolipoproteins form flexible structural scaffolds and important functional ligands on the particle surface and direct lipoprotein metabolism. Lipoproteins undergo multiple rounds of metabolic remodeling that is crucial to lipid transport. Important aspects of this remodeling, including apolipoprotein dissociation and particle fusion, are mimicked in thermal or chemical denaturation and are modulated by free energy barriers. Here we review the biophysical studies that revealed the kinetic mechanism of lipoprotein stabilization and unraveled its structural basis. The main focus is on high-density lipoprotein (HDL). An inverse correlation between stability and functions of various HDLs in cholesterol transport suggests the functional role of structural disorder. A mechanism for the conformational adaptation of the major HDL proteins, apoA-I and apoA-II, to the increasing lipid load is proposed. Together, these studies help understand why HDL forms discrete subclasses separated by kinetic barriers, which have distinct composition, conformation and functional properties. Understanding these properties may help improve HDL quality and develop novel therapies for cardiovascular disease. PMID:25749369

  19. High-density lipoprotein that supports Ureaplasma urealyticum growth.

    PubMed Central

    Sayed, I A; Sweat, F W

    1982-01-01

    A high-density lipoprotein with growth-promoting activity for Ureaplasma urealyticum was purified in high yield from equine serum by ammonium sulfate fractionation and molecular filtration. Fractions enriched in growth-promoting activity represented 5% of the total serum protein, and 30 micrograms of the purified protein per ml gave an activity equivalent to that from 100 micrograms of whole serum per ml. The serum was totally replaced by purified lipoprotein when tested in a soy peptone-yeast dialysate or when added to a chemically defined synthetic medium. Polyacrylamide gel electrophoresis indicated that one major protein with growth-promoting activity is present. A total of 10 proteins were distinguished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, with 75% of the total contributed by two proteins with molecular weights of 160,000 and 170,000. A total of 90% of the lipoprotein was an alpha-protein with a mobility of 0.67 in two-dimensional immunoelectrophoresis (albumin = 1.0). The active component was further characterized as high-density lipoprotein by density ultracentrifugation. Two components with S = 6.4 and S = 15.8 were distinguished by velocity sedimentation. The lipid was removed from lipoprotein during its precipitation with acetone. The growth-promoting activity of delipidized protein was dependent upon the addition of exogenous cholesterol, and [14C]cholesterol was transferred to urea-plasmic cells in cultures containing the delipidized protein. A major portion of the [14C]cholesterol remained associated with the protein during filtration on Sepharose 4B columns. Images PMID:7201468

  20. [Residual risk: The roles of triglycerides and high density lipoproteins].

    PubMed

    Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

    2016-06-01

    In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. PMID:27305303

  1. An evaluation of serum high density lipoproteins-phospholipids.

    PubMed

    Ide, H; Tsuji, M; Shimada, M; Kondo, T; Fujiya, S; Asanuma, Y; Agishi, Y

    1988-07-01

    Phospholipids in high density lipoproteins (HDL) is being used as a negative risk indicator of atherosclerosis. Phospholipids in HDL may not demonstrate the actual level of HDL-phospholipids when determined by the precipitation or ultracentrifugal methods, because HDL fractions contain very high density lipoproteins (VHDL) and albumin. In the present study, the true level of phospholipids in HDL was estimated using high performance liquid chromatography (HPLC), and it was compared with the level of phospholipids in HDL determined by the precipitation method. Sera from 18 healthy subjects were used as materials. In the HPLC method, the HDL fraction was extracted making sure that it contained no free albumin, which is albumin not bound to phospholipids. The HDL fraction was separated into subfractions. It was found that phospholipids in the VHDL fraction make a 20.2 +/- 7.3% (mean +/- S.D.) part of the total HDL-phospholipids. A large part of the VHDL fraction was constituted of albumin-bound phospholipids. A significant correlation was observed between HDL-phospholipids determined by the precipitation method, which contain albumin, and the actual HDL fraction phospholipids determined by HPLC, which do not contain VHDL (r = 0.903, p less than 0.01). These results suggest that HDL-phospholipids values determined by the precipitation method give useful clinical data. PMID:3176021

  2. Lipoprotein receptors in copper-deficient rats: high density lipoprotein binding to liver membranes

    SciTech Connect

    Hassel, C.A.; Lei, K.Y.; Marchello, J.A.

    1986-03-05

    In copper-deficient rats, the observed hyperlipoproteinemia was mainly due to the elevation in high density lipoproteins (HDL). This study was designed to determine whether an impairment in the binding of HDL to liver membrane is responsible for the hyperlipoproteinemia. Sixty male Sprague-Dawley rats were randomly divided into 2 treatments, namely copper (Cu) deficient and adequate (less than 1 and 8 mg Cu/kg of diet). After 8 weeks, plasma, heart and liver tissues were obtained. Reduction in liver Cu content and elevation in heart to body weight ratio and plasma cholesterol confirmed that rats fed the test diet were Cu-deficient. Plasma HDL isolated from both Cu-deficient and control rats were iodinated and bound to liver membranes prepared from rats of each treatment. Binding of /sup 125/I-HDL was competitively inhibited by unlabelled rat HDL from both treatments, but not by human LDL. Scatchard analysis of specific binding data showed that maximal /sup 125/I-HDL binding (per mg membrane protein) to membranes prepared from Cu-deficient rats was not lower than controls. Furthermore, the amount of /sup 125/I-HDL from deficient rats specifically bound to liver membranes prepared from either treatment was not less than the amount of /sup 125/I-HDL from control rats bound to the same membranes. The data suggest that the hyperlipoproteinemia in Cu-deficient rats may not have resulted from a decrease in the number of hepatic HDL binding sites.

  3. Change in composition of high density lipoprotein during gemfibrozil therapy.

    PubMed

    Sorisky, A; Ooi, T C; Simo, I E; Meuffels, M; Hindmarsh, J T; Nair, R

    1987-10-01

    We investigated the high density lipoprotein cholesterol (HDL-C) response in 20 middle-aged males during a 12-week course of gemfibrozil. Three aspects of the increase in HDL-C (25%) were studied and our observations are as follows: (1) subfraction analysis showed that HDL3-C rose earlier and to a larger extent (28%) than HDL2-C (15%), (2) analysis of variance group--time interaction effect and correlation studies of HDL-C and total triglycerides suggest the increase in HDL-C was due to a direct effect of gemfibrozil on HDL metabolism, and (3) HDL-C was the only one of 4 HDL components to increase. Apoprotein A-I (apo A-I) and HDL-phospholipid (HDL-PL) did not change, and HDL-triglyceride (HDL-TG) decreased. This pattern is consistent with a change in composition of HDL, i.e. cholesterol enrichment and triglyceride depletion. PMID:3118893

  4. Biominetic High Density Lipoproteins for the Delivery of Therapeutic Oligonucleotides

    NASA Astrophysics Data System (ADS)

    Tripathy, Sushant

    Advances in nanotechnology have brought about novel inorganic and hybrid nanoparticles with unique physico-chemical properties that make them suitable for a broad range of applications---from nano-circuitry to drug delivery. A significant part of those advancements have led to ground-breaking discoveries that have changed the approaches to formulation of therapeutics against diseases, such as cancer. Now-a-days the focus does not lie solely on finding a candidate small-molecule therapeutic with minimal adverse effects, but researchers are looking up to nanoparticles to improve biodistribution and biocompatibility profile of clinically proven therapeutics. The plethora of conjugation chemistries offered by currently extant inorganic nanoparticles have, in recent years, led to great leaps in the field of biomimicry---a modality that promises high biocompatibility. Further, in the pursuit of highly specific therapeutic molecules, researchers have turned to silencing oligonucleotides and some have already brought together the strengths of nanoparticles and silencing oligonucleotides in search of an efficacious therapy for cancer with minimal adverse effects. This dissertation work focuses on such a biomimetic platform---a gold nanoparticle based high density lipoprotein biomimetic (HDL NP), for the delivery of therapeutic oligonucleotides. The first chapter of this body of work introduces the molecular target of the silencing oligonucleotides---VEGFR2, and its role in the progression of solid tumor cancers. The background information also covers important aspects of natural high density lipoproteins (HDL), especially their innate capacity to bind and deliver exogenous and endogenous silencing oligonucleotides to tissues that express their high affinity receptor SRB1. We subsequently describe the synthesis of the biomimetic HDL NP and its oligonucleotide conjugates, and establish their biocompatibility. Further on, experimental data demonstrate the efficacy of silencing

  5. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis

    PubMed Central

    Ossoli, Alice; Pavanello, Chiara

    2016-01-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  6. High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis.

    PubMed

    Ossoli, Alice; Pavanello, Chiara; Calabresi, Laura

    2016-06-01

    Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system. PMID:27302716

  7. Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver.

    PubMed Central

    Hamilton, R L; Williams, M C; Fielding, C J; Havel, R J

    1976-01-01

    Rat livers were perfused for 6 h without added plasma proteins using washed erythrocytes and buffer in a recirculating system. An inhibitor to the enzyme lecithin-cholesterol acyltransferase (5,5'-dithionitrobenzoic acid) was added in some experiments to prevent modification of substrate-lipids contained in secreted lipoproteins. The inhibitor did not detectably alter hepatic ultrastructure or gas exchange, but it inhibited the secreted lecithin-cholesterol acyltransferase by more than 85%. Very low density lipoproteins in perfusate were unaltered but the high density lipoproteins obtained from livers perfused with the inhibitor appeared disk-shaped in negative stain by electron microscopy with a mean edge thickness of 46 +/- 5 A and a mean diameter of 190 +/- 25 A. The high density lipoproteins were composed predominantly of polar lipids and protein with only small amounts of cholesteryl esters and triglycerides. The major apoprotein of these discoidal fractions had the same electrophoretic mobility as the arginine-rich apoprotein, whereas plasma high density lipoproteins contained mainly the A-I approtein. In all these respects the discoidal perfusate high density lipoproteins closely resemble those found in human plasma which is deficient in lecithin-cholesterol acyltransferase. Perfusate high density lipoproteins obtained in the absence of the enzyme inhibitor more closely resembled plasma high density lipoproteins in chemical composition (content of cholesteryl esters and apoproteins) and in electron microscopic appearance. Purified lecithin-cholesterol acyltransferase synthesized cholesteryl esters at a substantially faster rate from substrate lipids of perfusate high density lipoproteins than those from plasma. The discoidal high density lipoproteins were the best substrate for this reaction. Thin sections of plasma high density lipoproteins indicated a spherical particle whereas discoidal high density lipoproteins stained with the characteristic trilaminar

  8. Distribution of High-Density Lipoprotein Subfractions and Hypertensive Status

    PubMed Central

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

    2015-01-01

    Abstract The exact mechanisms of hypertension contributing to atherosclerosis have not been fully elucidated. Although multiple studies have clarified the association with low-density lipoprotein (LDL) subfractions, uncertainty remains about its relationship with high-density lipoprotein (HDL) subfractions. Therefore, we aimed to comprehensively determine the relationship between distribution of HDL subfractions and hypertensive status. A total of 953 consecutive subjects without previous lipid-lowering drug treatment were enrolled and were categorized based on hypertension history (with hypertension [n = 550] or without hypertension [n = 403]). Baseline clinical and laboratory data were collected. HDL separation was performed using the Lipoprint System. Plasma large HDL-cholesterol (HDL-C) and large HDL percentage were dramatically lower whereas the small HDL-C and small HDL percentage were higher in patients with hypertension (all P < 0.05). The antihypertensive drug therapy was not associated with large or small HDL subfractions (on treatment vs not on treatment, P > 0.05; combination vs single drug therapy, P > 0.05). However, the blood pressure well-controlled patients have significantly lower small HDL subfraction (P < 0.05). Moreover, large HDL-C and percentage were inversely whereas small HDL percentage was positively associated with incident hypertension after adjusting potential confounders (all P < 0.05). In the multivariate model conducted in patients with and without hypertension separately, the cardio-protective value of large HDL-C was disappeared in patients with hypertension (OR 95%CI: 1.011 [0.974–1.049]). The distribution of HDL subfractions is closely associated with hypertensive status and hypertension may potentially impact the cardio-protective value of large HDL subfraction. PMID:26512616

  9. Proprotein convertases in high-density lipoprotein metabolism.

    PubMed

    Choi, Seungbum; Korstanje, Ron

    2013-01-01

    The proprotein convertase subtilisin/kexins (PCSKs) are a serine endopeptidase family. PCSK members cleave amino acid residues and modulate the activity of precursor proteins. Evidence from patients and animal models carrying genetic alterations in PCSK members show that PCSK members are involved in various metabolic processes. These studies further revealed the molecular mechanism by which genetic alteration of some PCSK members impairs normal molecular and physiological functions, which in turn lead to cardiovascular disease. High-density lipoprotein (HDL) is anti-atherogenic as it removes excessive amount of cholesterol from blood and peripheral tissues. Several PCSK members are involved in HDL metabolism. PCSK3, PCSK5, and PCSK6 process two triglyceride lipase family members, endothelial lipase and lipoprotein lipase, which are important for HDL remodeling. Recent studies in our lab found evidence that PCSK1 and PCSK9 are also involved in HDL metabolism. A mouse model carrying an amino acid substitution in PCSK1 showed an increase in serum apolipoprotein A1 (APOA1) level. Another mouse model lacking PCSK9 showed a decrease in APOE-containing HDL. In this review, we summarize the role of the five PCSK members in lipid, glucose, and bile acid (BA) metabolism, each of which can influence HDL metabolism. We propose an integrative model in which PCSK members regulate HDL metabolism through various molecular mechanisms and metabolic processes and genetic variation in some PCSK members may affect the efficiency of reverse cholesterol transport. PCSK members are considered as attractive therapeutic targets. A greater understanding of the molecular and physiological functions of PCSK members will improve therapeutic strategies and drug efficacy for cardiovascular disease where PCSK members play critical role, with fewer adverse effects. PMID:24252756

  10. High-density lipoprotein subpopulations in pathologic conditions.

    PubMed

    Asztalos, Bela F; Schaefer, Ernst J

    2003-04-01

    The role of low-density lipoprotein (LDL) cholesterol in coronary artery disease (CAD) and the impact of therapeutic agents on LDL cholesterol are well established. Less is known about the role of high-density lipoprotein (HDL) cholesterol and even less about the role of the different HDL subspecies in CAD. HDL particles vary in size and density, mainly because of differences in the number of apolipoprotein (apo) particles and the amount of cholesterol ester in the core of HDL. Apo A-I is essential and, together with lipid, sufficient for the formation of HDL particles. Apo A-I-containing HDL particles play a primary role in cholesterol efflux from membranes, at least in part through interactions with the adenosine triphosphate-binding cassette transporter A1 (ABCA1). Patients with Tangier disease have mutations in the gene encoding ABCA1, which result in functionally impaired protein, a marked deficiency in HDL cholesterol, and a high risk of premature CAD. Our studies of apo A-I-containing HDL subpopulations in various patient populations reveal that patients homozygous for Tangier disease have only the pre-beta(1) HDL subspecies. Tangier heterozygotes are severely depleted in the larger alpha- and pre-alpha-mobility subspecies. Patients with low HDL cholesterol levels and those with CAD also show deficiencies in the alpha(1) and pre-alpha(1-3) HDL subspecies. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) increase the levels of the large alpha(1) and pre-alpha(1) subpopulations and decrease the level of the small alpha(3) subpopulation. Thus, atorvastatin, for example, significantly moves the distribution of HDL particles toward normal, followed by simvastatin, pravastatin, and lovastatin in decreasing order of efficiency. A new statin, rosuvastatin, produces greater increases in HDL cholesterol than atorvastatin, but its effect on HDL particle distribution is yet to be determined. PMID:12679198

  11. Micro-RNAs and High-Density Lipoprotein Metabolism.

    PubMed

    Canfrán-Duque, Alberto; Lin, Chin-Sheng; Goedeke, Leigh; Suárez, Yajaira; Fernández-Hernando, Carlos

    2016-06-01

    Improved prevention and treatment of cardiovascular diseases is one of the challenges in Western societies, where ischemic heart disease and stroke are the leading cause of death. Early epidemiological studies have shown an inverse correlation between circulating high-density lipoprotein-cholesterol (HDL-C) and cardiovascular diseases. The cardioprotective effect of HDL is because of its ability to remove cholesterol from plaques in the artery wall to the liver for excretion by a process known as reverse cholesterol transport. Numerous studies have reported the role that micro-RNAs (miRNA) play in the regulation of the different steps in reverse cholesterol transport, including HDL biogenesis, cholesterol efflux, and cholesterol uptake in the liver and bile acid synthesis and secretion. Because of their ability to control different aspects of HDL metabolism and function, miRNAs have emerged as potential therapeutic targets to combat cardiovascular diseases. In this review, we summarize the recent advances in the miRNA-mediated control of HDL metabolism. We also discuss how HDL particles serve as carriers of miRNAs and the potential use of HDL-containing miRNAs as cardiovascular diseases biomarkers. PMID:27079881

  12. High Density Lipoprotein Cholesterol Increasing Therapy: The Unmet Cardiovascular Need

    PubMed Central

    Cimmino, Giovanni; Ciccarelli, Giovanni; Morello, Alberto; Ciccarelli, Michele; Golino, Paolo

    2015-01-01

    Despite aggressive strategies are now available to reduce LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. Several preclinical and clinical studies have shown that drug therapy ultimately leads to a regression of the angiographic lesions but also results in a reduction in cardiovascular events. The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein (CEPT) inhibitors, torcetrapib and dalcetrapib, has led to considerable doubt about the value of the current strategy to raise high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These clinical results, as well as animal studies, have revealed the complexity of HDL metabolism, assessing a more important role of functional quality compared to circulating quantity of HDL. As a result, HDL-based therapeutic interventions that maintain or enhance HDL functionality, such as improving its main property, the reverse cholesterol transport, require closer investigation. In this review, we will discuss HDL metabolism and function, clinical-trial data available for HDL-raising agents, and potential strategies for future HDL-based therapies. PMID:26535185

  13. Acrolein Impairs the Cholesterol Transport Functions of High Density Lipoproteins

    PubMed Central

    Chadwick, Alexandra C.; Holme, Rebecca L.; Chen, Yiliang; Thomas, Michael J.; Sorci-Thomas, Mary G.; Silverstein, Roy L.; Pritchard, Kirkwood A.; Sahoo, Daisy

    2015-01-01

    High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway. PMID:25849485

  14. High-density lipoprotein: a novel target for antirestenosis therapy.

    PubMed

    Yin, Kai; Agrawal, Devendra K

    2014-12-01

    Restenosis is an integral pathological process central to the recurrent vessel narrowing after interventional procedures. Although the mechanisms for restenosis are diverse in different pathological conditions, endothelial dysfunction, inflammation, vascular smooth muscle cell (SMC) proliferation, and myofibroblasts transition have been thought to play crucial role in the development of restenosis. Indeed, there is an inverse relationship between high-density lipoprotein (HDL) levels and risk for coronary heart disease (CHD). However, relatively studies on the direct assessment of HDL effect on restenosis are limited. In addition to involvement in the cholesterol reverse transport, many vascular protective effects of HDL, including protection of endothelium, antiinflammation, antithrombus actions, inhibition of SMC proliferation, and regulation by adventitial effects may contribute to the inhibition of restenosis, though the exact relationships between HDL and restenosis remain to be elucidated. This review summarizes the vascular protective effects of HDL, emphasizing the potential role of HDL in intimal hyperplasia and vascular remodeling, which may provide novel prophylactic and therapeutic strategies for antirestenosis. PMID:25043950

  15. High-density lipoprotein endocytosis in endothelial cells

    PubMed Central

    Fruhwürth, Stefanie; Pavelka, Margit; Bittman, Robert; Kovacs, Werner J; Walter, Katharina M; Röhrl, Clemens; Stangl, Herbert

    2013-01-01

    AIM: To describe the way stations of high-density lipoprotein (HDL) uptake and its lipid exchange in endothelial cells in vitro and in vivo. METHODS: A combination of fluorescence microscopy using novel fluorescent cholesterol surrogates and electron microscopy was used to analyze HDL endocytosis in great detail in primary human endothelial cells. Further, HDL uptake was quantified using radio-labeled HDL particles. To validate the in vitro findings mice were injected with fluorescently labeled HDL and particle uptake in the liver was analyzed using fluorescence microscopy. RESULTS: HDL uptake occurred via clathrin-coated pits, tubular endosomes and multivesicular bodies in human umbilical vein endothelial cells. During uptake and resecretion, HDL-derived cholesterol was exchanged at a faster rate than cholesteryl oleate, resembling the HDL particle pathway seen in hepatic cells. In addition, lysosomes were not involved in this process and thus HDL degradation was not detectable. In vivo, we found HDL mainly localized in mouse hepatic endothelial cells. HDL was not detected in parenchymal liver cells, indicating that lipid transfer from HDL to hepatocytes occurs primarily via scavenger receptor, class B, type I mediated selective uptake without concomitant HDL endocytosis. CONCLUSION: HDL endocytosis occurs via clathrin-coated pits, tubular endosomes and multivesicular bodies in human endothelial cells. Mouse endothelial cells showed a similar HDL uptake pattern in vivo indicating that the endothelium is one major site of HDL endocytosis and transcytosis. PMID:24340136

  16. High-density lipoprotein and inflammation in cardiovascular disease.

    PubMed

    Connelly, Margery A; Shalaurova, Irina; Otvos, James D

    2016-07-01

    Great advances are being made at the mechanistic level in the understanding of the structural and functional diversity of high-density lipoprotein (HDL). HDL particle subspecies of different sizes are now known to differ in the protein and lipid cargo they transport, conferring on them the ability to perform different functions that in aggregate would be expected to provide protection against the development of atherosclerosis and its downstream clinical consequences. Exacerbating what is already a very complex system is the finding that inflammation, via alteration of the proteomic and lipidomic composition of HDL subspecies, can modulate at least some of their functional activities. In contrast to the progress being made at the mechanistic level, HDL epidemiologic research has lagged behind, largely because the simple HDL biomarkers used (mainly just HDL cholesterol) lack the needed complexity. To address this deficiency, analyses will need to use multiple HDL subspecies and be conducted in such a way as to eliminate potential sources of confounding. To help account for the modulating influence of inflammation, effective use must also be made of inflammatory biomarkers including searching systematically for HDL-inflammation interactions. Using nuclear magnetic resonance (NMR)-measured HDL subclass data and a novel NMR-derived inflammatory biomarker, GlycA, we offer a case study example of the type of analytic approach considered necessary to advance HDL epidemiologic understanding. PMID:26850902

  17. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease and blood triglycerides reflect key metabolic processes including sensitivity to insulin. Blood lipoprotein and lipid concentrations are heritable. To date, the identification o...

  18. Myeloperoxidase-mediated oxidation of high-density lipoproteins: fingerprints of newly recognized potential proatherogenic lipoproteins.

    PubMed

    Malle, Ernst; Marsche, Gunther; Panzenboeck, Ute; Sattler, Wolfgang

    2006-01-15

    Substantial evidence supports the notion that oxidative processes participate in the pathogenesis of atherosclerotic heart disease. Major evidence for myeloperoxidase (MPO) as enzymatic catalyst for oxidative modification of lipoproteins in the artery wall has been suggested in numerous studies performed with low-density lipoprotein. In contrast to low-density lipoprotein, plasma levels of high-density lipoprotein (HDL)-cholesterol and apoAI, the major apolipoprotein of HDL, inversely correlate with the risk of developing coronary artery disease. These antiatherosclerotic effects are attributed mainly to HDL's capacity to transport excess cholesterol from arterial wall cells to the liver during 'reverse cholesterol transport'. There is now strong evidence that HDL is a selective in vivo target for MPO-catalyzed oxidation impairing the cardioprotective and antiinflammatory capacity of this antiatherogenic lipoprotein. MPO is enzymatically active in human lesion material and was found to be associated with HDL extracted from human atheroma. MPO-catalyzed oxidation products are highly enriched in circulating HDL from individuals with cardiovascular disease where MPO concentrations are also increased. The oxidative potential of MPO involves an array of intermediate-generated reactive oxygen and reactive nitrogen species and the ability of MPO to generate chlorinating oxidants-in particular hypochlorous acid/hypochlorite-under physiological conditions is a unique and defining activity for this enzyme. All these MPO-generated reactive products may affect structure and function of HDL as well as the activity of HDL-associated enzymes involved in conversion and remodeling of the lipoprotein particle, and represent clinically useful markers for atherosclerosis. PMID:16171772

  19. Itinerary of high density lipoproteins in endothelial cells.

    PubMed

    Perisa, Damir; Rohrer, Lucia; Kaech, Andres; von Eckardstein, Arnold

    2016-02-01

    High density lipoprotein (HDL) and its main protein component apolipoprotein A-I (ApoA-I) have multiple anti-atherogenic functions. Some of them are exerted within the vessel wall, so that HDL needs to pass the endothelial barrier. To elucidate their itinerary through endothelial cells (ECs), we labelled ApoA-I and HDL either fluorescently or with 1.4 nm nanogold and investigated their cellular localization by using immunofluorescent microscopy (IFM) and electron microscopy (EM). HDL as well as ApoA-I is taken up by ECs into the same route of intracellular trafficking. Time kinetics and pulse chase experiments revealed that HDL is trafficked through different vesicles. HDL partially co-localized with LDL, albumin, and transferrin. HDL did not co-localize with clathrin and caveolin-1. Fluorescent HDL was recovered at small proportions in early endosomes and endosome to trans-golgi network vesicles but not at all in recycling endosomes, in late endosomes or lysosomes. EM identified HDL mainly in large filled vesicles which however upon IFM did not colocalize with markers of multivesicular bodies or autophagosomes. The uptake or cellular distribution of HDL was altered upon pharmacological interference with cytochalasine D, colchicine and dynasore. Blockage of fluid phase uptake with Amiloride or EIPA did not reduce the uptake of HDL. Neither did we observe any co-localization of HDL with dextran as the marker of fluid phase uptake. In conclusion, HDL and ApoA-I are internalized and trafficked by endothelial cells through a non-classical endocytic route. PMID:26577406

  20. High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms.

    PubMed

    White, C Roger; Giordano, Samantha; Anantharamaiah, G M

    2016-09-01

    Ischemic injury is associated with acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting and open heart surgery. The timely re-establishment of blood flow is critical in order to minimize cardiac complications. Reperfusion after a prolonged ischemic period, however, can induce severe cardiomyocyte dysfunction with mitochondria serving as a major target of ischemia/reperfusion (I/R) injury. An increase in the formation of reactive oxygen species (ROS) induces damage to mitochondrial respiratory complexes leading to uncoupling of oxidative phosphorylation. Mitochondrial membrane perturbations also contribute to calcium overload, opening of the mitochondrial permeability transition pore (mPTP) and the release of apoptotic mediators into the cytoplasm. Clinical and experimental studies show that ischemic preconditioning (ICPRE) and postconditioning (ICPOST) attenuate mitochondrial injury and improve cardiac function in the context of I/R injury. This is achieved by the activation of two principal cell survival cascades: 1) the Reperfusion Injury Salvage Kinase (RISK) pathway; and 2) the Survivor Activating Factor Enhancement (SAFE) pathway. Recent data suggest that high density lipoprotein (HDL) mimics the effects of conditioning protocols and attenuates myocardial I/R injury via activation of the RISK and SAFE signaling cascades. In this review, we discuss the roles of apolipoproteinA-I (apoA-I), the major protein constituent of HDL, and sphingosine 1-phosphate (S1P), a lysosphingolipid associated with small, dense HDL particles as mediators of cardiomyocyte survival. Both apoA-I and S1P exert an infarct-sparing effect by preventing ROS-dependent injury and inhibiting the opening of the mPTP. PMID:27150975

  1. Speciated Human High Density Lipoprotein Protein Proximity Profiles†

    PubMed Central

    Gauthamadasa, Kekulawalage; Rosales, Corina; Pownall, Henry J.; Macha, Stephen; Jerome, W. Gray; Huang, Rong; Silva, R. A.Gangani. D.

    2010-01-01

    It is expected that the attendant structural heterogeneity of human high density lipoprotein (HDL) complexes is a determinant of its varied metabolic functions. To determine structural heterogeneity of HDL, major apolipoprotein stoichiometry profiles in human HDL were determined. First, HDL was separated into two main populations, with and without apolipoprotein (apo) A-II, LpA-I and LpA-I/A-II respectively. Each main population was further separated into six individual subfractions using size exclusion chromatography (SEC). Protein proximity profiles (PPP) of major apolipoproteins in each individual subfraction was determined by optimally cross-linking apolipoproteins within individual particles with bis(sulfosuccinimidyl)suberate (BS3), a bifunctional cross linker, followed by molecular weight determination by MALDI-MS. The PPPs of LpA-I subfractions indicated that the number of apoA-I molecules increased from two to three to four upon increase in the LpA-I particle size. On the other hand, the entire population of LpA-I/A-II demonstrated the presence of only two proximal apoA-I molecules per particle, while the number of apoA-II molecules varied from one dimeric apoA-II to two and then to three. For most of the above PPP profiles, an additional population that contained a single molecule of apoC-III in addition to apoA-I and/or apoA-II was detected. Upon composition analyses of individual subpopulations, LpA-I/A-II displayed comparable proportions for total protein (~58%), phospholipids (~21%) total cholesterol (~16%), triglycerides (~5%) and free cholesterol (~4%) across subfractions. LpA-I components, on the other hand, showed significant variability. This novel information on HDL subfractions will form a basis for better understanding particle specific functions of HDL. PMID:21073165

  2. Biomimetic High-Density Lipoproteins from a Gold Nanoparticle Template

    NASA Astrophysics Data System (ADS)

    Luthi, Andrea Jane

    For hundreds of years the field of chemistry has looked to nature for inspiration and insight to develop novel solutions for the treatment of human diseases. The ability of chemists to identify, mimic, and modifiy small molecules found in nature has led to the discovery and development of many important therapeutics. Chemistry on the nanoscale has made it possible to mimic natural, macromolecular structures that may also be useful for understanding and treating diseases. One example of such a structure is high-density lipoprotein (HDL). The goal of this work is to use a gold nanoparticle (Au NP) as a template to synthesize functional mimics of HDL and characterize their structure and function. Chapter 1 details the structure and function of natural HDL and how chemistry on the nanoscale provides new strategies for mimicking HDL. This Chapter also describes the first examples of using nanoparticles to mimic HDL. Chapter 2 reports the synthesis and characterization of biomimetic HDL using different sizes of Au NPs and different surface chemistries and how these variables can be used to tailor the properties of biomimetic HDL. From these studies the optimal strategy for synthesizing biomimetic HDL was determined. In Chapter 3, the optimization of the synthesis of biomimetic HDL is discussed as well as a full characterization of its structure. In addition, the work in this chapter shows that biomimetic HDL can be synthesized on a large scale without alterations to its structure or function. Chapter 4 focuses on understanding the pathways by which biomimetic HDL accepts cholesterol from macrophage cells. The results of these studies demonstrate that biomimetic HDL is able to accept cholesterol by both active and passive pathways of cholesterol efflux. In Chapter 5 the preliminary results of in vivo studies to characterize the pharmacokinetics and pharmacodynamics of biomimetic HDL are presented. These studies suggest that biomimetic HDL traffics through tissues prone to

  3. High-density lipoprotein proteome dynamics in human endotoxemia

    PubMed Central

    2011-01-01

    Background A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome. Results Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants. Conclusions

  4. High-Density Lipoprotein - A Hero, a Mirage, or a Witness?

    PubMed

    Sviridov, Dmitri

    2014-01-01

    Negative relationship between plasma high-density lipoprotein (HDL) levels and risk of cardiovascular disease (CVD) is a firmly established medical fact, but attempts to reproduce protective properties of HDL by pharmacologically elevating HDL levels were mostly unsuccessful. This conundrum presents a fundamental question: were the approaches used to raise HDL flawed or the protective effects of HDL are an epiphenomenon? Recent attempts to elevate plasma HDL were universally based on reducing HDL catabolism by blocking reverse cholesterol transport (RCT). Here, we argue that this mode of HDL elevation may be mechanistically different to natural mechanisms and thus be counterproductive. We further argue that independently of whether HDL is a driving force or a surrogate measure of the rate of RCT, approaches aimed at increasing HDL supply, rather than reducing its catabolism, would be most beneficial for speeding up RCT and improving protection against CVD. PMID:26664860

  5. High-Density Lipoprotein – A Hero, a Mirage, or a Witness?

    PubMed Central

    Sviridov, Dmitri

    2014-01-01

    Negative relationship between plasma high-density lipoprotein (HDL) levels and risk of cardiovascular disease (CVD) is a firmly established medical fact, but attempts to reproduce protective properties of HDL by pharmacologically elevating HDL levels were mostly unsuccessful. This conundrum presents a fundamental question: were the approaches used to raise HDL flawed or the protective effects of HDL are an epiphenomenon? Recent attempts to elevate plasma HDL were universally based on reducing HDL catabolism by blocking reverse cholesterol transport (RCT). Here, we argue that this mode of HDL elevation may be mechanistically different to natural mechanisms and thus be counterproductive. We further argue that independently of whether HDL is a driving force or a surrogate measure of the rate of RCT, approaches aimed at increasing HDL supply, rather than reducing its catabolism, would be most beneficial for speeding up RCT and improving protection against CVD. PMID:26664860

  6. High-density lipoprotein cholesterol on a roller coaster: where will the ride end?

    PubMed

    Kronenberg, Florian

    2016-04-01

    Bowe et al. report an association between low high-density lipoprotein cholesterol concentrations and various incident chronic kidney disease end points in a cohort of almost 2 million US veterans followed for 9 years. These impressive data should be a starting point for further investigations including genetic epidemiologic investigations as well as post hoc analyses of interventional trials that target high-density lipoprotein cholesterol and, finally, studies that focus on the functionality of high-density lipoprotein particles. PMID:26994572

  7. Current guidelines for high-density lipoprotein cholesterol in therapy and future directions

    PubMed Central

    Subedi, Bishnu H; Joshi, Parag H; Jones, Steven R; Martin, Seth S; Blaha, Michael J; Michos, Erin D

    2014-01-01

    Many studies have suggested that a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) is low high-density lipoprotein cholesterol (HDL-C). Therefore, increasing HDL-C with therapeutic agents has been considered an attractive strategy. In the prestatin era, fibrates and niacin monotherapy, which cause modest increases in HDL-C, reduced ASCVD events. Since their introduction, statins have become the cornerstone of lipoprotein therapy, the benefits of which are primarily attributed to decrease in low-density lipoprotein cholesterol. Findings from several randomized trials involving niacin or cholesteryl ester transfer protein inhibitors have challenged the concept that a quantitative elevation of plasma HDL-C will uniformly translate into ASCVD benefits. Consequently, the HDL, or more correctly, HDL-C hypothesis has become more controversial. There are no clear guidelines thus far for targeting HDL-C or HDL due to lack of solid outcomes data for HDL specific therapies. HDL-C levels are only one marker of HDL out of its several structural or functional properties. Novel approaches are ongoing in developing and assessing agents that closely mimic the structure of natural HDL or replicate its various functions, for example, reverse cholesterol transport, vasodilation, anti-inflammation, or inhibition of platelet aggregation. Potential new approaches like HDL infusions, delipidated HDL, liver X receptor agonists, Apo A-I upregulators, Apo A mimetics, and gene therapy are in early phase trials. This review will outline current therapies and describe future directions for HDL therapeutics. PMID:24748800

  8. Isolation and Characterization of an Abnormal High Density Lipoprotein in Tangier Disease

    PubMed Central

    Assmann, Gerd; Herbert, Peter N.; Fredrickson, Donald S.; Forte, Trudy

    1977-01-01

    The nature of the high density lipoproteins has been investigated in five patients homozygous for Tangier disease (familial high density lipoprotein deficiency). It has been established that Tangier high density lipoproteins, as isolated by ultracentrifugation, are morphologically heterogenous and contain several proteins (Apo B, albumin, and Apo A-II). An abnormal lipoprotein has been isolated from the d = 1.063-1.21 g/ml ultracentrifugal fraction by agarose-column chromatography which contains apoprotein A-II as the sole protein constituent. In negative-stain electron microscopy, these lipoproteins appeared as spherical particles 55-75 Å in diameter. By a variety of criteria (immunochemical, polyacrylamide electrophoresis, amino acid composition, and fluorescence measurements), apoprotein A-I the major apoprotein of normal high density lipoproteins and the C apoproteins were absent from this lipoprotein. As demonstrated by 125I very low density lipoprotein incubation experiments with Tangier plasma, C apoproteins did not associate with lipoproteins of d = 1.063-1.21 g/ml. Tangier apoprotein A-II, isolated to homogeneity by delipidation of the apoprotein A-II-containing lipoprotein or Sephadex G-200 guanidine-HCl chromatography of the d = 1.063-1.21 g/ml fraction, was indistinguishable from control apoprotein A-II with respect to amino acid composition and migration of tryptic peptides in urea-polyacrylamide electrophoresis. The ability of Tangier apoprotein A-II to bind phospholipid was demonstrated by in vitro reconstitution experiments and morphological and chemical analysis of lipid-protein complexes. It is concluded that normal high density lipoproteins, as defined by polypeptide composition and morphological appearance, are absent from Tangier plasma and that as a consequence, the impairment of C apoprotein metabolism contributes to the hypertriglyceridemia and fasting chylomicronemia observed in these patients. Images PMID:194920

  9. Effects of high-density lipoproteins on storage at 4 degrees C of fowl spermatozoa.

    PubMed

    Blesbois, E; Hermier, D

    1990-11-01

    Qualitative and quantitative characterization of lipoproteins found in seminal plasma from domestic cocks was performed after isolation by density gradient ultracentrifugation. Trigyceride-rich lipoproteins (very low, intermediate- and low density lipoproteins) were not detectable in seminal plasma. High-density lipoproteins (HDL), identified on the basis of size, chemical composition and protein moiety, were present at a concentration of 66 micrograms/ml. A fraction possibly corresponding to VHDL (very high density lipoproteins, 77% protein, 23% lipid) was also detected but appeared contaminated by a protein-rich opalescent material. Since HDL contains mostly phospholipid and cholesterol, the physiological role of these lipoproteins on the storage of fowl spermatozoa was studied. Replacing seminal plasma with a solution containing chicken HDL at physiological concentration (66 micrograms/ml) had no effect on fertilizing ability of spermatozoa stored at 4 degrees C for 24 h. However, higher concentrations of HDL (560 micrograms/ml) had deleterious effects on spermatozoa stored in vitro. PMID:2250247

  10. Characterization of high density lipoproteins in patients heterozygous for Tangier disease.

    PubMed Central

    Assmann, G; Simantke, O; Schaefer, H E; Smootz, E

    1977-01-01

    In this study a large family group affectd with Tangier disease has been investigated. Besides two homozygous propositi, several heterozygous patients have been identified on the basis of quantitative measurements of high density lipoproteins and their constitutive polypeptides. By a variety of quantitative immunological methods, such as one-dimensional Laurell eletrophoresis, two-dimensional immunoelectrophoresis, and double-antibody radioimmunoassay, the total amount of apoprotein A-I and apoprotein A-I contained in the serum of heterozygous patients and the distribution of these A apoproteins among serum lipoproteins have been determined. The molar ration of apoprotein A-I and apoprotein A-II contained in high density lipoproteins of heterozygous patients did not significantly differ from that of control preparations, although the total mass of high density lipoproteins was reduced by approximately 50%. The elution profile of high density lipoproteins from agarose columns and their morphological appearance, as ascertained by electron microscopy, were similar to control preparations. In addition to the quantitative alterations of serum lipoproteins, lipid storage in histiocytes of the rectal mucosa obtained from heterozygous patients has been documented. It is concluded that patients heterozygous for Tangier disease have normal high density lipoproteins in circulation, the total mass of which is reduced by approximately 50%. Images PMID:198431

  11. Total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol and coronary heart disease in Scotland.

    PubMed Central

    Hargreaves, A D; Logan, R L; Thomson, M; Elton, R A; Oliver, M F; Riemersma, R A

    1991-01-01

    OBJECTIVE--To investigate long term changes in total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations and in measures of other risk factors for coronary heart disease and to assess their importance for the development of coronary heart disease in Scottish men. DESIGN--Longitudinal study entailing follow up in 1988-9 of men investigated during a study in 1976. SETTING--Edinburgh, Scotland. SUBJECTS--107 men from Edinburgh who had taken part in a comparative study of risk factors for heart disease with Swedish men in 1976 when aged 40. INTERVENTION--The men were invited to attend a follow up clinic in 1988-9 for measurement of cholesterol concentrations and other risk factor measurements. Eighty three attended and 24 refused to or could not attend. MAIN OUTCOME MEASURES--Changes in total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations, body weight, weight to height index, prevalence of smoking, and alcohol intake; number of coronary artery disease events. RESULTS--Mean serum total cholesterol concentration increased over the 12 years mainly due to an increase in the low density lipoprotein cholesterol fraction (from 3.53 (SD 0.09) to 4.56 (0.11) mmol/l) despite a reduction in high density lipoprotein cholesterol concentration. Body weight and weight to height index increased. Fewer men smoked more than 15 cigarettes/day in 1988-9 than in 1976. Blood pressure remained stable and fasting triglyceride concentrations did not change. The frequency of corneal arcus doubled. Alcohol consumption decreased significantly. Eleven men developed clinical coronary heart disease. High low density lipoprotein and low high density lipoprotein cholesterol concentrations in 1976, but not total cholesterol concentration, significantly predicted coronary heart disease (p = 0.05). Almost all of the men who developed coronary heart disease were smokers (91% v 53%, p less than

  12. Alterations of high density lipoprotein subclasses in obese subjects.

    PubMed

    Tian, Li; Jia, Lianqun; Mingde, Fu; Tian, Ying; Xu, Yanhua; Tian, Haoming; Yang, Yuye

    2006-08-01

    The object of this study was to investigate the characteristics of lipid metabolism in obese subjects, with particular emphasis on the alteration of HDL subclass contents and distributions. A population of 581 Chinese individuals was divided into four groups (25 underweight subjects, 288 of desirable weight, 187 overweight, and 45 obese) according to body mass index (BMI). Apoprotein A-I (apoA-I) contents of plasma HDL sub-classes were determined by 2-D gel electrophoresis associated with an immunodetection method. The concentrations of TG and the apoA-I content of pre-beta 1-HDL were significantly higher (P < 0.01 and P < 0.01, respectively), but the levels of HDL cholesterol, and the apoA-I contents of HDL2a and HDL2b were significantly lower (P < 0.01, P < 0.05, and P < 0.01, respectively) in obese subjects than in subjects having a desirable weight. Moreover, with the elevation of BMI, small-sized pre-beta 1-HDL increased gradually and significantly, whereas large-sized HDL2b decreased gradually and significantly. Meanwhile, the variations in HDL subclass distribution were more obvious with the elevation of TG levels in obese as well as overweight subjects. In addition, Pearson correlation analysis revealed that BMI and TG levels were positively correlated with pre-beta 1-HDL but negatively correlated with HDL2b. Multiple regression analysis also showed that TG concentrations were associated independently and positively with high pre-beta 1-HDL and independently and negatively with low HDL2b in obese and overweight subjects. The HDL particle size was smaller in obese and overweight subjects. The shift to smaller size was more obvious with the elevation of BMI and TG, especially TG levels. These observations, in turn, indicated that HDL maturation might be abnormal, and reverse cholesterol transport might be impaired. PMID:17120933

  13. Enhanced delivery of lipophilic nutrients to the infant brain via high density lipoprotein.

    PubMed

    Naberhuis, J K; Lai, C-S

    2015-11-01

    Lipoproteins are the primary carriers of lipophilic cognitive nutrients such as docosahexaenoic acid, lutein, and α-tocopherol within circulation. The critical roles these nutrients play in growth and development are well established, and as such, their efficient delivery to the infant brain is crucial. Given the selectivity of the blood brain barrier, the lipoprotein fraction primarily responsible for brain delivery of these nutrients must be determined so that efforts aimed at increasing brain nutrient uptake, via lipoprotein profile manipulation, can be appropriately focused. Based on the preclinical and clinical data reviewed here, we hypothesize that high density lipoprotein is the fraction chiefly responsible for delivery of docosahexaenoic acid, lutein, and α-tocopherol to the infant brain. As high density lipoprotein levels tend to be lower in preterm, formula-fed infants as compared to their full-term, breast-fed counterparts, efforts aimed at increasing circulating high density lipoprotein levels, and subsequent delivery of cognitive lipophilic nutrients to the brain via manipulation of formula composition, may be most effective if targeted to this group. These efforts include (1) limiting the polyunsaturated: saturated fatty acid ratio; (2) increasing the casein: whey ratio; (3) altering the proportion of saturated fatty acids found in the sn-2 position of the parent triglyceride; (4) cholesterol supplementation; and (5) nucleotide supplementation. PMID:26323246

  14. [THE BECOMING IN PHYLOGENESIS OF TRANSFER IN INTERCELLULAR MEDIUM AND ACTIVE ABSORPTION OF POLYENOIC FATTY ACIDS BY CELLS SEQUENTIALLY OF HIGH DENSITY LIPOPROTEINS, LOW DENSITY LIPOPROTEINS AND HIGH DENSITY APOE-LIPOPROTEINS].

    PubMed

    Titov, V N

    2015-06-01

    After more than half-century of different conceptions, the theory of general pathology was used to substantiate that all lipoproteins are bi-layer:lipid by their structure. The main function of high density lipoproteins as of all lipoproteins is transfer of fatty acids to cells and only in second turn taking away of spirit cholesterol from cells. At the stages of phylogenesis high density lipoproteins, low density lipoproteins and very low density lipoproteins began to function in a subsequent way. The fatty acids were transferred by low density lipoproteins in polar lipids at passive absorption by cells. Later on, lipoproteins transfer fatty acids in non-polar ethers with spirits glycerin and spirit cholesterol. The cells absorb them by receptor endocytosis. The hepatocytes secret in blood palmitic, oleic, linoleic and linoleic very low density lipoproteins. The palmitic and oleic very low density lipoproteins absorb physiologically insulin-dependent cells apoE/B-100 = endocytosis. The linoleic and linoleic very low density lipoproteins after transition of polyethers cholesterol from high density lipoproteins turn into low density lipoproteins. The cells absorb them by apoB-100 = endocytosis. The formation of chylomicrons occurs in blood and hepatocytes absorb them by the way of apoB/E-48 = endocytosis. The absorption of poly-unsaturated fatty acids by cells with apoB-100 = endocytosis form sensitivity of animals to exogenous hyper spirit cholesterol and absorption of poly-unsaturated fatty acids by apoE/A-I = receptors form corresponding resistance. The ApoE in lipoproteins form cooperative ligands--apoE/B-48 for chylomicrons, apoE/B-100 for very low density lipoproteins and apoE/A-I for high density lipoproteins. The chylomicrons in blood form apoB-48 from complexes of triglycerides secreted by enterocytes. These views change conceptions of pathogenesis and prevention of atherosclerosis, metabolic syndrome and resistance to insulin whose pathogenesis is unified

  15. 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

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

    PubMed

    Rysz-Górzyńska, Magdalena; Banach, Maciej

    2016-08-01

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

  17. Purification of very high density lipoproteins by differential density gradient ultracentrifugation.

    PubMed

    Haunerland, N H; Ryan, R O; Law, J H; Bowers, W S

    1987-03-01

    Differential density gradient ultracentrifugation procedures, utilizing a vertical rotor, were developed for the preparative purification of very high density lipoproteins (VHDL, density greater than 1.21 g/ml). The VHDLs of several insect species were purified as follows. An initial density gradient ultracentrifugation step removed lipoproteins of lower density from the VHDL-fraction, which partially separated from the nonlipoproteins present in the infranatant. A complete separation was achieved by a second centrifugation step employing a modified gradient system. The use of a vertical rotor and specially designed discontinuous gradients allows a relatively fast, efficient, and economical isolation of the class of very high density lipoproteins. Similar gradient systems should be useful for the detection and purification of VHDLs from other sources. PMID:3578796

  18. The myeloperoxidase product hypochlorous acid generates irreversible high-density lipoprotein receptor inhibitors

    PubMed Central

    Binder, Veronika; Ljubojevic, Senka; Haybaeck, Johannes; Holzer, Michael; El-Gamal, Dalia; Schicho, Rudolf; Pieske, Burkert; Heinemann, Akos; Marsche, Gunther

    2014-01-01

    Objective Elevated levels of advanced oxidation protein products (AOPPs) have been described in several chronic inflammatory diseases, like chronic renal insufficiency, rheumatoid arthritis and atherosclerosis. Recent findings revealed that AOPPs are inhibitors of the major high-density lipoprotein (HDL) receptor, scavenger receptor class B, type 1 (SR-BI). Here we investigated what oxidation induced structural alterations convert plasma albumin into an HDL-receptor inhibitor. Approach and Results Exposure of albumin to the physiological oxidant, hypochlorous acid, generated high affinity SR-BI ligands. Protection of albumin lysine-residues prior exposure to hypochlorous acid as well as regeneration of N-chloramines after oxidation of albumin completely prevented binding of oxidized albumin to SR-BI, indicating that modification of albumin lysine-residues is required to generate SR-BI ligands. Of particular interest, N-chloramines within oxidized albumin promoted irreversible binding to SR-BI, resulting in permanent receptor blockade. We observed that the SR-BI inhibitory activity of albumin isolated from chronic kidney disease patients correlated with the content of the myeloperoxidase-specific oxidation product 3-chlorotyrosine and was associated with alterations in the composition of HDL. Conclusion Given that several potential atheroprotective activities of HDL are mediated by SR-BI, the present results raise the possibility that oxidized plasma albumin, through permanent SR-BI blockade, contributes to the pathophysiology of cardiovascular disease. PMID:23493288

  19. Investigations on the transport and metabolism of high density lipoprotein cholesteryl esters in African green monkeys

    SciTech Connect

    Sorci-Thomas, M.G.

    1984-01-01

    The metabolic fate of circulating high density lipoprotein cholesteryl esters was studied in African green monkeys to determine the significance of the lipid transfer reaction on the catabolism of lipoprotein cholesteryl esters. A method of doubly labeling both moieties of lipoprotein cholesteryl esters with (/sup 3/He)cholesteryl oleate and cholesteryl (/sup 14/C)oleate was developed for the purpose of studying plasma cholesteryl ester metabolism in vivo. In these studies the total plasma (/sup 3/He)cholesterol turnover resulted in production rates, which ranged from 10-17 mg/kg day, similar to previously reported values in African green monkeys and in normal lipoproteinemic humans. In contrast to the production rates calculated from the decay of plasma /sup 3/He-radioactivity, the production rates calculated from lipoproteins labeled with cholesteryl (/sup 14/C)oleate were approximately 2-3 times greater. In addition to these studies, a plasma cholesteryl ester transacylation activity was demonstrated in vitro when HDL containing doubly labeled cholesteryl esters were incubated with fresh plasma. These results demonstrated that high density lipoprotein cholesteryl esters undergo transacylation in vitro, resulting in release and reesterification of free (/sup 3/H)cholesterol.

  20. A very-high-density lipoprotein with clotting ability from hemolymph of sand crayfish, Ibacus ciliatus.

    PubMed

    Komatsu, M; Ando, S

    1998-03-01

    A very-high-density lipoprotein (VHDL) with a density of 1.27-1.29 g/ml was the most abundant lipoprotein in the hemolymph of the sand crayfish Ibacus ciliatus. The VHDL isolated by a density gradient ultracentrifugation consisted of 94% protein and 6% lipid reflecting its high density, and phospholipid was a predominant lipid component. The VHDL had an apolipoprotein of molecular mass 195 kDa and its N-terminal amino acid sequence was identified as follows: LQPGLEYQYRYNGRVAA. This sequence was similar to those of clotting proteins from the spiny lobster Panulirus interruptus and the freshwater crayfish Pacifastacus leniusculus. Transglutaminase and Ca2+ also induced the VHDL to clot. Considering large amounts of VHDL in the hemolymph of sand crayfish, the VHDL not only functions as lipid carrier but plays an important role in the defense process of crustacea. PMID:9571775

  1. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High--Density Lipoprotein Intervention Trial.

    PubMed

    Boden, W E

    2000-12-21

    The Framingham Heart Study found that high-density lipoprotein cholesterol (HDL-C) was the most potent lipid predictor of coronary artery disease risk in men and women >49 years of age. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), in which subjects were randomized to treatment with lovastatin or placebo, also reported a striking benefit of treatment, particularly in patients with HDL-C < or =35 mg/dL at baseline. Treatment with lovastatin was associated with a remarkable 45% reduction in events for this group. The Veterans Affairs HDL Intervention Trial (VA-HIT) randomized subjects to gemfibrozil or placebo. A high proportion of enrolled subjects with low HDL-C also had characteristics of the dysmetabolic syndrome. HDL-C likewise increased by 6% on treatment, total cholesterol was reduced by 4% and triglycerides by 31%. There was no change in low-density lipoprotein cholesterol (LDL-C) levels. These changes in lipid were associated with a cumulative 22% reduction in the trial primary endpoint of all-cause mortality and nonfatal myocardial infarction (MI). Additionally, significant reductions in secondary endpoints including death from coronary artery disease, nonfatal MI, stroke, transient ischemic attack, and carotid endarterectomy were associated with the increase in HDL-C. In VA-HIT, for every 1% increase in HDL-C, there was a 3% reduction in death or MI, a therapeutic benefit that eclipses the benefit associated with LDL-C reduction. PMID:11374850

  2. Modified low-density lipoproteins and high-density lipoproteins. From investigation tools to real in vivo players.

    PubMed

    Koller, Elisabeth; Volf, Ivo; Gurvitz, Aner; Koller, Franz

    2006-01-01

    It has long been known that the oxidative state of the various plasma lipoproteins modulates platelet aggregability, thereby contributing to atherogenesis. Low-density lipoprotein (LDL), occurring in vivo both in the native and oxidised forms, interacts directly with platelets, by binding to specific receptors. While the identity of the receptors for native LDL and some subfractions of high-density lipoproteins (HDL) remains disputed, apoE-containing HDL(2) binds to LRP8. The nature of these interactions as well as the distinction between candidate receptor proteins was elucidated using covalently modified apolipoproteins, which pointed to the participation of apolipoproteins in high affinity binding. However, the platelet effects initiated by binding of native lipoproteins remain controversial. Some of this ambiguity can be traced to the fact that native LDL inevitably undergoes substantial oxidisation upon modification, including by radiolabelling. The platelet-activating effects provoked by oxidised LDL are irrefutable, but many details remain unknown. The role of CD36 in platelet binding by oxidised LDL is well established, although additional receptors may exist. Much less is known about the interaction of oxidised HDL with platelets, since platelet activation was observed in some, but not all studies. Various frequently applied in vitro oxidation methods produce modified lipoprotein species that may not be relevant in vivo. Based on the reported modifications obtained by in vitro oxidation of LDL, early investigations focused mainly on the formation and the eventual effects of oxidised lipids. More recently, alterations to lipoproteins performed using hypochloric acid and myeloperoxidase redirected the attention to the role of modified apoproteins in triggering platelet responses. PMID:16877881

  3. Distribution of Brevetoxin (PbTx-3) in Mouse Plasma: Association with High-Density Lipoproteins

    PubMed Central

    Woofter, Ricky T.; Spiess, Page C.; Ramsdell, John S.

    2005-01-01

    We investigated the brevetoxin congener PbTx-3 to determine its distribution among carrier proteins, including albumin and blood lipoproteins. Using a radiolabeled brevetoxin tracer (PbTx-3), we found that 39% of the radiolabel remained associated with components in mouse plasma after > 15 kDa cutoff dialysis. Of this portion, only 6.8% was bound to serum albumin. We also examined the binding of brevetoxin to various lipoprotein fractions. Plasma, either spiked with PbTx-3 or from mice treated for 30 min with PbTx-3, was fractionated into different-sized lipoproteins by iodixanol gradient ultracentrifugation. Each fraction was then characterized and quantified by agarose gel electrophoresis and brevetoxin radioimmunoassay, respectively. In both the in vitro and in vivo experiments, the majority of brevetoxin immunoreactivity was restricted to only those gradient fractions that contained high-density lipoproteins (HDLs). Independent confirmation of brevetoxin binding to HDLs was provided by high molecular weight (100 kDa cutoff) dialysis of [3H]PbTx-3 from lipoprotein fractions as well as a scintillation proximity assay using [3H]PbTx-3 and purified human HDLs. This information on the association of brevetoxins with HDLs provides a new foundation for understanding the process by which the toxin is delivered to and removed from tissues and may permit more effective therapeutic measures to treat intoxication from brevetoxins and the related ciguatoxins. PMID:16263501

  4. Cholesteryl-ester transfer protein enhances the ability of high-density lipoprotein to inhibit low-density lipoprotein oxidation.

    PubMed

    Hine, David; Mackness, Bharti; Mackness, Mike

    2011-09-01

    Therapeutic strategies to increase high-density lipoprotein (HDL) to treat or prevent vascular disease include the use of cholesteryl-ester transfer protein (CETP) inhibitors. Here, we show, to the best of our knowledge for the first time, that addition of CETP to HDL enhances the ability of HDL to inhibit low-density lipoprotein oxidation by ∼ 30% for total HDL and HDL(2) (both P < 0.05) and 75% for HDL(3) (P < 0.01). Therefore, CETP inhibition may be detrimental to the antiatherosclerotic properties of HDL, and these findings may partly explain the failure of the CETP inhibitor, torcetrapib, treatment to retard vascular disease despite large increases in HDL, in addition to its "off target" toxicity, a property which appears not to be shared by other members of this class of CETP inhibitor currently under clinical trial. Further, detailed studies are urgently required. PMID:21815241

  5. Biomarkers associated with high-density lipoproteins in atherosclerotic kidney disease.

    PubMed

    Rye, Kerry-Anne

    2014-04-01

    High-density lipoproteins (HDL) originate as discoidal particles that are rapidly converted by lecithin:cholesterol acyltransferase (LCAT) into the spherical particles that predominate in normal human plasma. Spherical HDL consist of multiple populations of particles that vary widely in size, composition and function. Human population studies have established that high plasma HDL cholesterol levels are associated with a reduced incidence of cardiovascular disease. The mechanistic basis of this relationship is not well understood, but most likely involves a number of the cardioprotective functions of HDL. These include the ability of apolipoprotein (apo) A-I, the main apolipoprotein constituent of HDL, to remove cholesterol from macrophages in the artery wall. HDL also have antioxidant and anti-inflammatory properties that are potentially cardioprotective. Evidence that some of these beneficial properties are compromised in people with diabetes and renal disease is emerging. Persistently elevated plasma glucose levels in people with diabetes and poor glycemic control can lead to irreversible, non-enzymatic glycation of plasma proteins, including apoA-I. Non-enzymatically glycated proteins are also prevalent in people with diabetes and end-stage renal disease who are at high cardiovascular risk. Evidence that non-enzymatically glycated apoA-I inhibits the LCAT reaction and impairs some of the cardioprotective properties of HDL is also emerging. This review is concerned with how non-enzymatic glycation of apoA-I affects the ability of LCAT to convert discoidal HDL into spherical HDL, how it affects cholesterol efflux from macrophages and how it affects the anti-inflammatory and antioxidant properties of HDL. PMID:24052156

  6. Association of the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio and concentrations of plasma lipids with high-density lipoprotein subclass distribution in the Chinese population

    PubMed Central

    2010-01-01

    Background To evaluate the relationship between the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio and HDL subclass distribution and to further examine and discuss the potential impact of LDL-C and HDL-C together with TG on HDL subclass metabolism. Results Small-sized preβ1-HDL, HDL3b and HDL3a increased significantly while large-sized HDL2a and HDL2b decreased significantly as the LDL-C/HDL-C ratio increased. The subjects in low HDL-C level (< 1.03 mmol/L) who had an elevation of the LDL-C/HDL-C ratio and a reduction of HDL2b/preβ1-HDL regardless of an undesirable or high LDL-C level. At desirable LDL-C levels (< 3.34 mmol/L), the HDL2b/preβ1-HDL ratio was 5.4 for the subjects with a high HDL-C concentration (≥ 1.55 mmol/L); however, at high LDL-C levels (≥ 3.36 mmol/L), the ratio of LDL-C/HDL-C was 2.8 in subjects, and an extremely low HDL2b/preβ1-HDL value although with high HDL-C concentration. Conclusion With increase of the LDL-C/HDL-C ratio, there was a general shift toward smaller-sized HDL particles, which implied that the maturation process of HDL was blocked. High HDL-C concentrations can regulate the HDL subclass distribution at desirable and borderline LDL-C levels but cannot counteract the influence of high LDL-C levels on HDL subclass distribution. PMID:20615262

  7. [Beta amyloid in blood and cerebrospinal fluid is associated with high density lipoproteins].

    PubMed

    Kudinova, N V; Kudinov, A R; Berezov, T T

    1996-01-01

    Cerebrovascular and parenchymal amyloid deposits found in brains of Alzheimer's disease, Down's syndrome and normal aging are mainly composed of aggregated amyloid beta protein (A beta), a unique peptide 39 to 44 amino acids long. A similar but soluble A beta (s A beta) has been identified in plasma, cerebrospinal fluid (CSF) and cell supernatants, indicating that it is a normal protein. We report here that s A beta in normal human plasma and CSF is complexed to high density lipoprotein (HDL) 3 and very high density lipoprotein (VHDL). Biotinylated synthetic peptide A beta 1-40 was traced in normal human plasma in in vitro experiments. Both tracer biotin-labeled A beta 1-40 and native s A beta were specifically recovered in HDL3 and VHDL as it was assessed in immunoprecipitation experiments of purified plasma lipoproteins and lipoprotein depleted plasma. This fact prompted us to ascertain whether the interaction of s A beta with HDL does occur in normal human CSF in vivo. For this purpose normals human CSF was fractionated by means of sequential flotation ultracentrifugation. The presence of s A beta in the resulting lipoprotein fractions as well as in the lipoprotein depleted CSF was analysed by immunoblot analysis, electron and immune-electron microscopy and native size exclusion chromatography. Immunoblot analysis with 6E10 monoclonal anti-A beta antibodies revealed s A beta association with all HDL subspecies of CSF, primarily HDL3 and VHDL and immunoelectron microscopy confirmed an association of s A beta with CSF-HDL particles of 16.8 + 3.2 nm. Native size exclusion chromatography followed by immunoblot analysis with antibodies against A beta and different apoliproproteins indicated an association of s A beta with HDL complexes of approximately 200 kDa molecular weight. Soluble A beta association with HDL3 and VHDL may be involved in maintaining the solubility of A beta in biological fluids and points to a possible role of lipoproteins and lipoprotein lipid

  8. Single step reconstitution of multifunctional high-density lipoprotein-derived nanomaterials using microfluidics.

    PubMed

    Kim, YongTae; Fay, Francois; Cormode, David P; Sanchez-Gaytan, Brenda L; Tang, Jun; Hennessy, Elizabeth J; Ma, Mingming; Moore, Kathryn; Farokhzad, Omid C; Fisher, Edward Allen; Mulder, Willem J M; Langer, Robert; Fayad, Zahi A

    2013-11-26

    High-density lipoprotein (HDL) is a natural nanoparticle that transports peripheral cholesterol to the liver. Reconstituted high-density lipoprotein (rHDL) exhibits antiatherothrombotic properties and is being considered as a natural treatment for cardiovascular diseases. Furthermore, HDL nanoparticle platforms have been created for targeted delivery of therapeutic and diagnostic agents. The current methods for HDL reconstitution involve lengthy procedures that are challenging to scale up. A central need in the synthesis of rHDL, and multifunctional nanomaterials in general, is to establish large-scale production of reproducible and homogeneous batches in a simple and efficient fashion. Here, we present a large-scale microfluidics-based manufacturing method for single-step synthesis of HDL-mimicking nanomaterials (μHDL). μHDL is shown to have the same properties (e.g., size, morphology, bioactivity) as conventionally reconstituted HDL and native HDL. In addition, we were able to incorporate simvastatin (a hydrophobic drug) into μHDL, as well as gold, iron oxide, quantum dot nanocrystals or fluorophores to enable its detection by computed tomography (CT), magnetic resonance imaging (MRI), or fluorescence microscopy, respectively. Our approach may contribute to effective development and optimization of lipoprotein-based nanomaterials for medical imaging and drug delivery. PMID:24079940

  9. Reconstituted high-density lipoprotein neutralizes gram-negative bacterial lipopolysaccharides in human whole blood.

    PubMed Central

    Parker, T S; Levine, D M; Chang, J C; Laxer, J; Coffin, C C; Rubin, A L

    1995-01-01

    We have tested hypotheses relating lipoprotein structure to function as measured by the relative ability to neutralize endotoxin by comparing natural human lipoproteins, a chemically defined form of reconstituted high-density lipoprotein (R-HDL), and a lipid emulsion (Intralipid). The human whole-blood system was used as an in vitro model of lipopolysaccharide (LPS) binding protein and CD14-dependent activation of cytokine production. When lipoproteins were compared on the basis of protein content, R-HDL was most effective in reducing tumor necrosis factor alpha (TNF-alpha) production followed in order by very low density lipoprotein, low-density lipoprotein, Intralipid, and natural HDL. However, when these particles were compared by protein, phospholipid, cholesterol, or triglyceride content by stepwise linear regression analysis, only phospholipid was correlated to effectiveness (r2 = 0.873; P < 0.0001). Anti-CD14 monoclonal antibodies MY4 and 3C10 inhibited LPS binding protein and CD14-dependent activation of TNF-alpha production by LPS at LPS concentrations up to approximately 1.0 ng/ml. R-HDL (2 mg of protein per ml) blocked TNF-alpha production by LPS from both smooth- and rough-type gram-negative bacteria at concentrations up to 100 ng of LPS per ml but had little effect on heat-killed gram-positive Staphylococcus aureus and no effect on other LPS-independent stimuli tested. These results support our hypothesis that LPS is neutralized by binding to phospholipid on the surface of R-HDL and demonstrate that R-HDL is a potent inhibitor of the induction of TNF-alpha by LPS from both rough- and smooth-form gram-negative bacteria in whole human blood. PMID:7528733

  10. Folded functional lipid-poor apolipoprotein A-I obtained by heating of high-density lipoproteins: relevance to high-density lipoprotein biogenesis.

    PubMed

    Jayaraman, Shobini; Cavigiolio, Giorgio; Gursky, Olga

    2012-03-15

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

  11. Binding of Salmonella typhimurium lipopolysaccharides to rat high-density lipoproteins.

    PubMed Central

    Munford, R S; Hall, C L; Dietschy, J M

    1981-01-01

    These studies were undertaken to investigate the binding of gram-negative bacterial lipopolysaccharides (LPS) to high-density lipoproteins (HDL) of rat plasma. Purified Salmonella typhimurium LPS, intrinsically labeled with [3H]-galactose, bound rapidly in vitro to isolated rat HDL. Maximal binding of LPS to HDL occurred when LPS and HDL were incubated with lipoprotein-free plasma (rho greater than 1.21 g/ml). Since LPS, when purified, form large aggregates, we tested the hypothesis that disaggregation of LPS enhances LPS-HDL binding. We found that calcium chloride (1 mM), an agent which prevents LPS disaggregation, inhibited binding of LPS to HDL by interfering with the modification of LPS by lipoprotein-free plasma. Conversely, sodium deoxycholate (0.15 g/dl), which disaggregates LPS, greatly increased binding of LPS to HDL in the absence of lipoprotein-free plasma. Analysis of labeled LPS by sodium deodecyl sulfate-polyacrylamide gel electrophoresis showed only minor differences in the sizes of LPS molecules before and after binding to HDL, suggesting that chemical modification of LPS is not required for binding. The results provide evidence that disaggregation increases the binding of LPS to HDL. PMID:7037642

  12. 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

  13. Immunohistochemical detection of a very high density lipoprotein (VHDL) in ovarian follicles of Triatoma infestans.

    PubMed

    González, M S; Ronderos, J R; Rimoldi, O J; Brenner, R R

    2001-04-01

    The ability of Triatoma infestans ovarian follicles to synthesize a very high-density lipoprotein (VHDL) has been examined by immunohistochemical methods. This kind of lipoprotein can be envisaged as a storage hexameric protein present in the hemolymph of some insect species. VHDL immunoreactivity is observed in oocytes at different stages of maturation. The antigen is present in the oocyte cytoplasm as well as in the follicular epithelial cells. The immunopositive reaction in the apical surface of follicle cells suggests both a VHDL synthesis and a secretion process. Furthermore, VHDL seems to be stored into oocyte in yolk granules. On the contrary, no immunopositive reaction is observed in the intracellular spaces between follicle cells, suggesting that VHDL is not incorporated from hemolymph into the oocyte. PMID:11387873

  14. The impact of plasma triglyceride and apolipoproteins concentrations on high-density lipoprotein subclasses distribution

    PubMed Central

    2011-01-01

    Objective To investigate the effect of triglyceride (TG) integrates with plasma major components of apolipoproteins in HDL subclasses distribution and further elicited the TG-apolipoproteins (apos) interaction in the processes of high density lipoprotein (HDL) mature metabolic and atherosclerosis related diseases. Methods Contents of plasma HDL subclasses were quantities by two-dimensional gel electrophoresis associated with immunodetection in 500 Chinese subjects. Results Contents of preβ1-HDL, HDL3a, and apoB-100 level along with apoB-100/A-I ratio were significantly increased, whereas there was a significant reduction in the contents of HDL2, apoA-I level as well as apoC-III/C-II ratio with increased TG concentration. Moreover, preβ1-HDL contents is elevated about 9 mg/L and HDL2b contents can be reduced 21 mg/L for 0.5 mmol/L increment in TG concentration. Moreover, with increase of apoA-I levels, HDL2b contents were marginally elevated in any TG concentration group. Furthermore, despite of in the apoB-100/A-I < 0.9 group, the contents of preβ1-HDL increased, and those of HDL2b decreased significantly for subjects in both high and very high TG levels compared to that in normal TG levels. Similarly, in the apoB-100/A-I ≥ 0.9 group, the distribution of HDL subclasses also showed abnormality for subjects with normal TG levels. Conclusions The particle size of HDL subclasses tend to small with TG levels increased which indicated that HDL maturation might be impeded and efficiency of reverse cholesterol transport(RCT) might be weakened. These data suggest that TG levels were not only significantly associated with but liner with the contents of preβ1-HDL and HDL2b. They also raise the possibility that the TG levels effect on HDL maturation metabolism are subjected to plasma apolipoproteins and apolipoproteins ratios. PMID:21251287

  15. Plasma lipoprotein composition in alcoholic hepatitis: accumulation of apolipoprotein E-rich high density lipoprotein and preferential reappearance of "light'-HDL during partial recovery.

    PubMed

    Weidman, S W; Ragland, J B; Sabesin, S M

    1982-05-01

    patients, the d > 1.006 g/ml unesterified cholesterol and triglyceride levels decreased, while esterified cholesterol, HDL-cholesterol, and apoA-I levels increased. The first HDL fractions to reappear were lipoproteins with HDL(2) density characteristics, as evidenced by simultaneous increases of apoA-I, apoA-II, cholesteryl esters and phospholipids. Lipoproteins with HDL(3) density characteristics appeared later. Long-term (6-10 months) follow-up studies indicated a substantial elevation of HDL cholesterol and apoA-I in three of the four patients that appeared to have resulted from further increases in their HDL(2)-like subspecies. The above results illustrate the diversity of abnormal lipoproteins in alcoholic hepatitis and the ability of density gradient ultra-centrifugation combined with lipid and apolipoprotein quantitation, electron microscopy, and polyacrylamide gel electrophoresis to partially resolve those lipoproteins in the d > 1.006 g/ml plasma fraction.-Weidman, S. W., J. B. Ragland, and S. M. Sabesin. Plasma lipoprotein composition in alcoholic hepatitis: accumulation of apolipoprotein E-rich high density lipoprotein and preferential reappearance of "light"-HDL during partial recovery. PMID:7097121

  16. Synthetic high-density lipoprotein-like nanoparticles for cancer therapy

    PubMed Central

    Foit, Linda; Giles, Francis J.; Gordon, Leo I.; Thaxton, C. Shad

    2015-01-01

    Summary High-density lipoproteins (HDLs) are a diverse group of natural nanoparticles that are most well-known for their role in cholesterol transport. However, HDLs have diverse functions that provide significant opportunities for cancer therapy. Presented is a focused review of the ways that synthetic versions of HDL have been used as targeted therapies for cancer, and as vehicles for the delivery of diverse therapeutic cargo to cancer cells. As such, synthetic HDLs are likely to play a central role in the development of next generation cancer therapies. PMID:25487833

  17. Co-isolation of extracellular vesicles and high-density lipoproteins using density gradient ultracentrifugation

    PubMed Central

    Yuana, Yuana; Levels, Johannes; Grootemaat, Anita; Sturk, Auguste; Nieuwland, Rienk

    2014-01-01

    Extracellular vesicles (EVs) facilitate intercellular communication by carrying bioactive molecules such as proteins, messenger RNA, and micro (mi)RNAs. Recently, high-density lipoproteins (HDL) isolated from human plasma were also reported to transport miRNA to other cells. HDL, when isolated from human plasma, ranges in density between 1.063 and 1.21 g/mL, which grossly overlap with the reported density of EVs. Consequently, HDL and EV will be co-isolated when using density gradient ultracentrifugation. Thus, more stringent isolation/separation procedures of EV and HDL are essential to know their relative contribution to the pool of circulating bioactive molecules. PMID:25018865

  18. Nigerian propolis improves blood glucose, glycated hemoglobin A1c, very low-density lipoprotein, and high-density lipoprotein levels in rat models of diabetes

    PubMed Central

    Oladayo, Mustafa Ibrahim

    2016-01-01

    Objective: According to our previous studies, propolis of Nigerian origin showed some evidence of hypoglycemic and hypolipidemic activities in addition to its ability to ameliorate oxidative-stress-induced organ dysfunction. This study was carried out to determine whether an ethanolic extract of Nigerian propolis (EENP) improves glycated hemoglobin A1c (HbA1c), fasting plasma glucose, very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) concentrations in rats that have alloxan diabetes. Materials and Methods: Diabetes was induced with alloxan (110 mg/kg). Animals were divided into 5 groups (n = 5); Group 1 was non-diabetic receiving normal saline and Group 2 was diabetic but also received only normal saline. Groups 3, 4, and 5 were diabetic receiving 200 mg/kg propolis, 300 mg/kg propolis, and 150 mg/kg metformin, respectively, for 42 days. Results: Hyperglycemia, elevated serum level of VLDL, elevated plasma level of HbA1c, and decreased levels of HDL were observed in the diabetic untreated animals. Nigerian propolis decreased blood glucose level and serum level of VLDL but elevated HDL level. These changes were significant (P < 0.05). The levels of plasma HbA1c were also reduced in the propolis-treated groups, and the reduction was significant (P < 0.05). Conclusion: Nigerian propolis contains compounds exhibiting hypoglycemic, antihyperlipidemic, and HbA1c reducing activities. PMID:27366348

  19. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) t...

  20. Unique Features of High-Density Lipoproteins in the Japanese: In Population and in Genetic Factors

    PubMed Central

    Yokoyama, Shinji

    2015-01-01

    Despite its gradual increase in the past several decades, the prevalence of atherosclerotic vascular disease is low in Japan. This is largely attributed to difference in lifestyle, especially food and dietary habits, and it may be reflected in certain clinical parameters. Plasma high-density lipoprotein (HDL) levels, a strong counter risk for atherosclerosis, are indeed high among the Japanese. Accordingly, lower HDL seems to contribute more to the development of coronary heart disease (CHD) than an increase in non-HDL lipoproteins at a population level in Japan. Interestingly, average HDL levels in Japan have increased further in the past two decades, and are markedly higher than in Western populations. The reasons and consequences for public health of this increase are still unknown. Simulation for the efficacy of raising HDL cholesterol predicts a decrease in CHD of 70% in Japan, greater than the extent by reducing low-density lipoprotein cholesterol predicted by simulation or achieved in a statin trial. On the other hand, a substantial portion of hyperalphalipoproteinemic population in Japan is accounted for by genetic deficiency of cholesteryl ester transfer protein (CETP), which is also commonly unique in East Asian populations. It is still controversial whether CETP mutations are antiatherogenic. Hepatic Schistosomiasis is proposed as a potential screening factor for historic accumulation of CETP deficiency in East Asia. PMID:25849946

  1. Carbohydrate composition of serum low and high density lipoproteins of nonhuman primate species.

    PubMed

    Pargaonkar, P S; Radhakrishnamurthy, B; Srinivasan, S R; Berenson, G S

    1977-01-01

    1. Carbohydrate composition of serum low and high density lipoproteins obtained from 5 nonhuman primate species (chimpanzee, patas, baboon, rhesus, and spider) and humans was studied. 2. Individual lipoproteins were isolated from pooled sera of each species by ultracentrifugal flotation between the densities 1.019-1.063 for LDL-2; 1.063-1.12 for HDL-2; and 1.12-1.21 for HDL-3. After delipidation, sialic acid, fucose, glucosamine, mannose, galactose, and glucose were determined on apo LDL-2, apo HDL-2, and apo HDL-3. 3. Glucosamine, galactose, and mannose constituted a major component of the sugars in apo LDL-2, with similar relative proportions in all species. Sialic acid, fucose, and glucose formed a minor component, the proportions of which varied greatly among the species. 4. Unlike apo LDL-2, sialic acid, fucose, and glucosamine constituted the bulk of the sugars in apo HDL-2 and apo HDL-3. Mannose, galactose, and glucose were minor components, with galactose predominating. 5. Qualitative differences were observed in electrophoretic mobilities of apo HDL-2 and apo HDL-3 on polyacrylamide gel. One faster moving band was unique to chimpanzee. 6. Intraspecies differences in the content of sialic acid and fucose of apolipoproteins may be related to lipoprotein metabolism and species susceptibility (or resistance) to either spontaneous or diet-induced atherosclerosis. PMID:233783

  2. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits.

    PubMed

    Badimon, J J; Badimon, L; Galvez, A; Dische, R; Fuster, V

    1989-03-01

    The effects of in vivo administration of high density lipoprotein-very high density lipoprotein (HDL-VHDL) on the development of aortic fatty streaks were studied in cholesterol-fed rabbits. The rabbits received a 0.5% cholesterol-rich diet for 8 weeks. During this period, the HDL-VHDL group was intravenously administered with 50 mg/week of homologous HDL-VHDL protein; the control group received normal saline (0.9% NaCl). HDL-VHDL fraction was obtained at density range 1.063 to 1.25 gm/ml by ultracentrifugation of normal rabbit plasma. Along the study, plasma lipid levels followed a similar profile in both groups. At the completion of the study, atherosclerotic-like lipid-rich lesions covered 37.9 +/- 6% (X +/- SEM) of the intimal aortic surface in the control group, and 14.9 +/- 2.1% in the treated group (p less than 0.001). The values of total and free cholesterol, esterified cholesterol, and phospholipids deposited within vessel wall were significantly lower in the aortas of the HDL-VHDL treated group than those in the control group. Cholesterol accumulation in the livers was also significantly lower (p less than 0.01) in the treated group than in the control. We concluded that administration of homologous HDL-VHDL lipoprotein fraction to cholesterol-fed rabbits, dramatically inhibited the extent of aortic fatty streaks and lowered lipid deposition in the arterial wall and liver without modification of the plasma lipid levels. PMID:2927083

  3. Postprandial Changes in High Density Lipoproteins in Rats Subjected to Gavage Administration of Virgin Olive Oil

    PubMed Central

    Martínez-Beamonte, Roberto; Navarro, María A.; Acin, Sergio; Guillén, Natalia; Barranquero, Cristina; Arnal, Carmen; Surra, Joaquín; Osada, Jesus

    2013-01-01

    Background and Aims The present study was designed to verify the influence of acute fat loading on high density lipoprotein (HDL) composition, and the involvement of liver and different segments of small intestine in the changes observed. Methods and Results To address these issues, rats were administered a bolus of 5-ml of extra-virgin olive oil and sacrificed 4 and 8 hours after feeding. In these animals, lipoproteins were analyzed and gene expressions of apolipoprotein and HDL enzymes were assessed in duodenum, jejunum, ileum and liver. Using this experimental design, total plasma and HDL phospholipids increased at the 8-hour-time-point due to increased sphingomyelin content. An increase in apolipoprotein A4 was also observed mainly in lipid-poor HDL. Increased expression of intestinal Apoa1, Apoa4 and Sgms1 mRNA was accompanied by hepatic decreases in the first two genes in liver. Hepatic expression of Abcg1, Apoa1bp, Apoa2, Apoe, Ptlp, Pon1 and Scarb1 decreased significantly following fat gavage, while no changes were observed for Abca1, Lcat or Pla2g7. Significant associations were also noted for hepatic expression of apolipoproteins and Pon1. Manipulation of postprandial triglycerides using an inhibitor of microsomal transfer protein -CP-346086- or of lipoprotein lipase –tyloxapol- did not influence hepatic expression of Apoa1 or Apoa4 mRNA. Conclusion All these data indicate that dietary fat modifies the phospholipid composition of rat HDL, suggesting a mechanism of down-regulation of hepatic HDL when intestine is the main source of those particles and a coordinated regulation of hepatic components of these lipoproteins at the mRNA level, independently of plasma postprandial triglycerides. PMID:23383120

  4. Detection of haptoglobin in the high-density lipoprotein and the very high-density lipoprotein fractions from sera of calves with experimental pneumonia and cows with naturally occurring fatty liver.

    PubMed

    Katoh, N; Nakagawa, H

    1999-02-01

    In addition to the lipoprotein-deficient d > 1.25 fraction, haptoglobin was detected in the high-density lipoprotein (HDL) and the very high-density lipoprotein (VHDL) fractions from sera of calves with experimental pneumonia and cows with naturally occurring fatty liver. It was not found in the chylomicrons, very low-density lipoprotein and low-density lipoprotein fractions. Washing of the HDL fraction did not decrease the haptoglobin concentration. Transferrin and immunoglobulin G were immunoblotted to examine the possibility of contamination of the lipoprotein fractions by the d > 1.25 fraction. The two serum proteins were detected only in the d > 1.25 fraction, not in any lipoprotein fractions. The distribution pattern of haptoglobin in the lipoprotein fractions was distinct from that of serum albumin. Concentrations of haptoglobin in the HDL fractions from pneumonic sera were largely proportional to those in whole sera. Cholesteryl ester concentrations were decreased in sera from calves with pneumonia, as in cows with fatty liver. A protein immunologically related to hemoglobin was also detected in particular in the VHDL fractions from sera of both groups. These results suggest that haptoglobin or a complex with the hemoglobin-like protein may have a role or roles related to the lipid metabolism. PMID:10081748

  5. Structural basis of human high-density lipoprotein formation and assembly at sub nanometer resolution.

    PubMed

    Sivashanmugam, Arun; Yang, Yunhuang; Murray, Victoria; McCullough, Christopher; Chen, Bin; Ren, Xuefeng; Li, Qianqian; Wang, Jianjun

    2008-01-01

    Human high-density lipoproteins (HDL) are protein/lipid particles of nanometer sizes. These nano particles are critical for transportation of the "bad cholesterol" from peripheral tissues back to the liver for clearance. An inverse correlation has been observed between the plasma HDL concentration and atherosclerosis. Furthermore, the HDL particle has also been utilized as a vehicle for drug delivery and for intracellular cell biology studies of membrane proteins. The structural basis of HDL formation and assembly, however, is poorly understood. Using high-resolution structural approaches, the formation and assembly of the HDL particle is being examined at atomic resolution, which is reviewed in this chapter. We will mainly focus on our own NMR studies of different apoAI conformations with a brief summary of previously published work by other laboratories. PMID:19195557

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

    PubMed

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

    2015-11-01

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

  7. High-density-lipoprotein cholesterol and types of alcoholic beverages consumed among men and women.

    PubMed Central

    Parker, D R; McPhillips, J B; Derby, C A; Gans, K M; Lasater, T M; Carleton, R A

    1996-01-01

    OBJECTIVES. Differences by sex in the relationship between high-density-lipoprotein (HDL) cholesterol and consumption of alcoholic beverages were examined in 1516 individuals. METHODS. Questionnaires and blood-sample data from cross-sectional surveys were analyzed. RESULTS. Both beer and liquor were independently associated with increased HDL cholesterol in the total group, in men, and in women after covariates were controlled for. Wine was associated with a significant increase in HDL cholesterol in women only. CONCLUSIONS. Among women and men, amount may be more important than type of alcoholic beverage consumed. The independent effect of wine on HDL cholesterol among men remains unclear since few men in this population consumed wine exclusively or in large quantities. PMID:8669505

  8. High density lipoprotein: it’s not just about lipid transport anymore

    PubMed Central

    Gordon, Scott M.; Hofmann, Susanna; Askew, David S.; Davidson, W. Sean

    2011-01-01

    Plasma levels of high density lipoprotein cholesterol (HDL-C) have long been associated with protection against cardiovascular disease (CVD) in large populations. However, HDL-C has been significantly less useful for predicting CVD risk in individual patients. This has ignited a new debate on the merits of measuring HDL quantity versus quality in terms of protective potential. In addition, numerous recent studies have begun to uncover HDL functions that vary surprisingly from traditional lipid transport roles. In this paper, we review recent findings that point to important functions for HDL that go well beyond lipid transport. These discoveries suggest that HDL might be a platform that mediates protection from a host of disease states ranging from CVD to diabetes to infectious disease. PMID:21067941

  9. High density lipoprotein and metabolic disease: Potential benefits of restoring its functional properties

    PubMed Central

    Klancic, Teja; Woodward, Lavinia; Hofmann, Susanna M.; Fisher, Edward A.

    2016-01-01

    Background High density lipoproteins (HDLs) are thought to be atheroprotective and to reduce the risk of cardiovascular disease (CVD). Besides their antioxidant, antithrombotic, anti-inflammatory, anti-apoptotic properties in the vasculature, HDLs also improve glucose metabolism in skeletal muscle. Scope of the review Herein, we review the functional role of HDLs to improve metabolic disorders, especially those involving insulin resistance and to induce regression of CVD with a particular focus on current pharmacological treatment options as well as lifestyle interventions, particularly exercise. Major conclusions Functional properties of HDLs continue to be considered important mediators to reverse metabolic dysfunction and to regress atherosclerotic cardiovascular disease. Lifestyle changes are often recommended to reduce the risk of CVD, with exercise being one of the most important of these. Understanding how exercise improves HDL function will likely lead to new approaches to battle the expanding burden of obesity and the metabolic syndrome. PMID:27110484

  10. Pharmacogenetics of paraoxonase activity: elucidating the role of high-density lipoprotein in disease

    PubMed Central

    Kim, Daniel Seung; Marsillach, Judit; Furlong, Clement E; Jarvik, Gail P

    2014-01-01

    PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also associated with numerous human diseases, including cardiovascular disease, Parkinson's disease and cancer. In addition, PON1 metabolizes a broad variety of substrates, including toxic organophosphorous compounds, statin adducts, glucocorticoids, the likely atherogenic l-homocysteine thiolactone and the quorum-sensing factor of Pseudomonas aeruginosa. Numerous cardiovascular and antidiabetic pharmacologic agents, dietary macronutrients, lifestyle factors and antioxidant supplements affect PON1 expression and enzyme activity levels. Owing to the importance of PON1 to HDL function and its individual association with diverse human diseases, pharmacogenomic interactions between PON1 and the various factors that alter its expression and activity may represent an important therapeutic target for future investigation. PMID:24024900

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

    PubMed Central

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

    2014-01-01

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

  12. Effect of apolipoprotein E-free high density lipoproteins on cholesterol metabolism in cultured pig hepatocytes

    SciTech Connect

    Bachorik, P.S.; Virgil, D.G.; Kwiterovich, P.O. Jr.

    1987-10-05

    We studied cholesterol synthesis from (/sup 14/C)acetate, cholesterol esterification from (/sup 14/C)oleate, and cellular cholesterol and cholesteryl ester levels after incubating cells with apoE-free high density lipoproteins (HDL) or low density lipoproteins (LDL). LDL suppressed synthesis by up to 60%, stimulated esterification by up to 280%, and increased cell cholesteryl ester content about 4-fold. Esterification increased within 2 h, but synthesis was not suppressed until after 6 h. ApoE-free HDL suppressed esterification by about 50% within 2 h. Cholesterol synthesis was changed very little within 6 h, unless esterification was maximally suppressed; synthesis was then stimulated about 4-fold. HDL lowered cellular unesterified cholesterol by 13-20% within 2 h and promoted the removal of newly synthesized cholesterol and cholesteryl esters. These changes were transient; by 24 h, both esterification and cellular unesterified cholesterol returned to control levels, and cholesteryl esters increased 2-3-fold. HDL core lipid was taken up selectively from /sup 125/I-labeled (/sup 3/H)cholesteryl ester- and ether-labeled HDL. LDL core lipid uptake was proportional to LDL apoprotein uptake. The findings suggest that 1) the cells respond initially to HDL or LDL with changes in esterification, and 2) HDL mediates both the removal of free cholesterol from the cell and the delivery of HDL cholesteryl esters to the cell.

  13. High-density lipoprotein associated with secondary vitellogenesis in the hemolymph of the crayfish Cherax quadricarinatus.

    PubMed

    Yehezkel, G; Chayoth, R; Abdu, U; Khalaila, I; Sagi, A

    2000-11-01

    The high-density lipoproteins LPI and LPII were isolated from the hemolymph of the crayfish Cherax quadricarinatus by gradient ultracentrifugation and high-performance liquid chromatography (HPLC). Both lipoproteins contained a carotenoid moiety. LPI is comprised of a single polypeptide with an approximate molecular mass of 96 kDa. LPII was composed of two similar native components, LPIIa and LPIIb, both having polypeptides of 80 and 177 kDa. Both under natural conditions and after endocrine manipulations, LPI was present in males and in females, regardless of the female reproductive stage. LPII was present only in secondary-vitellogenic females, but not during the winter reproductive arrest period. LPII was also absent from young females that had received androgenic gland implants. LPII also appeared in the hemolymph of intersex individuals from which the androgenic gland had been removed. It is therefore suggested that LPII serves as a marker indicating the onset of secondary vitellogenesis in C. quad'iariicarintus females. PMID:11126772

  14. High-Density Lipoprotein Binds to Mycobacterium avium and Affects the Infection of THP-1 Macrophages.

    PubMed

    Ichimura, Naoya; Sato, Megumi; Yoshimoto, Akira; Yano, Kouji; Ohkawa, Ryunosuke; Kasama, Takeshi; Tozuka, Minoru

    2016-01-01

    High-density lipoprotein (HDL) is involved in innate immunity toward various infectious diseases. Concerning bacteria, HDL is known to bind to lipopolysaccharide (LPS) and to neutralize its physiological activity. On the other hand, cholesterol is known to play an important role in mycobacterial entry into host cells and in survival in the intracellular environment. However, the pathogenicity of Mycobacterium avium (M. avium) infection, which tends to increase worldwide, remains poorly studied. Here we report that HDL indicated a stronger interaction with M. avium than that with other Gram-negative bacteria containing abundant LPS. A binding of apolipoprotein (apo) A-I, the main protein component of HDL, with a specific lipid of M. avium might participate in this interaction. HDL did not have a direct bactericidal activity toward M. avium but attenuated the engulfment of M. avium by THP-1 macrophages. HDL also did not affect bacterial killing after ingestion of live M. avium by THP-1 macrophage. Furthermore, HDL strongly promoted the formation of lipid droplets in M. avium-infected THP-1 macrophages. These observations provide new insights into the relationship between M. avium infection and host lipoproteins, especially HDL. Thus, HDL may help M. avium to escape from host innate immunity. PMID:27516907

  15. New function for high density lipoproteins. Their participation in intravascular reactions of bacterial lipopolysaccharides.

    PubMed Central

    Ulevitch, R J; Johnston, A R; Weinstein, D B

    1979-01-01

    The addition of bacterial lipopolysaccharide (LPS) from Escherichia coli 0111:B4 or Salmonella minnesota R595 to plasma (or serum) resulted in a marked reduction of the hydrated buoyant density of the parent LPS (0111:B4 [d = 1.44 g/cm3] and R595 [d = 1.38 g/cm3]), to d less than 1.2 g/cm3. This reduction in buoyant density to less than 1.2 g/cm3 of the LPS required plasma (or serum) lipid. Delipidation of plasma (or serum) by extraction with n-butanol/diisopropyl ether (40/60, vol:vol) prevented the conversion of the parent LPS to a form with d less than 1.2 g/cm3. Reversal of the effect of delipidation was accomplished by the addition of physiologic concentrations of high density lipoprotein (HDL). In contrast, as much as two times normal serum concentration of low density or very low density lipoprotein were ineffective. The ability of normal plasma (or serum) to inhibit the pyrogenic activity of LPS, lost after delipidation, was also restored after the addition of HDL. Preliminary results suggested that prior modifications of the LPS, probably disaggregation, may be required before interaction with HDL. PMID:227936

  16. High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk

    PubMed Central

    Hafiane, Anouar; Genest, Jacques

    2015-01-01

    Plasma high density lipoprotein cholesterol (HDL) comprises a heterogeneous family of lipoprotein species, differing in surface charge, size and lipid and protein compositions. While HDL cholesterol (C) mass is a strong, graded and coherent biomarker of cardiovascular risk, genetic and clinical trial data suggest that the simple measurement of HDL-C may not be causal in preventing atherosclerosis nor reflect HDL functionality. Indeed, the measurement of HDL-C may be a biomarker of cardiovascular health. To assess the issue of HDL function as a potential therapeutic target, robust and simple analytical methods are required. The complex pleiotropic effects of HDL make the development of a single measurement challenging. Development of laboratory assays that accurately HDL function must be developed validated and brought to high-throughput for clinical purposes. This review discusses the limitations of current laboratory technologies for methods that separate and quantify HDL and potential application to predict CVD, with an emphasis on emergent approaches as potential biomarkers in clinical practice. PMID:26674734

  17. Serum Paraoxonase 1 Activity Is Associated with Fatty Acid Composition of High Density Lipoprotein

    PubMed Central

    Boshtam, Maryam; Pourfarzam, Morteza; Ani, Mohsen; Naderi, Gholam Ali; Basati, Gholam; Mansourian, Marjan; Dinani, Narges Jafari; Asgary, Seddigheh; Abdi, Soheila

    2013-01-01

    Introduction. Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. Methods. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Results. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω6 fatty acids of HDL. Conclusion. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health. PMID:24167374

  18. High-Density Lipoprotein Binds to Mycobacterium avium and Affects the Infection of THP-1 Macrophages

    PubMed Central

    Ichimura, Naoya; Sato, Megumi; Yoshimoto, Akira; Yano, Kouji; Ohkawa, Ryunosuke; Kasama, Takeshi

    2016-01-01

    High-density lipoprotein (HDL) is involved in innate immunity toward various infectious diseases. Concerning bacteria, HDL is known to bind to lipopolysaccharide (LPS) and to neutralize its physiological activity. On the other hand, cholesterol is known to play an important role in mycobacterial entry into host cells and in survival in the intracellular environment. However, the pathogenicity of Mycobacterium avium (M. avium) infection, which tends to increase worldwide, remains poorly studied. Here we report that HDL indicated a stronger interaction with M. avium than that with other Gram-negative bacteria containing abundant LPS. A binding of apolipoprotein (apo) A-I, the main protein component of HDL, with a specific lipid of M. avium might participate in this interaction. HDL did not have a direct bactericidal activity toward M. avium but attenuated the engulfment of M. avium by THP-1 macrophages. HDL also did not affect bacterial killing after ingestion of live M. avium by THP-1 macrophage. Furthermore, HDL strongly promoted the formation of lipid droplets in M. avium-infected THP-1 macrophages. These observations provide new insights into the relationship between M. avium infection and host lipoproteins, especially HDL. Thus, HDL may help M. avium to escape from host innate immunity. PMID:27516907

  19. High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk.

    PubMed

    Hafiane, Anouar; Genest, Jacques

    2015-06-01

    Plasma high density lipoprotein cholesterol (HDL) comprises a heterogeneous family of lipoprotein species, differing in surface charge, size and lipid and protein compositions. While HDL cholesterol (C) mass is a strong, graded and coherent biomarker of cardiovascular risk, genetic and clinical trial data suggest that the simple measurement of HDL-C may not be causal in preventing atherosclerosis nor reflect HDL functionality. Indeed, the measurement of HDL-C may be a biomarker of cardiovascular health. To assess the issue of HDL function as a potential therapeutic target, robust and simple analytical methods are required. The complex pleiotropic effects of HDL make the development of a single measurement challenging. Development of laboratory assays that accurately HDL function must be developed validated and brought to high-throughput for clinical purposes. This review discusses the limitations of current laboratory technologies for methods that separate and quantify HDL and potential application to predict CVD, with an emphasis on emergent approaches as potential biomarkers in clinical practice. PMID:26674734

  20. Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics

    PubMed Central

    Salazar, Juan; Olivar, Luis Carlos; Ramos, Eduardo; Chávez-Castillo, Mervin; Rojas, Joselyn; Bermúdez, Valmore

    2015-01-01

    High-Density Lipoprotein-Cholesterol (HDL-C) is regarded as an important protective factor against cardiovascular disease, with abundant evidence of an inverse relationship between its serum levels and risk of cardiovascular disease, as well as various antiatherogenic, antioxidant, and anti-inflammatory properties. Nevertheless, observations of hereditary syndromes featuring scant HDL-C concentration in absence of premature atherosclerotic disease suggest HDL-C levels may not be the best predictor of cardiovascular disease. Indeed, the beneficial effects of HDL may not depend solely on their concentration, but also on their quality. Distinct subfractions of this lipoprotein appear to be constituted by specific protein-lipid conglomerates necessary for different physiologic and pathophysiologic functions. However, in a chronic inflammatory microenvironment, diverse components of the HDL proteome and lipid core suffer alterations, which propel a shift towards a dysfunctional state, where HDL-C becomes proatherogenic, prooxidant, and proinflammatory. This heterogeneity highlights the need for further specialized molecular studies in this aspect, in order to achieve a better understanding of this dysfunctional state; with an emphasis on the potential role for proteomics and lipidomics as valuable methods in the search of novel therapeutic approaches for cardiovascular disease. PMID:26634153

  1. Usefulness of High-Density Lipoprotein Cholesterol to Predict Survival in Pulmonary Arterial Hypertension.

    PubMed

    Larsen, Carolyn M; McCully, Robert B; Murphy, Joseph G; Kushwaha, Sudhir S; Frantz, Robert P; Kane, Garvan C

    2016-07-15

    It has been suggested that lipoprotein abnormalities may contribute to the pulmonary arteriolar dysfunction observed in pulmonary arterial hypertension (PAH). High-density lipoprotein cholesterol (HDL) has vasodilatory, anti-inflammatory, and endothelial protective properties. We hypothesized that a higher serum HDL level may be advantageous for survival in PAH and that the serum HDL level at diagnosis would be an independent predictor of survival in PAH and be additive to previously validated predictors of survival. This study included all patients with PAH seen at the Mayo Clinic Pulmonary Hypertension Clinic from January 1, 1995, to December 31, 2009, who had a baseline HDL measurement. Mortality was analyzed over 5 years using the Kaplan-Meier method. Univariate and multivariable Cox proportional hazards ratios were calculated to evaluate the relation between baseline HDL level and survival. HDL levels were available for 227 patients. Higher HDL levels were associated with significantly lower mortality. Patients with an HDL >54 mg/dl at diagnosis had a 5-year survival of 59%. By comparison those with an HDL <34 mg/dl had a 5-year survival of 30%. On multivariate analysis, higher HDL was associated with an age-adjusted risk ratio for death of 0.78 (CI 0.67 to 0.91; p <0.01) per 10 mg/dl increase. In conclusion, HDL was an independent predictor of survival in PAH. PMID:27291969

  2. ANALYSIS OF DRUG INTERACTIONS WITH HIGH DENSITY LIPOPROTEIN BY HIGH-PERFORMANCE AFFINITY CHROMATOGRAPHY

    PubMed Central

    Chen, Sike; Sobansky, Matthew R.; Hage, David S.

    2009-01-01

    Columns containing immobilized lipoproteins were prepared for the analysis of drug interactions with these particles by high-performance affinity chromatography. This approach was evaluated by using it to examine the binding of high density lipoprotein (HDL) to the drugs propranolol or verapamil. HDL was immobilized by the Schiff base method onto silica and gave HPLC columns with reproducible binding to propranolol over four to five days of continuous operation at pH 7.4. Frontal analysis experiments indicated that two types of interactions were occurring between R/S-propranolol and HDL at 37°C: saturable binding with an association equilibrium constant (Ka) of 1.1–1.9 × 105 M−1, and non-saturable binding with an overall affinity constant (n Ka) of 3.7–4.1 × 104 M−1. Similar results were found at 4 and 27°C. Verapamil also gave similar behavior, with a Ka of 6.0 × 104 M−1 at 37°C for the saturable sites and a n Ka value for the non-saturable sites of 2.5 × 104 M−1. These measured affinities gave good agreement with solution-phase values. The results indicated HPAC can be used to study drug interactions with HDL, providing information that should be valuable in obtaining a better description of how drugs are transported within the body. PMID:19833090

  3. High-Density Lipoprotein Prevents Endoplasmic Reticulum Stress-Induced Downregulation of Liver LOX-1 Expression.

    PubMed

    Hong, Dan; Li, Ling-Fang; Gao, Hai-Chao; Wang, Xiang; Li, Chuan-Chang; Luo, Ying; Bai, Yong-Ping; Zhang, Guo-Gang

    2015-01-01

    Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a specific cell-surface receptor for oxidized-low-density lipoprotein (ox-LDL). The impact of high-density lipoprotein (HDL) on endoplasmic reticulum (ER) stress-mediated alteration of the LOX-1 level in hepatocytes remains unclear. We aimed to investigate the impact on LOX-1 expression by tunicamycin (TM)-induced ER stress and to determine the effect of HDL on TM-affected LOX-1 expression in hepatic L02 cells. Overexpression or silencing of related cellular genes was conducted in TM-treated cells. mRNA expression was evaluated using real-time polymerase chain reaction (PCR). Protein expression was analyzed by western blot and immunocytochemistry. Lipid uptake was examined by DiI-ox-LDL, followed by flow cytometric analysis. The results showed that TM induced the upregulation of ER chaperone GRP78, downregulation of LOX-1 expression, and lipid uptake. Knock down of IRE1 or XBP-1 effectively restored LOX-1 expression and improved lipid uptake in TM-treated cells. HDL treatment prevented the negative impact on LOX-1 expression and lipid uptake induced by TM. Additionally, 1-10 μg/mL HDL significantly reduced the GRP78, IRE1, and XBP-1 expression levels in TM-treated cells. Our findings reveal that HDL could prevent the TM-induced reduction of LOX-1 expression via inhibiting the IRE1/XBP-1 pathway, suggesting a new mechanism for beneficial roles of HDL in improving lipid metabolism. PMID:25923692

  4. Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction.

    PubMed

    Gu, Xiaodong; Huang, Ying; Levison, Bruce S; Gerstenecker, Gary; DiDonato, Anthony J; Hazen, Leah B; Lee, Joonsue; Gogonea, Valentin; DiDonato, Joseph A; Hazen, Stanley L

    2016-01-22

    Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated protein with atherosclerosis-protective and systemic anti-oxidant functions. We recently showed that PON1, myeloperoxidase, and HDL bind to one another in vivo forming a functional ternary complex (Huang, Y., Wu, Z., Riwanto, M., Gao, S., Levison, B. S., Gu, X., Fu, X., Wagner, M. A., Besler, C., Gerstenecker, G., Zhang, R., Li, X. M., Didonato, A. J., Gogonea, V., Tang, W. H., et al. (2013) J. Clin. Invest. 123, 3815-3828). However, specific residues on PON1 involved in the HDL-PON1 interaction remain unclear. Unambiguous identification of protein residues involved in docking interactions to lipid surfaces poses considerable methodological challenges. Here we describe a new strategy that uses a novel synthetic photoactivatable and click chemistry-taggable phospholipid probe, which, when incorporated into HDL, was used to identify amino acid residues on PON1 that directly interact with the lipoprotein phospholipid surface. Several specific PON1 residues (Leu-9, Tyr-185, and Tyr-293) were identified through covalent cross-links with the lipid probes using affinity isolation coupled to liquid chromatography with on-line tandem mass spectrometry. Based upon the crystal structure for PON1, the identified residues are all localized in relatively close proximity on the surface of PON1, defining a domain that binds to the HDL lipid surface. Site-specific mutagenesis of the identified PON1 residues (Leu-9, Tyr-185, and Tyr-293), coupled with functional studies, reveals their importance in PON1 binding to HDL and both PON1 catalytic activity and stability. Specifically, the residues identified on PON1 provide important structural insights into the PON1-HDL interaction. More generally, the new photoactivatable and affinity-tagged lipid probe developed herein should prove to be a valuable tool for identifying contact sites supporting protein interactions with lipid interfaces such as found on cell membranes

  5. Structural Insights into High Density Lipoprotein: Old Models and New Facts

    PubMed Central

    Gogonea, Valentin

    2016-01-01

    The physiological link between circulating high density lipoprotein (HDL) levels and cardiovascular disease is well-documented, albeit its intricacies are not well-understood. An improved appreciation of HDL function and overall role in vascular health and disease requires at its foundation a better understanding of the lipoprotein's molecular structure, its formation, and its process of maturation through interactions with various plasma enzymes and cell receptors that intervene along the pathway of reverse cholesterol transport. This review focuses on summarizing recent developments in the field of lipid free apoA-I and HDL structure, with emphasis on new insights revealed by newly published nascent and spherical HDL models constructed by combining low resolution structures obtained from small angle neutron scattering (SANS) with contrast variation and geometrical constraints derived from hydrogen–deuterium exchange (HDX), crosslinking mass spectrometry, electron microscopy, Förster resonance energy transfer, and electron spin resonance. Recently published low resolution structures of nascent and spherical HDL obtained from SANS with contrast variation and isotopic labeling of apolipoprotein A-I (apoA-I) will be critically reviewed and discussed in terms of how they accommodate existing biophysical structural data from alternative approaches. The new low resolution structures revealed and also provided some answers to long standing questions concerning lipid organization and particle maturation of lipoproteins. The review will discuss the merits of newly proposed SANS based all atom models for nascent and spherical HDL, and compare them with accepted models. Finally, naturally occurring and bioengineered mutations in apoA-I, and their impact on HDL phenotype, are reviewed and discuss together with new therapeutics employed for restoring HDL function. PMID:26793109

  6. Unidirectional transfer in vivo of high-density lipoprotein cholesteryl esters to lower-density lipoproteins in the pig, an animal species without plasma cholesteryl ester transfer activity.

    PubMed

    Terpstra, A H; Stucchi, A F; Foxall, T L; Shwaery, G T; Vespa, D B; Nicolosi, R J

    1993-12-01

    The metabolism of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesteryl esters (CE) was studied in the pig, an animal species without plasma cholesteryl ester transfer activity (CETA). In the first series of experiments, LDL and HDL from normocholesterolemic pigs were radiolabeled with cholesteryl (1-14C)oleate and intravenously administered to two groups of four normocholesterolemic pigs. Radioactive tracer in LDL remained associated with the LDL fraction, and there was no transfer of LDL-CE to HDL. The transport rate (which represents the production and disposal rate) of LDL-CE in normocholesterolemic pigs was 39 mumol CE/h/L. However, radiolabeled HDL-CE were transferred to LDL (25%), and 36% of the LDL-CE mass was derived from the HDL. The transport rate of HDL-CE was 54 mumol CE/h/L, and the flux of HDL-CE to LDL was 14 mumol CE/h/L. There was no accumulation of radiolabeled HDL-CE in very-low-density lipoprotein (VLDL), which suggests that there was no transfer to VLDL. However, this does not rule out the possibility that either the very low levels of VLDL-CE (< 0.09 mmol/L) or the rapid turnover rate of the VLDL pool might have prevented the accumulation of substantial amounts of tracer in VLDL. Therefore, in a second set of experiments, the kinetics of HDL-CE were studied in high-fat-and high-cholesterol-fed pigs with elevated VLDL-CE concentrations (1.92 mmol/L). Hypercholesterolemia was associated with increased transport rates of LDL-CE (165 mumol/h/L) and HDL-CE (78 mumol/h/L) and with an increased flux of HDL-CE to LDL (78 mumol/h/L).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8246765

  7. [Cholesterol bound to high density lipoproteins: critical review of the methods of analysis and personal data].

    PubMed

    Orso Giacone, G

    1982-01-01

    It is widely known that atherosclerosis through its complication, i.e. heart and brain infarction, is at the present the main cause of death. The atherosclerotic process has been shown in correlation with hyperlipemia especially as far as the plasma lipoprotein cholesterol level is concerned. A preminent role in removing cholesterol from tissues and arterial walls then in preventing atherosclerosis is played by a specific class of plasma lipoproteins, the high density lipoproteins (HDL). Since the HDL-colesterol level seems to have an inverse correlation with the atherosclerotic disease it is of primary importance to define a reliable and reproducible technique to measure it. One of the aims of this paper was to examine the different methods now available for such a determination. This analysis has underlined the discrepancy among the reference values reported in the literature. However, all the authors agree that only the simultaneous measurement of total and HDL-colesterol levels is of prognostic value. Personal studies are here reported on the relationship between total and HDL-colesterol levels and risk factor of cardiovascular diseases. The two mentioned laboratory analyses have been performed on blood samples from 250 between male and female human subjects of different age. The obtained results show that the highest HDL-colesterol concentrations determined by a lipoprotein precipitation procedure with dextran sulphate, are typical in the first ten years of life both in male and in female, while the lowest levels of plasma HDL-cholesterol have been evintiated during the fifth decade of life, when the total cholesterol and the risk of cardiovascular complications rich the highest values. In a following set of investigations, the already examined blood parameters together with the risk factor values have been examined in two groups of subjects, the first one represented by adult healthy persons the second one by patients of similar age from a cardiovascular

  8. Effects of serum amyloid A on the structure and antioxidant ability of high-density lipoprotein.

    PubMed

    Sato, Megumi; Ohkawa, Ryunosuke; Yoshimoto, Akira; Yano, Kouji; Ichimura, Naoya; Nishimori, Madoka; Okubo, Shigeo; Yatomi, Yutaka; Tozuka, Minoru

    2016-08-01

    Serum amyloid A (SAA) levels increase during acute and chronic inflammation and are mainly associated with high-density lipoprotein (HDL). In the present study, we investigated the effect of SAA on the composition, surface charge, particle size and antioxidant ability of HDL using recombinant human SAA (rhSAA) and HDL samples from patients with inflammation. We confirmed that rhSAA bound to HDL3 and released apolipoprotein A-I (apoA-I) from HDL without an apparent change in particle size. Forty-one patients were stratified into three groups based on serum SAA concentrations: Low (SAA ≤ 8 μg/ml), Middle (8 < SAA ≤ 100 μg/ml) and High (SAA > 100 μg/ml). The ratios of apoA-I to total protein mass, relative cholesterol content and negative charge of HDL samples obtained from patients with high SAA levels were lower than that for samples from patients with low SAA levels. Various particle sizes of HDL were observed in three groups regardless of serum SAA levels. Antioxidant ability of rhSAA, evaluated as the effect on the formation of conjugated diene in low-density lipoprotein (LDL) induced by oxidation using copper sulfate, was higher than that of apoA-I. Consistent with this result, reconstituted SAA-containing HDL (SAA-HDL) indicated higher antioxidant ability compared with normal HDL. Furthermore, HDL samples obtained from High SAA group patients also showed the highest antioxidant ability among the three groups. Consequently, SAA affects the composition and surface charge of HDL by displacement of apoA-I and enhances its antioxidant ability. PMID:27422844

  9. Metabolic fate of sphingomyelin of high-density lipoprotein in rat plasma

    SciTech Connect

    Bentejac, M.; Bugaut, M.; Delachambre, M.C.; Lecerf, J. )

    1990-10-01

    The metabolic fate of high density lipoprotein (HDL) sphingomyelin in plasma was studied in rats over a 24-hr period after injection of HDL containing sphingomyelin which was {sup 14}C-labeled in the stearic (18:0) or lignoceric acid (24:0) moiety and {sup 3}H-labeled in the choline methyl groups. Decay of label in plasma followed three phases. The first two phases were similar for both isotopes and both types of sphingomyelin (t1/2 approximately 10 and 110 min). However, during the third phase (from 10 hr after injection), {sup 3}H label disappeared more slowly than {sup 14}C label from 18:0 sphingomyelin, whereas the {sup 3}H/{sup 14}C ratio remained relatively constant when 24:0 sphingomyelin was used. Intact, doubly-labeled 18:0 sphingomyelin disappeared from HDL rapidly (t1/2 = 38 min) by tissue uptake and by transfer to very low density lipoprotein (VLDL). VLDL contained up to 12% of the sphingomyelin 1 hr after injection. This is the first demonstration of a transfer in vivo of sphingomyelin from HDL to VLDL. A similarly rapid transfer was also observed in vitro. Some nontritiated, ({sup 14}C)18:0 or ({sup 14}C)24:0 sphingomyelin was redistributed more slowly into HDL. Doubly-labeled phosphatidylcholine appeared in VLDL and HDL within 1 hr after injection and reached 1.8 and 2.1% of the injected {sup 14}C and {sup 3}H in VLDL at 1 hr, and 4.8 and 6.9% in HDL at 3 hr, respectively.

  10. Chain dynamics of selectively deuterated fatty acids in high-density lipoproteins studied by deuterium NMR

    SciTech Connect

    Parmar, Y.I.; Gorrissen, H.; Wassall, S.R.; Cushley, R.J.

    1985-01-01

    Deuterium order parameters have been determined for approximately 5 mol% selectively deuterated palmitic acid incorporated into the outer monolayer of high-density lipoproteins (HDL/sub 3/). The values are SCD = 0.38 for (2,2-/sup 2/H/sub 2/)palmitic acid, 0.38 for (4,4-/sup 2/H/sub 2/)palmitic acid, 0.37 for (5,5,6,6-/sup 2/H/sub 4/)palmitic acid, 0.23 for (11,11,12,12-/sup 2/H/sub 4/)palmitic acid, and 0.05 for (16,16,16-/sup 2/H/sub 3/)palmitic acid. Comparison of the acyl chain order parameters in HDL/sub 3/ with acyl chain order parameters determined recently for approximately 5 mol% deuterated palmitic acid in sonicated unilamellar vesicles, composed of the same ratio of phosphatidylcholine/sphingomyelin (85/15 w/w) found in HDL/sub 3/, shows that acyl chain order in the HDL/sub 3/ monolayer is approximately 3-5 times higher than in the vesicle bilayer. The acyl chain order in the lipoprotein monolayer is approximately 1.5-2 times higher than in the bilayer of phosphatidylcholine multilamellar dispersions. Deuterium longitudinal relaxation times have been measured for deuterated palmitic acid in HDL/sub 3/, and the values T/sub 1/ approximately 16 ms for C/sub 2/H/sub 2/ and 170 ms for C/sub 2/H/sub 3/ groups are a factor of more than 2 times smaller than found in phospholipid bilayers.

  11. Characteristics of High-density Lipoprotein Subclasses Distribution for Subjects with Desirable Total Cholesterol Levels

    PubMed Central

    2011-01-01

    Background To investigate alteration of high density lipoproteins (HDL) subclasses distribution in different total cholesterol (TC) levels, mainly the characteristics of HDL subclasses distribution in desirable TC levels and analyze the related mechanisms. Methods ApoA-I contents of plasma HDL subclasses were determined by 2-dimensional gel electrophoresis coupled with immunodetection. 486 Chinese Adults subjects were assigned to different TC groups according to the third Report of NCEP (ATP- III) guidelines. Results The increase in contents of small preβ1-HDL, HDL3c, HDL3b, and HDL3a particles clustered and reduce in HDL2b with increased of TC. The distribution of HDL subclasses have shown abnormality characterized by the lower HDL2b (324.2 mg/L) contents and the higher preβ1-HDL (90.4 mg/L) contents for desirable TC Chinese subjects. Among 176 desirable TC subjects, 58.6% subjects with triglyceride (TG) < 2.26 mmol/L, 61.2% subjects with HDL-C ≥1.03 mmol/L and 88.6% subjects with low density lipoprotein cholesterol(LDL-C) < 3.34 mmol/L, and the profile of HDL subclasses distribution for above these subjects was reasonable. Conclusions The particles size of HDL subclasses shifted towards smaller with increased TC levels. The TC was liner with HDL2b contents and those can be reduced 17 mg/L for 0.5 mmol/L increment in TC levels. The HDL subclasses distribution phenotype was not expectation for Chinese Population with desirable TC levels. Thus, from the HDL subclasses distribution point, when assessing the coronary heart disease(CHD) risk not only rely on the TC levels, but also the concentrations of TG, HDL-C and LDL-C must considered in case the potential risk for desirable TC subjects with other plasma lipids metabolism disorders. PMID:21513524

  12. Gestational diabetes mellitus modulates neonatal high-density lipoprotein composition and its functional heterogeneity.

    PubMed

    Sreckovic, Ivana; Birner-Gruenberger, Ruth; Besenboeck, Carolin; Miljkovic, Milica; Stojakovic, Tatjana; Scharnagl, Hubert; Marsche, Gunther; Lang, Uwe; Kotur-Stevuljevic, Jelena; Jelic-Ivanovic, Zorana; Desoye, Gernot; Wadsack, Christian

    2014-11-01

    Gestational diabetes mellitus (GDM) is related to neonatal macrosomia and an increased risk of vascular events. We hypothesized that GDM exerts qualitative effects on neonatal high-density lipoprotein (HDL). HDL was isolated from control (n=11) and GDM maternal/neonatal donors (n=9) and subjected to shotgun proteomics. Differences in HDL mobility were assessed by FPLC and native gel-electrophoresis. Paraoxonase (PON1) activity, cholesterol ester-transfer protein (CETP) mass and activity, phospholipid, triglyceride and cholesterol concentrations were quantified with commercial kits. Total anti-oxidative capacity and cholesterol efflux capability of HDLs were measured. Four proteins involved in lipid metabolism, inflammation and innate immunity were differentially expressed between controls and GDM neonates. ApoM (decreased, p<0.05) and SAA1 (increased, p<0.05) showed the same differences on both, maternal and neonatal GDM HDL. Lower PON1 protein expression was corroborated by lower activity (p<0.05) which in turn was associated with attenuated anti-oxidant capacity of GDM HDL. Protein changes were accompanied by increased levels of triglycerides and decreased levels of cholesterol esters, respectively. The observed differences in GDM HDL lipid moiety may be related to CETP mass and activity alterations. The rate of cholesterol efflux from term trophoblasts to maternal and from placental endothelial cells to neonatal GDM HDL was impaired (p<0.05). In conclusion, GDM causes changes in HDL composition and is intimately associated with impaired cholesterol efflux capability as well as diminished anti-oxidative particle properties. Remodeling of neonatal GDM HDL in utero supports the hypothesis that maternal conditions in pregnancy impact neonatal lipoprotein metabolism. PMID:25130684

  13. Effects of serum amyloid A on the structure and antioxidant ability of high-density lipoprotein

    PubMed Central

    Sato, Megumi; Ohkawa, Ryunosuke; Yoshimoto, Akira; Yano, Kouji; Ichimura, Naoya; Nishimori, Madoka; Okubo, Shigeo; Yatomi, Yutaka; Tozuka, Minoru

    2016-01-01

    Serum amyloid A (SAA) levels increase during acute and chronic inflammation and are mainly associated with high-density lipoprotein (HDL). In the present study, we investigated the effect of SAA on the composition, surface charge, particle size and antioxidant ability of HDL using recombinant human SAA (rhSAA) and HDL samples from patients with inflammation. We confirmed that rhSAA bound to HDL3 and released apolipoprotein A-I (apoA-I) from HDL without an apparent change in particle size. Forty-one patients were stratified into three groups based on serum SAA concentrations: Low (SAA ≤ 8 μg/ml), Middle (8 < SAA ≤ 100 μg/ml) and High (SAA > 100 μg/ml). The ratios of apoA-I to total protein mass, relative cholesterol content and negative charge of HDL samples obtained from patients with high SAA levels were lower than that for samples from patients with low SAA levels. Various particle sizes of HDL were observed in three groups regardless of serum SAA levels. Antioxidant ability of rhSAA, evaluated as the effect on the formation of conjugated diene in low-density lipoprotein (LDL) induced by oxidation using copper sulfate, was higher than that of apoA-I. Consistent with this result, reconstituted SAA-containing HDL (SAA-HDL) indicated higher antioxidant ability compared with normal HDL. Furthermore, HDL samples obtained from High SAA group patients also showed the highest antioxidant ability among the three groups. Consequently, SAA affects the composition and surface charge of HDL by displacement of apoA-I and enhances its antioxidant ability. PMID:27422844

  14. Residual Cardiovascular Risk in Chronic Kidney Disease: Role of High-density Lipoprotein

    PubMed Central

    Kon, Valentina; Yang, Haichun; Fazio, Sergio

    2016-01-01

    Although reducing low-density lipoprotein-cholesterol (LDL-C) levels with lipid-lowering agents (statins) decreases cardiovascular disease (CVD) risk, a substantial residual risk (up to 70% of baseline) remains after treatment in most patient populations. High-density lipoprotein (HDL) is a potential contributor to residual risk, and low HDL-cholesterol (HDL-C) is an established risk factor for CVD. However, in contrast to conventional lipid-lowering therapies, recent studies show that pharmacologic increases in HDL-C levels do not bring about clinical benefits. These observations have given rise to the concept of dysfunctional HDL where increases in serum HDL-C may not be beneficial because HDL loss of function is not corrected by or even intensified by the therapy. Chronic kidney disease (CKD) increases CVD risk, and patients whose CKD progresses to end-stage renal disease (ESRD) requiring dialysis are at the highest CVD risk of any patient type studied. The ESRD population is also unique in its lack of significant benefit from standard lipid-lowering interventions. Recent studies indicate that HDL-C levels do not predict CVD in the CKD population. Moreover, CKD profoundly alters metabolism and composition of HDL particles and impairs their protective effects on functions such as cellular cholesterol efflux, endothelial protection, and control of inflammation and oxidation. Thus, CKD-induced perturbations in HDL may contribute to the excess CVD in CKD patients. Understanding the mechanisms of vascular protection in renal disease can present new therapeutic targets for intervention in this population. PMID:26009251

  15. Physical inactivity interacts with an endothelial lipase polymorphism to modulate high density lipoprotein cholesterol in the GOLDN study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Plasma high density lipoprotein (HDL) cholesterol (HDL-C) concentration is highly heritable but is also modifiable by environmental factors including physical activity. HDL-C response to exercise varies among individuals, and this variability may be associated with genetic polymorphism...

  16. 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

  17. High-density lipoprotein is a potential growth factor for adrenocortical cells

    SciTech Connect

    Murao, Koji . E-mail: mkoji@kms.ac.jp; Imachi, Hitomi; Cao, Wenming; Yu, Xiao; Li, Junhua; Yoshida, Kazuya; Ahmed, Rania A.M.; Matsumoto, Kensuke; Nishiuchi, Takamasa; Ishida, Toshihiko; Wong, Norman C.W.

    2006-05-26

    The entry of cholesterol contained within high-density lipoprotein (HDL) into adrenocortical cells is mediated by a human homologue of SR-BI, CD36, and LIMPII Analogous-1 (CLA-1) and thus augmenting their growth. To address the role of CLA-1, we created a mutant mCLA that lacked the C-terminal tail. HDL CE selective uptake by cells carrying the mCLA-1 receptor was fully active and equivalent to those transfected with full-length CLA-1 (fCLA-1). Expression of mCLA inhibited the proliferation of an adrenocortical cell line and the incorporation of [{sup 3}H]thymidine into the cells. This effect was sensitive to wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K). Our transcriptional studies revealed that the inhibitory action of mCLA required the transcriptional factor AP-1 and the effect of HDL on AP-1 activation was also abrogated by wortmannin. These findings raise the possibility that the inhibitors of the effects of HDL may be of therapeutic value for adrenocortical tumor.

  18. Bone and high-density lipoprotein: The beginning of a beautiful friendship.

    PubMed

    Papachristou, Dionysios J; Blair, Harry C

    2016-02-18

    There is a tight link between bone and lipid metabolic pathways. In this vein, several studies focused on the exploration of high-density lipoprotein (HDL) in the pathobiology of bone diseases, with emphasis to the osteoarthritis (OA) and osteoporosis, the most common bone pathologies. Indeed, epidemiological and in vitro data have connected reduced HDL levels or dysfunctional HDL with cartilage destruction and OA development. Recent studies uncovered functional links between HDL and OA fueling the interesting hypothesis that OA could be a chronic element of the metabolic syndrome. Other studies have linked HDL to bone mineral density. Even though at epidemiological levels the results are conflicting, studies in animals as well as in vitro experiments have shown that HDL facilitates osteoblastogensis and bone synthesis and most probably affects osteoclastogenesis and osteoclast bone resorption. Notably, reduced HDL levels result in increased bone marrow adiposity affecting bone cells function. Unveiling the mechanisms that connect HDL and bone/cartilage homeostasis may contribute to the design of novel therapeutic agents for the improvement of bone and cartilage quality and thus for the treatment of related pathological conditions. PMID:26925377

  19. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

    NASA Astrophysics Data System (ADS)

    Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

    2014-01-01

    Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

  20. Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion).

    PubMed

    Wada, Masamichi; Iso, Tatsuya; Asztalos, Bela F; Takama, Noriaki; Nakajima, Tadashi; Seta, Yukihiro; Kaneko, Katsumi; Taniguchi, Yasuhiro; Kobayashi, Hideo; Nakajima, Katsuyuki; Schaefer, Ernst J; Kurabayashi, Masahiko

    2009-11-01

    We report a novel apolipoprotein A-I (apoA-I) mutation identified in a 64-year-old patient with marked plasma high density lipoprotein (HDL) cholesterol (4 mg/dl) and apoA-I (5mg/dl) deficiency, prior myocardial infarction, and moderate corneal opacities. Coronary angiography revealed extensive atherosclerosis in all three major vessels. Genomic DNA sequencing of the proband revealed a homozygous novel deletion of two successive adenine residues in codon 138 in the apoA-I gene, resulting in a frameshift mutation at amino acid residues 138-178, which we have designated as apoA-I Tomioka. His elder brother was also homozygous for apoA-I Tomioka with marked HDL cholesterol and apoA-I deficiency, but had no clinical evidence of coronary heart disease. Other family members including three siblings and two sons were heterozygous for the mutation, and had approximately 50% of normal plasma HDL cholesterol, and apoA-I. Analysis of apoA-I-containing HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I HDL particles in the homozygotes, while in heterozygotes, the mean concentrations of apoA-I in large alpha-1 and very small prebeta-1 HDL subpopulations were significantly decreased at about 35% of normal. Thus, apoA-I Tomioka, a novel deletion mutation in codon 138 of the apoA-I gene, is the causative defect in this case of HDL deficiency. PMID:19473658

  1. High-density lipoprotein-mediated transcellular cholesterol transport in mouse aortic endothelial cells.

    PubMed

    Miao, LiXia; Okoro, Emmanuel U; Cao, ZhiJan; Yang, Hong; Motley-Johnson, Evangeline; Guo, Zhongmao

    2015-09-18

    Accumulation of unesterified cholesterol-rich lipid vesicles in the subendothelial space contributes to atherogenesis. Transport of cholesterol from the subendothelial intima back to the circulating blood inhibits atherosclerosis development; however, the mechanism for this process has not been fully defined. Using cultured mouse aortic endothelial cells (MAECs), we observed that unesterified cholesterol can be transported across the endothelial cell monolayer from the basolateral to the apical compartment. Administration of high-density lipoprotein (HDL) or apolipoprotein AI (apoAI) to the apical compartment enhanced transendothelial cholesterol transport in a concentration-dependent manner. Knockdown of ATP-binding cassette transporter G1 (ABCG1) or scavenger receptor class B type I (SR-B1), or inhibition of SR-B1 diminished HDL-induced transendothelial cholesterol transport; while knockdown of ABCA1 reduced apoAI-mediated cholesterol transport. HDL enhanced phosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt in MAECs. However, inhibition of PI3K or Akt did not reduce HDL-induced transendothelial cholesterol transport. These results suggest that HDL enhances transendothelial cholesterol transport by activation of a mechanism involving ABCA1, ABCG1 and SR-B1 but not involving PI3K and Akt. PMID:26255968

  2. Network-Based Analysis on Orthogonal Separation of Human Plasma Uncovers Distinct High Density Lipoprotein Complexes.

    PubMed

    Li, Hailong; Gordon, Scott M; Zhu, Xiaoting; Deng, Jingyuan; Swertfeger, Debi K; Davidson, W Sean; Lu, L Jason

    2015-08-01

    High density lipoprotein (HDL) particles are blood-borne complexes whose plasma levels have been associated with protection from cardiovascular disease (CVD). Recent studies have demonstrated the existence of distinct HDL subspecies; however, these have been difficult to isolate and characterize biochemically. Here, we present the first report that employs a network-based approach to systematically infer HDL subspecies. Healthy human plasma was separated into 58 fractions using our previously published three orthogonal chromatography techniques. Similar local migration patterns among HDL proteins were captured with a novel similarity score, and individual comigration networks were constructed for each fraction. By employing a graph mining algorithm, we identified 183 overlapped cliques, among which 38 were further selected as candidate HDL subparticles. Each of these 38 subparticles had at least two literature supports. In addition, GO function enrichment analysis showed that they were enriched with fundamental biological and CVD protective functions. Furthermore, gene knockout experiments in mouse model supported the validity of these subparticles related to three apolipoproteins. Finally, analysis of an apoA-I deficient human patient's plasma provided additional support for apoA-I related complexes. Further biochemical characterization of these putative subspecies may facilitate the mechanistic research of CVD and guide targeted therapeutics aimed at its mitigation. PMID:26057100

  3. Revising the high-density lipoprotein targeting strategies - insights from human and preclinical studies.

    PubMed

    Nesan, Dinushan; Ng, Dominic S

    2014-12-01

    In recent years, the high-density lipoprotein (HDL) hypothesis has been challenged. Several completed randomized clinical trials continue to fall short in demonstrating HDL, or at least HDL-cholesterol (HDL-C) levels, as being a consistent target in the prevention of cardiovascular diseases. However, population studies and findings in lipid modifying trials continue to strongly support HDL-C as a superb risk predictor. It is increasingly evident that the complexity of HDL metabolism confounds the use of HDL-C concentration as a unified target. However, important insights continue to emerge from the post hoc analyses of recently completed (i) fibrate-based FIELD and ACCORD trials, including the unexpected beneficial effect of fibrates in microvascular diseases, (ii) the niacin-based AIM-HIGH and HPS2-THRIVE studies, (iii) recombinant HDL-based as well as (iv) the completed CETP inhibitor-based trials. These together with on-going mechanistic studies on novel pathways, which include the unique roles of microRNAs, post-translational remodeling of HDL and novel pathways related to HDL modulators will provide valuable insights to guide how best to refocus and redesign the conceptual framework for selecting HDL-based targets. PMID:25115413

  4. Bone and high-density lipoprotein: The beginning of a beautiful friendship

    PubMed Central

    Papachristou, Dionysios J; Blair, Harry C

    2016-01-01

    There is a tight link between bone and lipid metabolic pathways. In this vein, several studies focused on the exploration of high-density lipoprotein (HDL) in the pathobiology of bone diseases, with emphasis to the osteoarthritis (OA) and osteoporosis, the most common bone pathologies. Indeed, epidemiological and in vitro data have connected reduced HDL levels or dysfunctional HDL with cartilage destruction and OA development. Recent studies uncovered functional links between HDL and OA fueling the interesting hypothesis that OA could be a chronic element of the metabolic syndrome. Other studies have linked HDL to bone mineral density. Even though at epidemiological levels the results are conflicting, studies in animals as well as in vitro experiments have shown that HDL facilitates osteoblastogensis and bone synthesis and most probably affects osteoclastogenesis and osteoclast bone resorption. Notably, reduced HDL levels result in increased bone marrow adiposity affecting bone cells function. Unveiling the mechanisms that connect HDL and bone/cartilage homeostasis may contribute to the design of novel therapeutic agents for the improvement of bone and cartilage quality and thus for the treatment of related pathological conditions. PMID:26925377

  5. Fluorescence correlation spectroscopy to measure the metabolism of high-density lipoprotein

    NASA Astrophysics Data System (ADS)

    Deitrick, Russell; Gibson, Emily; Razzaghi, Hamid

    2009-10-01

    High-density lipoprotein (HDL), referred to as the ``good cholesterol'', carries free cholesterol to the liver to be filtered from the bloodstream and is important to our understanding of atherosclerosis. HDL is metabolized in part by the enzyme Endothelial Lipase (EL). With this project we will use fluorescence correlation spectroscopy (FCS) to study the metabolism of HDL by EL comparing wild type with different genetic mutations. FCS is an advanced microscopy technique in which we record fluctuations in the fluorescence of dye-labeled molecules (in this case, HDL labeled with Nile Red) as they freely diffuse through a small focal volume. This data can be analyzed mathematically using the cross-correlation function, from which we can ultimately ascertain much information. In our case, we are interested in the diffusion coefficient which, via the Stokes-Einstein relation for a sphere, we can determine the size of HDL as it undergoes the process of metabolism. Preliminary results seem to indicate that the metabolic process occurs very quickly, that the final size of HDL depends primarily on the concentration of EL, and that the wild and mutant variants of EL have a similar effectiveness. In following experiments, we hope to investigate these relationships further.

  6. Targeted Delivery of Small Interfering RNA Using Reconstituted High-Density Lipoprotein Nanoparticles12

    PubMed Central

    Shahzad, Mian MK; Mangala, Lingegowda S; Han, Hee Dong; Lu, Chunhua; Bottsford-Miller, Justin; Nishimura, Masato; Mora, Edna M; Lee, Jeong-Won; Stone, Rebecca L; Pecot, Chad V; Thanapprapasr, Duangmani; Roh, Ju-Won; Gaur, Puja; Nair, Maya P; Park, Yun-Yong; Sabnis, Nirupama; Deavers, Michael T; Lee, Ju-Seog; Ellis, Lee M; Lopez-Berestein, Gabriel; McConathy, Walter J; Prokai, Laszlo; Lacko, Andras G; Sood, Anil K

    2011-01-01

    RNA interference holds tremendous potential as a therapeutic approach, especially in the treatment of malignant tumors. However, efficient and biocompatible delivery methods are needed for systemic delivery of small interfering RNA (siRNA). To maintain a high level of growth, tumor cells scavenge high-density lipoprotein (HDL) particles by overexpressing its receptor: scavenger receptor type B1 (SR-B1). In this study, we exploited this cellular characteristic to achieve efficient siRNA delivery and established a novel formulation of siRNA by incorporating it into reconstituted HDL (rHDL) nanoparticles. Here, we demonstrate that rHDL nanoparticles facilitate highly efficient systemic delivery of siRNA in vivo, mediated by the SR-B1. Moreover, in therapeutic proof-of-concept studies, these nanoparticles were effective in silencing the expression of two proteins that are key to cancer growth and metastasis (signal transducer and activator of transcription 3 and focal adhesion kinase) in orthotopic mouse models of ovarian and colorectal cancer. These data indicate that an rHDL nanoparticle is a novel and highly efficient siRNA carrier, and therefore, this novel technology could serve as the foundation for new cancer therapeutic approaches. PMID:21472135

  7. Correlation between high density lipoprotein and monocyte subpopulations among stable coronary atherosclerotic heart disease patients

    PubMed Central

    Yang, Rong-Hai; Liu, Ying-Feng; Wang, Xue-Jun; Liang, Jian-Guang; Liu, Jia-Chao

    2015-01-01

    High density lipoprotein (HDL) is a structurally and functionally heterogeneous molecular particle whose function is unclear in atherosclerosis at present. Studies show that small HDL functional imbalance may exist in Coronary Atherosclerotic Heart Disease (CAD) patients. Monocyte is considered to play an important role in atherosclerosis, in accordance with the expression of superficial CD14 and CD16, it can be divided into three subpopulations. The purpose of this study was to explore the relation between HDL and monocyte subpopulations among CAD patients. We report 90 cases of stable CAD patients and define the monocyte subpopulations as classical monocyte (CD14++CD16-; CM), intermediate monocyte (CD14+CD16+; IM), and non-classical monocyte (CD14+CD16++; NCM); HDL group is measured by polyacrylamide gel electrophoresis. The results indicated that the small HDL in blood serum has a correlation with proinflammatory NCM in circulation but a negative correction with CM and no relationship with diabetes, saccharify hemoglobin, hypertension, smoking history and taking dose of statins drugs and severity of disease. In conclusion, this study primarily confirms that micromolecule HDL level correlates with the increase of non-classical monocyte subpopulations and decrease of classical monocyte quantity. Thus demonstrates the proinflammatory correlation between micromolecule HDL and internal immunity in the development of stable atherosclerosis. PMID:26629252

  8. Synthetic High-Density Lipoprotein-Like Nanoparticles as Cancer Therapy

    PubMed Central

    McMahon, Kaylin M.; Foit, Linda; Angeloni, Nicholas L.; Giles, Francis J.; Gordon, Leo I.; Thaxton, C. Shad

    2015-01-01

    High-density lipoproteins (HDL) are diverse natural nanoparticles that carry cholesterol and are best known for the role that they play in cardiovascular disease. However, due to their unique targeting capabilities, diverse molecular cargo, and natural functions beyond cholesterol transport, it is becoming increasingly appreciated that HDLs are critical to cancer development and progression. Accordingly, this chapter highlights ongoing research focused on the connections between HDL and cancer in order to design new drugs and targeted drug delivery vehicles. Research is focused on synthesizing biomimetic HDL-like nanoparticles (NP) that can be loaded with diverse therapeutic cargo (e.g. chemotherapies, nucleic acids, proteins) and specifically targeted to cancer cells. Beyond drug delivery, new data is emerging that HDL-like NPs may be therapeutically active in certain tumor types, for example B cell lymphoma. Overall, HDL-like NPs are becoming increasingly appreciated as targeted, biocompatible, and efficient therapies for cancer, and may soon become indispensable agents in the cancer therapeutic armamentarium. PMID:25895867

  9. High Density Lipoproteins for the Systemic Delivery of short interfering RNA

    PubMed Central

    McMahon, Kaylin M.; Thaxton, C. Shad

    2014-01-01

    Introduction RNA interference (RNAi) is a powerful mechanism for gene silencing with the potential to greatly impact the development of new therapies for many human diseases. Short interfering RNAs (siRNAs) may be the ideal molecules for therapeutic RNAi. However, therapeutic siRNAs face significant challenges that must be overcome prior to widespread clinical use. Many efforts have been made to overcome the hurdles associated with systemic administration of siRNA; however, current approaches are still limited. As such, there is an urgent need to develop new strategies for siRNA delivery that have the potential to impact a broad spectrum of systemic diseases. Areas covered This review focuses on the promise of siRNA therapies and highlights current siRNA delivery methods. With an eye toward new strategies, this review first introduces high density lipoproteins (HDL) and their natural functions, and then transitions into how HDLs may provide significant opportunities as next generation siRNA delivery vehicles. Importantly, this review describes how synthetic HDLs leverage the natural ability of HDL to stabilize and deliver siRNAs. Expert Opinion HDLs are natural nanoparticles that are critical to understanding the systemic delivery of therapeutic nucleic acids, like siRNA. Methods to synthesize biomimetic HDLs are being explored and data demonstrate that this type of delivery vehicle may be highly beneficial for targeted and efficacious systemic delivery of siRNAs. PMID:24313310

  10. High-density lipoprotein therapy inhibits Porphyromonas gingivalis-induced abdominal aortic aneurysm progression.

    PubMed

    Delbosc, Sandrine; Rouer, Martin; Alsac, Jean-Marc; Louedec, Liliane; Al Shoukr, Faisal; Rouzet, François; Michel, Jean-Baptiste; Meilhac, Olivier

    2016-04-01

    Clinical and experimental studies have highlighted the potential implication of periondontal bacteria contamination in the pathogenesis of abdominal aortic aneurysms (AAA). In addition to their role in reverse cholesterol transport, high-density lipoproteins (HDLs) display multiple functions, including anti-inflammatory and lipopolysaccharide scavenging properties. Low plasma levels of HDL-cholesterol have been reported in AAA patients. We tested the effect of a HDL therapy in Sprague-Dawley rat model of AAA, obtained by intraluminal elastase infusion followed by repeated injections of Porphyromonas gingivalis (Pg). HDLs, isolated by ultracentrifugation of plasma from healthy human volunteers, were co-injected intravenously (10 mg/kg) with Pg (1.107 Colony Forming Unit) one, eight and 15 days after elastase perfusion. Rats were sacrificed one week after the last injection. Our results show that Pg injections promote the formation of a persistent neutrophil-rich thrombus associated with increased aortic diameter in this AAA model. HDLs significantly reduced the increased AAA diameter induced by Pg. Histology showed the onset of a healing process in the Pg/HDL group. HDL injections also reduced neutrophil activation in Pg-injected rats associated with decreased cytokine levels in conditioned media and plasma. Scintigraphic analysis showed an intense uptake of 99mTc-HDL by the AAA suggesting that HDLs could exert their beneficial effect by acting directly on the thrombus components. HDL supplementation may therefore constitute a new therapeutic tool for AAA treatment. PMID:26676721

  11. Liver disease alters high-density lipoprotein composition, metabolism and function.

    PubMed

    Trieb, Markus; Horvath, Angela; Birner-Gruenberger, Ruth; Spindelboeck, Walter; Stadlbauer, Vanessa; Taschler, Ulrike; Curcic, Sanja; Stauber, Rudolf E; Holzer, Michael; Pasterk, Lisa; Heinemann, Akos; Marsche, Gunther

    2016-07-01

    High-density lipoproteins (HDL) are important endogenous inhibitors of inflammatory responses. Functional impairment of HDL might contribute to the excess mortality experienced by patients with liver disease, but the effect of cirrhosis on HDL metabolism and function remain elusive. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function using apolipoprotein (apo) B-depleted sera from patients with compensated cirrhosis, patients with acutely decompensated cirrhosis and healthy controls. We observed that sera of cirrhotic patients showed reduced levels of HDL-cholesterol and profoundly suppressed activities of several enzymes involved in HDL maturation and metabolism. Native gel electrophoresis analyses revealed that cirrhotic serum HDL shifts towards the larger HDL2 subclass. Proteomic assessment of isolated HDL identified several proteins, including apoA-I, apoC-III, apoE, paraoxonase 1 and acute phase serum amyloid A to be significantly altered in cirrhotic patients. With regard to function, these alterations in levels, composition and structure of HDL were strongly associated with metrics of function of apoB-depleted sera, including cholesterol efflux capability, paraoxonase activity, the ability to inhibit monocyte production of cytokines and endothelial regenerative activities. Of particular interest, cholesterol efflux capacity appeared to be strongly associated with liver disease mortality. Our findings may be clinically relevant and improve our ability to monitor cirrhotic patients at high risk. PMID:27106140

  12. Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly.

    PubMed

    Segrest, Jere P; Jones, Martin K; Catte, Andrea; Manchekar, Medha; Datta, Geeta; Zhang, Lei; Zhang, Robin; Li, Ling; Patterson, James C; Palgunachari, Mayakonda N; Oram, Jack F; Ren, Gang

    2015-07-01

    Biogenesis of high-density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density, driven by excess PL or membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol. PMID:26095027

  13. 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

  14. The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict?

    PubMed

    Rosenson, Robert S

    2016-05-01

    Classical epidemiology has established the incremental contribution of the high-density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins. PMID:26966281

  15. Purification and properties of the very high density lipoprotein from the hemolymph of adult Triatoma infestans.

    PubMed

    Rimoldi, O J; Soulages, J L; González, S M; Peluffo, R O; Brenner, R R

    1989-06-01

    The very high density lipoprotein (VHDL) of Triatoma infestans hemolymph from adult males has been isolated and purified by two-step density gradient ultracentrifugation. It appears to be homogeneous as judged by native polyacrylamide gel electrophoresis. The content of VHDL in hemolymph was estimated to be 8 mg protein/ml. The purified protein has a molecular weight (Mr) of 450,000, is composed of six subunits of Mr approximately equal to 77,000, and possesses a high content of aromatic amino acids. This protein is glycosylated and contains 3% of lipids by weight with a remarkable amount of free fatty acids (25% of total lipids). The T. infestans VHDL has a different lipid and amino acid composition from lipophorin. The lipid composition and the spectroscopic studies using cis-parinaric acid indicated a high fatty acid binding affinity. It has nine binding sites per mol of VHDL. Competence studies revealed that VHDL has its highest affinity for the binding of palmitic acid followed by stearic and arachidonic acids. PMID:2677201

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

    PubMed Central

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

    2013-01-01

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

  17. Intercorrelations among plasma high density lipoprotein, obesity and triglycerides in a normal population

    SciTech Connect

    Albrink, M.J.; Krauss, R.M.; Lindgren, F.T.; von der Groeben, J.; Pan, S.; Wood, P.D.

    1980-01-01

    The interrelationships among fatness measures, plasma triglycerides and high density lipoproteins (HDL) were examined in 131 normal adult subjects: 38 men aged 27 to 46, 50 men aged 47 to 66, 29 women aged 27 to 46 and 24 women aged 47 to 66. None of the women were taking estrogens or oral contraceptive medication. The HDL concentration was subdivided into HDL/sub 2b/, HDL/sub 2a/ and HDL by a computerized fitting of the total schileren pattern to reference schlieren patterns. Anthropometric measures employed included skinfolds at 3 sites, 2 weight/height indices and 2 girth measurements. A high correlation was found among the various fatness measures. These measures were negatively correlated with total HDL, reflecting the negative correlation between fatness measures and HDL/sub 2/ (as the sum of HDL/sub 2a/ and /sub 2b/). Fatness measures showed no relationship to HDL/sub 3/. There was also an inverse correlation between triglyceride concentration and HDL/sub 2/. No particular fatness measure was better than any other for demonstrating the inverse correlation with HDL but multiple correlations using all of the measures of obesity improved the correlations. Partial correlations controlling for fatness did not reduce any of the significnt correlations between triglycerides and HDL/sub 2/ to insignificance. The weak correlation between fatness and triglycerides was reduced to insigifnicance when controlled for HDL/sub 2/.

  18. A Statin-Loaded Reconstituted High-Density Lipoprotein Nanoparticle Inhibits Atherosclerotic Plaque Inflammation

    PubMed Central

    Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S.G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J.M.

    2014-01-01

    Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation. PMID:24445279

  19. Anti-psoriatic treatment extends beyond the skin: Recovering of high-density lipoprotein function

    PubMed Central

    Marsche, Gunther; Holzer, Michael; Wolf, Peter

    2016-01-01

    Epidemiological and clinical studies have shown a consistent association of psoriasis with systemic metabolic disorders including an increased prevalence of diabetes, obesity and cardiovascular disease. Psoriasis is accompanied by systemic inflammation and low levels of high-density lipoprotein (HDL)-cholesterol. Recent studies provided clear evidence that psoriasis affects HDL composition and function. HDL isolated from psoriatic patients showed a significantly impaired capability to mobilize cholesterol from macrophages, a crucial step in reverse cholesterol transport and markedly lower paraoxonase activity, a protein that co-transports with HDL in serum with well-known anti-atherogenic properties. Of particular interest, successful anti-psoriatic therapy significantly improved HDL composition and function independently of serum HDL-cholesterol levels. These novel findings suggest that the conventional approaches of evaluating cardiovascular risk in psoriasis may be in need of refinement. As these data argue for a loss of beneficial activities of HDL in psoriatic patients, altered HDL functionality should be considered when evaluating the lipid status of patients. PMID:24980461

  20. The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma.

    PubMed

    Koudinov, A; Matsubara, E; Frangione, B; Ghiso, J

    1994-12-15

    The amyloid fibrils of Alzheimer's neuritic plaques and cerebral blood vessels are mainly composed of aggregated forms of a 39 to 44 amino acids peptide, named amyloid beta (A beta). A similar although soluble form of A beta (sA beta) has been identified in plasma, cerebrospinal fluid and cell culture supernatants, indicating that it is produced under physiologic conditions. We report here that sA beta in normal human plasma is associated with lipoprotein particles, in particular to the HDL3 and VHDL fractions where it is complexed to ApoJ and, to a lesser extent, to ApoAI. This was assessed by immunoprecipitation experiments of purified plasma lipoproteins and lipoprotein-depleted plasma and confirmed by means of amino acid sequence analysis. Moreover, biotinylated synthetic peptide A beta 1-40 was traced in normal human plasma in in vitro experiments. As in the case of sA beta, biotinylated A beta 1-40 was specifically recovered in the HDL3 and VHDL fractions. This data together with the previous demonstration that A beta 1-40 is taken up into the brain via a specific mechanism and possibly as an A beta 1-40-ApoJ complex indicate a role for HDL3- and VHDL-containing ApoJ in the transport of the peptide in circulation and suggest their involvement in the delivery of sA beta across the blood-brain barrier. PMID:7802646

  1. Alpha slow-moving high-density-lipoprotein subfraction in serum of a patient with radiation enteritis and peritoneal carcinosis

    SciTech Connect

    Peynet, J.; Legrand, A.; Messing, B.; Thuillier, F.; Rousselet, F.

    1989-04-01

    An alpha slow-moving high-density-lipoprotein (HDL) subfraction was seen in a patient presenting with radiation enteritis and peritoneal carcinosis, who was given long-term cyclic parenteral nutrition. This subfraction, observed in addition to normal HDL, was precipitated with low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) by sodium phosphotungstate-magnesium chloride. The patient's serum lipoproteins were analyzed after fractionation by density gradient ultracentrifugation. The alpha slow-moving HDL floated in the ultracentrifugation subfractions with densities ranging from 1.028 to 1.084 kg/L, and their main apolipoproteins included apolipoprotein E in addition to apolipoprotein A-I. These HDL were larger than HDL2. The pathogenesis of this unusual HDL subfraction is hypothesized.

  2. Relative atherogenicity and predictive value of non-high-density lipoprotein cholesterol for coronary heart disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although low-density lipoprotein cholesterol (LDL-C) is a well-established atherogenic factor for coronary heart disease, it does not completely represent the risk associated with atherogenic lipoproteins in the presence of high triglyceride (TG) levels. Constituent lipoproteins constituting non–hig...

  3. High-Density Lipoprotein Function in Exudative Age-Related Macular Degeneration

    PubMed Central

    Pertl, Laura; Kern, Sabine; Weger, Martin; Hausberger, Silke; Trieb, Markus; Gasser-Steiner, Vanessa; Haas, Anton; Scharnagl, Hubert; Heinemann, Akos; Marsche, Gunther

    2016-01-01

    Purpose High-density lipoproteins (HDL) have long been implicated in the pathogenesis of age-related macular degeneration (AMD). However, conflicting results have been reported with regard to the associations of AMD with HDL-cholesterol levels. The present study is the first to assess HDL composition and metrics of HDL function in patients with exudative AMD and control patients. Methods Blood samples were collected from 29 patients with exudative AMD and 26 age-matched control patients. Major HDL associated apolipoproteins were determined in apoB-depleted serum by immunoturbidimetry or ELISA, HDL-associated lipids were quantified enzymatically. To get an integrated measure of HDL quantity and quality, we assessed several metrics of HDL function, including cholesterol efflux capacity, anti-oxidative and anti-inflammatory activities using apoB-depleted serum from study participants. Results In our study, we observed that the HDL associated acute phase protein serum amyloid A (SAA) was significantly increased in AMD patients (p<0.01), whereas all other assessed apolipoproteins including ApoA-I, apoA-II, apoC-II, apoC-III and apoE as well as major HDL associated lipids were not altered. HDL efflux capacity, anti-oxidative capacity and arylesterase activity were not different in AMD patients when compared with the control group. The ability of apoB-depleted serum to inhibit monocyte NF-κB expression was significantly improved in AMD patients (mean difference (MD) -5.6, p<0.01). Moreover, lipoprotein-associated phospholipase A2 activity, a marker of vascular inflammation, was decreased in AMD subjects (MD -24.1, p<0.01). Conclusions The investigated metrics of HDL composition and HDL function were not associated with exudative AMD in this study, despite an increased content of HDL associated SAA in AMD patients. Unexpectedly, anti-inflammatory activity of apoB-depleted serum was even increased in our study. Our data suggest that the investigated parameters of serum HDL

  4. High-density lipoprotein cholesterol values independently and inversely predict cardiac troponin T and I concentration

    PubMed Central

    Lo Cascio, Claudia; Brocco, Giorgio; Danese, Elisa; Montagnana, Martina; Bassi, Antonella; Caruso, Beatrice; Bovo, Chiara; Salvagno, Gian Luca

    2016-01-01

    Background This retrospective study was planned to establish potential associations between circulating values of cardiac troponins and those of conventional blood lipids. Methods The study population consisted of patients attending an inpatient clinic of the University Hospital of Verona during the year 2015 as part of routine cardiovascular risk assessment. No exclusion criteria were applied. Serum lipids including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) were measured using reference enzymatic techniques, whereas troponin T (TnT) was measured using a high-sensitivity (HS) immunoassay. A second analysis was also performed in the General Hospital of Verona, extracting data from the local laboratory database of all patients in whom troponin I (TnI) and blood lipids were simultaneously measured during the same year. Results In univariate analysis, HS-TnT was found to be associated with age, sex, TC, LDL-C, HDL-C, but not with TG. In multivariate linear regression analysis, age (positive correlation; P<0.001) and HDL-C (negative correlation; P=0.032) remained significantly associated with HS-TnT. The frequency of HS-TnT values >50 ng/L was higher in subjects with HDL-C <1 mmol/L than in those with HDL-C ≥1 mmol/L [odds ratio (OR), 1.84; 95% confidence interval (CI), 1.03–3.32]. The frequency of HS-TnT values >50 ng/L was also higher in elderly subjects than in younger ones (OR, 2.10; 95% CI, 1.15–3.84). The combination of age and HDL-C explained 35% of overall variability of TnT concentration. In the second analysis, HDL-C was also found to be an independent and negative predictor of TnI in multivariate linear regression analysis (P=0.010). The combination of age and HDL-C explained approximately 28% of the overall variability of TnI concentration. Conclusions Our study suggests that HDL-C values inversely predict cardiac troponins concentration irrespective of age

  5. Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis

    PubMed Central

    Chen, Suet Nee; Cilingiroglu, Mehmet; Todd, Josh; Lombardi, Raffaella; Willerson, James T; Gotto, Antonio M; Ballantyne, Christie M; Marian, AJ

    2009-01-01

    Background Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. Methods We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Results Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. Conclusion Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma

  6. Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus

    PubMed Central

    Drew, Brian G.; Carey, Andrew L.; Natoli, Alaina K.; Formosa, Melissa F.; Vizi, Donna; Reddy-Luthmoodoo, Medini; Weir, Jacquelyn M.; Barlow, Christopher K.; van Hall, Gerrit; Meikle, Peter J.; Duffy, Stephen J.; Kingwell, Bronwyn A.

    2011-01-01

    We recently demonstrated that reconstituted high-density lipoprotein (rHDL) modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin. Given the key roles of both AMPK and insulin in fatty acid metabolism, the current study investigated the effect of rHDL infusion on fatty acid oxidation and lipolysis. Thirteen patients with type 2 diabetes received separate infusions of rHDL and placebo in a randomized, cross-over study. Fatty acid metabolism was assessed using steady-state tracer methodology, and plasma lipids were measured by mass spectrometry (lipidomics). In vitro studies were undertaken in 3T3-L1 adipocytes. rHDL infusion inhibited fasting-induced lipolysis (P = 0.03), fatty acid oxidation (P < 0.01), and circulating glycerol (P = 0.04). In vitro, HDL inhibited adipocyte lipolysis in part via activation of AMPK, providing a possible mechanistic link for the apparent reductions in lipolysis observed in vivo. In contrast, circulating NEFA increased after rHDL infusion (P < 0.01). Lipidomic analyses implicated phospholipase hydrolysis of rHDL-associated phosphatidylcholine as the cause, rather than lipolysis of endogenous fat stores. rHDL infusion inhibits fasting-induced lipolysis and oxidation in patients with type 2 diabetes, potentially through both AMPK activation in adipose tissue and elevation of plasma insulin. The phospholipid component of rHDL also has the potentially undesirable effect of increasing circulating NEFA. PMID:21224289

  7. Impaired High-Density Lipoprotein Anti-Oxidant Function Predicts Poor Outcome in Critically Ill Patients

    PubMed Central

    Schrutka, Lore; Goliasch, Georg; Meyer, Brigitte; Wurm, Raphael; Koller, Lorenz; Kriechbaumer, Lukas; Heinz, Gottfried; Pacher, Richard; Lang, Irene M

    2016-01-01

    Introduction Oxidative stress affects clinical outcome in critically ill patients. Although high-density lipoprotein (HDL) particles generally possess anti-oxidant capacities, deleterious properties of HDL have been described in acutely ill patients. The impact of anti-oxidant HDL capacities on clinical outcome in critically ill patients is unknown. We therefore analyzed the predictive value of anti-oxidant HDL function on mortality in an unselected cohort of critically ill patients. Method We prospectively enrolled 270 consecutive patients admitted to a university-affiliated intensive care unit (ICU) and determined anti-oxidant HDL function using the HDL oxidant index (HOI). Based on their HOI, the study population was stratified into patients with impaired anti-oxidant HDL function and the residual study population. Results During a median follow-up time of 9.8 years (IQR: 9.2 to 10.0), 69% of patients died. Cox regression analysis revealed a significant and independent association between impaired anti-oxidant HDL function and short-term mortality with an adjusted HR of 1.65 (95% CI 1.22–2.24; p = 0.001) as well as 10-year mortality with an adj. HR of 1.19 (95% CI 1.02–1.40; p = 0.032) when compared to the residual study population. Anti-oxidant HDL function correlated with the amount of oxidative stress as determined by Cu/Zn superoxide dismutase (r = 0.38; p<0.001). Conclusion Impaired anti-oxidant HDL function represents a strong and independent predictor of 30-day mortality as well as long-term mortality in critically ill patients. PMID:26978526

  8. Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein.

    PubMed

    Hajduk, S L; Moore, D R; Vasudevacharya, J; Siqueira, H; Torri, A F; Tytler, E M; Esko, J D

    1989-03-25

    Trypanosoma brucei brucei is an important pathogen of domestic cattle in sub-Saharan Africa and is closely related to the human sleeping sickness parasites, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. However, T. b. brucei is non-infectious to humans. The restriction of the host range of T. b. brucei results from the sensitivity of the parasite to lysis by toxic human high density lipoproteins (HDL) (Rifkin, M. R. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 3450-3454). We show in this report that trypanosome lytic activity is not a universal feature of all human HDL particles but rather that it is associated with a minor subclass of HDL. We have purified the lytic activity about 8,000-fold and have identified and characterized the subspecies of HDL responsible for trypanosome lysis. This class of HDL has a relative molecular weight of 490,000, a buoyant density of 1.21-1.24 g/ml, and a particle diameter of 150-210 A. It contains apolipoproteins AI, AII, CI, CII, and CIII, and monoclonal antibodies against apo-AI and apo-AII inhibit trypanocidal activity. In addition to these common apolipoproteins, the particles also contain at least three unique proteins, as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. Treatment of the particles with dithiothreitol resulted in the disappearance of two of the proteins and abolished trypanocidal activity. Two-dimensional gel electrophoresis showed that these proteins were a disulfide-linked trimer of 45,000, 36,000, and 13,500-Da polypeptides and dimers of the 36,000- and 13,500-Da polypeptides or of 65,000- and 8,500-Da polypeptides. Studies on the lysis of T. b. brucei by the purified particle suggest that the lytic pathway may involve the uptake of the trypanocidal subspecies of HDL by endocytosis. PMID:2494183

  9. Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics

    SciTech Connect

    Sakamuri, Rama Murthy; Price, Dominique N.; Lee, Myungsun; Cho, Sang Nae; Barry, Clifton E.; Via, Laura E.; Swanson, Basil I.; Mukundan, Harshini

    2013-02-14

    Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum, and demonstrate that the circulating concentrations of ‘monomeric’ LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. Furthermore, this phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilic in nature and may also be associated with host lipid carriers. Such interactions are likely to affect host–pathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics.

  10. APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema.

    PubMed

    Burkart, Kristin M; Manichaikul, Ani; Wilk, Jemma B; Ahmed, Firas S; Burke, Gregory L; Enright, Paul; Hansel, Nadia N; Haynes, Demondes; Heckbert, Susan R; Hoffman, Eric A; Kaufman, Joel D; Kurai, Jun; Loehr, Laura; London, Stephanie J; Meng, Yang; O'Connor, George T; Oelsner, Elizabeth; Petrini, Marcy; Pottinger, Tess D; Powell, Charles A; Redline, Susan; Rotter, Jerome I; Smith, Lewis J; Soler Artigas, María; Tobin, Martin D; Tsai, Michael Y; Watson, Karol; White, Wendy; Young, Taylor R; Rich, Stephen S; Barr, R Graham

    2014-04-01

    Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema. PMID:23900982

  11. Erythrocyte echinocytosis in liver disease. Role of abnormal plasma high density lipoproteins.

    PubMed Central

    Owen, J S; Brown, D J; Harry, D S; McIntyre, N; Beaven, G H; Isenberg, H; Gratzer, W B

    1985-01-01

    Echinocytes were frequently found in patients with liver disease when their blood was examined in wet films, but rarely detected in dried, stained smears. When normal erythrocytes (discocytes) were incubated with physiologic concentrations of the abnormal high density lipoproteins (HDL) from some jaundiced patients, echinocytosis developed within seconds. Other plasma fractions were not echinocytogenic. There was a close correlation between the number of echinocytes found in vivo and the ability of the corresponding HDL to induce discocyte-echinocyte transformation. On incubation with normal HDL, echinocytes generated in vitro rapidly reverted to a normal shape, and echinocytes from patients showed a similar trend. Echinocytosis occurred without change in membrane cholesterol content, as did its reversal, and was not caused by membrane uptake of lysolecithin or bile acids. Abnormal, echinocytogenic HDL showed saturable binding to approximately 5,000 sites per normal erythrocyte with an association constant of 10(8) M-1. Nonechinocytogenic patient HDL and normal HDL showed only nonsaturable binding. Several minor components of electrophoretically separated erythrocyte membrane proteins bound the abnormal HDL; pretreatment of the cells with trypsin or pronase reduced or eliminated binding. Echinocytosis by abnormal HDL required receptor occupancy, rather than transfer of constituents to or from the membrane, because cells reversibly prefixed in the discoid shape by wheat germ agglutinin, and then exposed to abnormal HDL, did not become echinocytes when the HDL and lectin were successively removed. Binding did not cause dephosphorylation of spectrin. We conclude that the echinocytes of liver disease are generated from discocytes by abnormal HDL, and we infer that the shape change is mediated by cell-surface receptors for abnormal HDL molecules. Images PMID:4077979

  12. Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics

    DOE PAGESBeta

    Sakamuri, Rama Murthy; Price, Dominique N.; Lee, Myungsun; Cho, Sang Nae; Barry, Clifton E.; Via, Laura E.; Swanson, Basil I.; Mukundan, Harshini

    2013-02-14

    Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum,more » and demonstrate that the circulating concentrations of ‘monomeric’ LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. Furthermore, this phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilic in nature and may also be associated with host lipid carriers. Such interactions are likely to affect host–pathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics.« less

  13. Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism*

    PubMed Central

    Gunawardane, Ruwanthi N.; Fordstrom, Preston; Piper, Derek E.; Masterman, Stephanie; Siu, Sophia; Liu, Dongming; Brown, Mike; Lu, Mei; Tang, Jie; Zhang, Richard; Cheng, Janet; Gates, Andrew; Meininger, David; Chan, Joyce; Carlson, Tim; Walker, Nigel; Schwarz, Margrit; Delaney, John; Zhou, Mingyue

    2016-01-01

    Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. PMID:26644477

  14. Does high-density lipoprotein protect vascular function in healthy pregnancy?

    PubMed

    Sulaiman, Wan N Wan; Caslake, Muriel J; Delles, Christian; Karlsson, Helen; Mulder, Monique T; Graham, Delyth; Freeman, Dilys J

    2016-04-01

    The maternal adaptation to pregnancy includes hyperlipidaemia, oxidative stress and chronic inflammation. In non-pregnant individuals, these processes are usually associated with poor vascular function. However, maternal vascular function is enhanced in pregnancy. It is not understood how this is achieved in the face of the adverse metabolic and inflammatory environment. Research into cardiovascular disease demonstrates that plasma HDL (high-density lipoprotein), by merit of its functionality rather than its plasma concentration, exerts protective effects on the vascular endothelium. HDL has vasodilatory, antioxidant, anti-thrombotic and anti-inflammatory effects, and can protect against endothelial cell damage. In pregnancy, the plasma HDL concentration starts to rise at 10 weeks of gestation, peaking at 20 weeks. The initial rise in plasma HDL occurs around the time of the establishment of the feto-placental circulation, a time when the trophoblast plugs in the maternal spiral arteries are released, generating oxidative stress. Thus there is the intriguing possibility that new HDL of improved function is synthesized around the time of the establishment of the feto-placental circulation. In obese pregnancy and, to a greater extent, in pre-eclampsia, plasma HDL levels are significantly decreased and maternal vascular function is reduced. Wire myography studies have shown an association between the plasma content of apolipoprotein AI, the major protein constituent of HDL, and blood vessel relaxation. These observations lead us to hypothesize that HDL concentration, and function, increases in pregnancy in order to protect the maternal vascular endothelium and that in pre-eclampsia this fails to occur. PMID:26888561

  15. Polymer-coated pH-responsive high-density lipoproteins.

    PubMed

    Kim, Hyungjin; Okamoto, Haruki; Felber, Arnaud E; Polomska, Anna; Morone, Nobuhiro; Heuser, John E; Leroux, Jean-Christophe; Murakami, Tatsuya

    2016-04-28

    Intracellular drug delivery by nanoparticles is often hampered by their endosomal entrapment followed by their degradation in the lysosomal compartment and/or exocytosis. Here, we show that internalization and endosomal escape of cargoes in a cationized natural nanocarrier, high-density lipoprotein (HDL), can be controlled in a pH-dependent manner through stable complexation with a membranolytic anionic block polymer. A genetically and chemically cationized form of HDL (catHDL) is prepared for the first time by both genetic fusion with YGRKKRRQRRR peptide and incorporation of 1,2-dioleoyloxy-3-(trimethylammonium)propane. Upon addition of poly(ethylene glycol)-block-poly(propyl methacrylate-co-methacrylic acid) (PA), catHDL yields inhibition of internalization at neutral pH and its subsequent recovery at mildly acidic pH. catHDL forms a stable discoidal-shape complex with PA (catHDL/PA) (ca. 50nm in diameter), even in the presence of serum. Significant enhancement of endosomal escape of a catHDL component is observed after a 1-h treatment of human cancer cells with catHDL/PA. Doxorubicin and curcumin, fluorescent anti-cancer drugs, encapsulated into catHDL/PA are also translocated outside of endosomes, compared with that into catHDL, and their cytotoxicities are enhanced inside the cells. These data suggest that catHDL/PA may have a potential benefit to improve the cellular delivery and endosomal escape of therapeutics under mildly acidic conditions such as in tumor tissues. PMID:26959846

  16. Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism.

    PubMed

    Gunawardane, Ruwanthi N; Fordstrom, Preston; Piper, Derek E; Masterman, Stephanie; Siu, Sophia; Liu, Dongming; Brown, Mike; Lu, Mei; Tang, Jie; Zhang, Richard; Cheng, Janet; Gates, Andrew; Meininger, David; Chan, Joyce; Carlson, Tim; Walker, Nigel; Schwarz, Margrit; Delaney, John; Zhou, Mingyue

    2016-02-01

    Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. PMID:26644477

  17. Metrics of High-Density Lipoprotein Function and Hospital Mortality in Acute Heart Failure Patients

    PubMed Central

    Potočnjak, Ines; Degoricija, Vesna; Trbušić, Matias; Terešak, Sanda Dokoza; Radulović, Bojana; Pregartner, Gudrun; Berghold, Andrea; Tiran, Beate; Marsche, Gunther; Frank, Saša

    2016-01-01

    Objective The functionality of high-density lipoprotein (HDL) is impaired in chronic ischaemic heart failure (HF). However, the relationship between HDL functionality and outcomes in acute HF (AHF) has not been studied. The present study investigates whether the metrics of HDL functionality, including HDL cholesterol efflux capacity and HDL-associated paraoxonase (PON)-1 arylesterase (AE) activity are associated with hospital mortality in AHF patients. Methods and Results The study was performed as a prospective, single-centre, observational research on 152 patients, defined and categorised according to the ESC and ACCF/AHA Guidelines for HF by time of onset, final clinical presentation and ejection fraction. The mean age of the included patients (52% female) was 75.2 years (SD 10.3) and hospital mortality was 14.5%. HDL cholesterol efflux capacity was examined by measuring the capacity of apoB depleted serum to remove tritium-labelled cholesterol from cultured macrophages. The AE activity of the HDL fraction was examined by a photometric assay. In a univariable regression analysis, low cholesterol efflux, but not AE activity, was significantly associated with hospital mortality [odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64–0.96, p = 0.019]. In multivariable analysis progressively adjusting for important clinical and laboratory parameters the association obtained for cholesterol efflux capacity and hospital mortality by univariable analysis, despite a stable OR, did not stay significant (p = 0.179). Conclusion Our results suggest that HDL cholesterol efflux capacity (but not AE activity) contributes to, but is not an independent risk factor for, hospital mortality in AHF patients. Larger studies are needed to draw firm conclusions. PMID:27304214

  18. High-Density Lipoprotein Function Measurement in Human Studies: Focus on Cholesterol Efflux Capacity

    PubMed Central

    Rohatgi, Anand

    2015-01-01

    A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). However, several observations have highlighted the shortcomings of using cholesterol content as the sole reflection of HDL metabolism. In particular, several large randomized controlled trials of extended release niacin and cholesteryl-ester transfer protein (CETP) inhibitors on background statin therapy have failed to show improvement in ASCVD outcomes despite significant increases in HDL-C. Reverse cholesterol transport (RCT) is the principal HDL function that impacts macrophage foam cell formation and other functions such as endothelial activation of endothelial nitric oxide synthase, monocyte adhesion, and platelet aggregation. Cholesterol efflux from macrophages to plasma/serum reflects the first critical step of RCT and is considered a key anti-atherosclerotic function of HDL. Whether this function is operative in humans remains to be seen, but recent studies assessing cholesterol efflux in humans suggest that the cholesterol efflux capacity (CEC) of human plasma or serum is a potent marker of ASCVD risk. This review describes the methodology of measuring CEC ex vivo from human samples and the findings to date linking CEC to human disease. Studies to date confirm that CEC can be reliably measured using stored human blood samples as cholesterol acceptors and suggest that CEC may be a promising new biomarker for atherosclerotic and metabolic diseases. Further studies are needed to standardize measurements and clarify the role CEC may play in predicting risk of developing disease and response to therapies. PMID:25968932

  19. High-Density Lipoprotein Function Measurement in Human Studies: Focus on Cholesterol Efflux Capacity.

    PubMed

    Rohatgi, Anand

    2015-01-01

    A low plasma level of high-density lipoprotein (HDL) cholesterol (HDL-C) is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). However, several observations have highlighted the shortcomings of using cholesterol content as the sole reflection of HDL metabolism. In particular, several large randomized controlled trials of extended release niacin and cholesteryl-ester transfer protein (CETP) inhibitors on background statin therapy have failed to show improvement in ASCVD outcomes despite significant increases in HDL-C. Reverse cholesterol transport (RCT) is the principal HDL function that impacts macrophage foam cell formation and other functions such as endothelial activation of endothelial nitric oxide synthase, monocyte adhesion, and platelet aggregation. Cholesterol efflux from macrophages to plasma/serum reflects the first critical step of RCT and is considered a key anti-atherosclerotic function of HDL. Whether this function is operative in humans remains to be seen, but recent studies assessing cholesterol efflux in humans suggest that the cholesterol efflux capacity (CEC) of human plasma or serum is a potent marker of ASCVD risk. This review describes the methodology of measuring CEC ex vivo from human samples and the findings to date linking CEC to human disease. Studies to date confirm that CEC can be reliably measured using stored human blood samples as cholesterol acceptors and suggest that CEC may be a promising new biomarker for atherosclerotic and metabolic diseases. Further studies are needed to standardize measurements and clarify the role CEC may play in predicting risk of developing disease and response to therapies. PMID:25968932

  20. Association of lipoarabinomannan with high density lipoprotein in blood: implications for diagnostics.

    PubMed

    Sakamuri, Rama Murthy; Price, Dominique N; Lee, Myungsun; Cho, Sang Nae; Barry, Clifton E; Via, Laura E; Swanson, Basil I; Mukundan, Harshini

    2013-05-01

    Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We have also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum, and demonstrate that the circulating concentrations of 'monomeric' LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. This phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilic in nature and may also be associated with host lipid carriers. Such interactions are likely to affect host-pathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics. PMID:23507184

  1. Direct Measurement of the Structure of Reconstituted High-Density Lipoproteins by Cryo-EM.

    PubMed

    Murray, Stephen C; Gillard, Baiba K; Ludtke, Steven J; Pownall, Henry J

    2016-02-23

    Early forms of high-density lipoproteins (HDL), nascent HDL, are formed by the interaction of apolipoprotein AI with macrophage and hepatic ATP-binding cassette transporter member 1. Various plasma activities convert nascent to mature HDL, comprising phosphatidylcholine (PC) and cholesterol, which are selectively removed by hepatic receptors. This process is important in reducing the cholesterol burden of arterial wall macrophages, an important cell type in all stages of atherosclerosis. Interaction of apolipoprotein AI with dimyristoyl (DM)PC forms reconstituted (r)HDL, which is a good model of nascent HDL. rHDL have been used as an antiathersclerosis therapy that enhances reverse cholesterol transport in humans and animal models. Thus, identification of the structure of rHDL would inform about that of nascent HDL and how rHDL improves reverse cholesterol transport in an atheroprotective way. Early studies of rHDL suggested a discoidal structure, which included pairs of antiparallel helices of apolipoprotein AI circumscribing a phospholipid bilayer. Another rHDL model based on small angle neutron scattering supported a double superhelical structure. Herein, we report a cryo-electron microscopy-based model of a large rHDL formed spontaneously from apolipoprotein AI, cholesterol, and excess DMPC and isolated to near homogeneity. After reconstruction we obtained an rHDL structure comprising DMPC, cholesterol, and apolipoprotein AI (423:74:1 mol/mol) forming a discoidal particle 360 Å in diameter and 45 Å thick; these dimensions are consistent with the stoichiometry of the particles. Given that cryo-electron microscopy directly observes projections of individual rHDL particles in different orientations, we can unambiguously state that rHDL particles are protein bounded discoidal bilayers. PMID:26743047

  2. 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

  3. Accurate Quantification of High Density Lipoprotein Particle Concentration by Calibrated Ion Mobility Analysis

    PubMed Central

    Hutchins, Patrick M.; Ronsein, Graziella E.; Monette, Jeffrey S.; Pamir, Nathalie; Wimberger, Jake; He, Yi; Anantharamaiah, G.M.; Kim, Daniel Seung; Ranchalis, Jane E.; Jarvik, Gail P.; Vaisar, Tomas; Heinecke, Jay W.

    2015-01-01

    Background It is critical to develop new metrics to determine whether high density lipoprotein (HDL) is cardioprotective in humans. One promising approach is HDL particle concentration (HDL-P) – the size and concentration of HDL in plasma or serum. However, the two methods currently used to determine HDL-P yield concentrations that differ more than 5-fold. We therefore developed and validated an improved approach to quantify HDL-P, termed calibrated ion mobility analysis (calibrated IMA). Methods HDL was isolated from plasma by ultracentrifugation, introduced into the gas phase with electrospray ionization, separated by size, and quantified by particle counting. A calibration curve constructed with purified proteins was used to correct for the ionization efficiency of HDL particles. Results The concentrations of gold nanoparticles and reconstituted HDLs measured by calibrated IMA were indistinguishable from concentrations determined by orthogonal methods. In plasma of control (n=40) and cerebrovascular disease (n=40) subjects, three subspecies of HDL were reproducibility measured, with an estimated total HDL-P of 13.4±2.4 µM (mean±SD). HDL-C accounted for 48% of the variance in HDL-P. HDL-P was significantly lower in subjects with cerebrovascular disease, and this difference remained significant after adjustment for HDL cholesterol levels. Conclusions Calibrated IMA accurately and reproducibly determined the concentration of gold nanoparticles and synthetic HDL, strongly suggesting the method could accurately quantify HDL particle concentration. Importantly, the estimated stoichiometry of apoA-I determined by calibrated IMA was 3–4 per HDL particle, in excellent agreement with current structural models. Furthermore, HDL-P associated with cardiovascular disease status in a clinical population independently of HDL cholesterol. PMID:25225166

  4. Relation between high density lipoprotein cholesterol and coronary artery disease in asymptomatic men

    SciTech Connect

    Uhl, G.S.; Troxler, R.G.; Hickman, J.R. Jr.; Clark, D.

    1981-11-01

    The well established inverse relation of high density lipoprotein cholesterol (HDL) and the risk of coronary artery disease was tested in a cross-sectional group of 572 asymptomatic aircrew members who were being screened for risk of coronary artery disease. A battery of tests was performed, including determinations of fasting serum cholesterol, HDL cholesterol and triglycerides and performance of a maximal symptom-limited exercise tolerance test. Of the 572 patients, 132 also had an abnormal S-T segment response to exercise testing or were otherwise believed to have an increased risk of organic heart disease and subsequently underwent coronary angiography. Significant coronary artery disease was found in 16 men and minimal or subcritical coronary disease in 14; coronary angiograms were normal in the remaining 102 men. The remaining 440 men, who were believed to have a 1 percent chance of having coronary artery disease by sequential testing of risk factors and treadmill testing, had a mean cholesterol level of 213 mg/100 ml, a mean HDL cholesterol of 51 mg/100 ml and a mean cholesterol/HDL ratio of 4.4. The mean values of cholesterol, HDL cholesterol and cholesterol/HDL cholesterol did not differ significantly in men with normal angiographic finding and those with subcritical coronary disease. However, 14 of 16 men with coronary artery disease had a cholesterol/HDL ratio of 6.0 or more whereas only 4 men with normal coronary arteries had a ratio of 6.0 or more. Of the classical coronary risk factors evaluated, the cholesterol/HDL ratio of 6.0 or more had the highest odds ratio (172:1). It appears that determination of HDL cholesterol level helps to identify asymptomatic persons with a greater risk of having coronary artery disease.

  5. Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice.

    PubMed

    Hellström, Martin; Ericsson, Madelene; Johansson, Bengt; Faraz, Mahmood; Anderson, Fredrick; Henriksson, Roger; Nilsson, Stefan K; Hedman, Håkan

    2016-06-01

    Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wild-type mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans. PMID:27009049

  6. Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice

    PubMed Central

    Wei, H; Averill, M M; McMillen, T S; Dastvan, F; Mitra, P; Subramanian, S; Tang, C; Chait, A; LeBoeuf, R C

    2014-01-01

    Background: Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition. Methods: To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I−/−) and apoA-I transgenic (apoA-Itg/tg) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies. Results: ApoA-I−/− mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I−/− mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I−/− mice, apoA-Itg/tg mice gained relatively less weight than WT mice, consistent with other reports. ApoA-Itg/tg mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content. Conclusions: Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity. PMID:24567123

  7. Reduction in Postoperative High-Density Lipoprotein Cholesterol Levels in Children Undergoing the Fontan Operation

    PubMed Central

    Argraves, W. Scott; Graham, Eric M.; Slate, Elizabeth H.; Atz, Andrew M.; Bradley, Scott M.; McQuinn, Tim C.; Wilkerson, Brent A.; Wing, Shane B.

    2015-01-01

    Despite the emerging relevance of high-density lipoprotein (HDL) in the inflammatory cascade and vascular barrier integrity, HDL levels in children undergoing cardiac surgery are unexplored. As a measure of HDL levels, the HDL-cholesterol (HDL-C) in single-ventricle patients was quantified before and after the Fontan operation, and it was determined whether relationships existed between the duration and the type of postoperative pleural effusions. The study prospectively enrolled 12 children undergoing the Fontan operation. Plasma HDL-C levels were measured before and after cardiopulmonary bypass. The outcome variables of interest were the duration and type of chest tube drainage (chylous vs. nonchylous). The Kendall rank correlation coefficient and the Wilcoxon rank sum test were used. There were 11 complete observations. The median preoperative HDL-C level for all the subjects was 30 mg/dl (range, 24–53 mg/dl), and the median postcardiopulmonary bypass level was 21 mg/dl (range, 14–46 mg/dl) (p = 0.004). There was a tendency toward a moderate inverse correlation (–0.42) between the postcardiopulmonary bypass HDL-C level and the duration of chest tube drainage, but the result was not statistically significant (p = 0.07). In the chylous effusion group, the median postcardiopulmonary bypass HDL-C tended to be lower (16 vs. 23 mg/dl; p = 0.09). After the Fontan operation, the plasma HDL-C levels in children are significantly reduced. It is reasonable to conclude that the reduction in HDL-C reflects reduced plasma levels of HDL particles, which may have pertinent implications in postoperative pleural effusions given the antiinflammatory and endothelial barrier functions of HDL. PMID:22411716

  8. Evaluation of high density lipoprotein as a circulating biomarker of Gaucher disease activity

    PubMed Central

    Stein, Philip; Yang, Ruhua; Liu, Jun; Pastores, Gregory M.; Mistry, Pramod K.

    2011-01-01

    Circulating biomarkers are important surrogates for monitoring disease activity in type I Gaucher disease (GD1). We and others have reported low high-density lipoprotein (HDL) in GD1. We assessed HDL cholesterol as a biomarker of GD1, with respect to its correlation with indicators of disease severity and its response to imiglucerase enzyme replacement therapy (ERT). In 278 consecutively evaluated GD1 patients, we correlated HDL cholesterol, chitotriosidase, and angiotensin-converting enzyme (ACE) with indicators of disease severity. Additionally, we measured the response of these biomarkers to ERT. HDL cholesterol was negatively correlated with spleen volume, liver volume, and GD severity score index; the magnitude of this association of disease severity with HDL cholesterol was similar to that for ACE and for chitotriosidase. Within individual patients monitored over many years, there was a strikingly strong correlation of HDL with liver and spleen volumes; there was a similarly strong correlation of chitotriosidase and ACE with disease severity in individual patients monitored serially over many years (chitotriosidase r=0.96 to 0.98, ACE r =0.88 to 0.94, and HDL r=−0.84 to −0.94, p<0.001). ERT for 3 years resulted in a striking increase of HDL while serum levels of chitotriosidase and ACE decreased. Our results reveal markedly low HDL cholesterol in untreated GD1, a correlation with indicators of disease severity in GD1, and a rise towards normal after ERT. These findings suggest HDL cholesterol merits inclusion within the “biomarker basket” for monitoring of patients with GD1. PMID:21290183

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

    PubMed

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

    2002-12-01

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

  10. Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effect of hormone therapy (HT) on the plasma concentration of remnant lipoprotein cholesterol (RLP-C) and high density lipoprotein (HDL) subpopulations and the contribution of HT-related changes in these lipoproteins to the progression of coronary heart disease (CHD) were examined in 256 postmen...

  11. The very-high-density lipoprotein fraction of rabbit plasma is rich in tissue-derived cholesterol.

    PubMed

    Nanjee, M N; Miller, N E

    1991-11-01

    When plasma from rabbits, which several weeks earlier had been infused with [3H]cholesterol, was subjected to equilibrium density gradient ultracentrifugation, the specific radioactivity of cholesterol in the very-high-density lipoprotein (VHDL) fraction (d 1.22-1.32 g/ml) was three to 8-fold greater (mean, 5.5-fold; P less than 0.001) than that in high-density lipoproteins (HDL; d 1.06-1.21 g/ml). On size exclusion chromatography of plasma, no increase in specific radioactivity was seen in particles smaller than HDL. These findings suggest that those apolipoprotein-lipid complexes that dissociate from HDL during ultracentrifugation to form the VHDL fraction contain proportionately more tissue-derived cholesterol than do those that are more tightly bound to HDL. PMID:1932106

  12. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels.

    PubMed

    Hausenloy, D J; Yellon, D M

    2008-11-01

    The last 20 years have witnessed dramatic reductions in cardiovascular risk using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") to lower levels of low-density lipoprotein cholesterol (LDL-C). Using this approach one can achieve a reduction in the risk of major cardiovascular events of 21% for every 1 mmol/l (39 mg/dl) decrease in LDL-C. However, despite intensive therapy with high dose "statins" to lower LDL-C levels below 2.6 mmol/l (100 mg/dl), the risk of a major cardiovascular event in patients with established coronary artery disease remains significant at a level approaching an annual risk of 9%, paving the way for new strategies for reducing the residual cardiovascular risk in this patient group. Early epidemiological studies have identified low levels of high-density lipoprotein cholesterol (HDL-C) (<1.0 mmol/l or 40 mg/dl), a common feature of type 2 diabetes mellitus and the metabolic syndrome, to be an independent determinant of increased cardiovascular risk. The beneficial effects of HDL-C on the cardiovascular system have been attributed to its ability to remove cellular cholesterol, as well as its anti-inflammatory, antioxidant and antithrombotic properties, which act in concert to improve endothelial function and inhibit atherosclerosis, thereby reducing cardiovascular risk. As such, raising HDL-C in patients with aggressively lowered LDL-C provides an additional strategy for addressing the residual cardiovascular risk present in these patients groups. Studies suggest that for every 0.03 mmol/l (1.0 mg/dl) increase in HDL-C, cardiovascular risk is reduced by 2-3%. Raising HDL-C can be achieved by both lifestyle changes and pharmacological means, the former of which include smoking cessation, aerobic exercise, weight loss and dietary manipulation. Therapeutic strategies have included niacin, fibrates, thiazolidinediones and bile acid sequestrants. Newly developed pharmacological agents include apolipoprotein A-I mimetics and

  13. Purification and properties of a very high density lipoprotein from the hemolymph of the honeybee Apis mellifera.

    PubMed

    Shipman, B A; Ryan, R O; Schmidt, J O; Law, J H

    1987-04-01

    A larval-specific very high density lipoprotein (VHDL) has been isolated from the hemolymph of the honeybee Apis mellifera. VHDL was isolated by a combination of density gradient ultracentrifugation and gel filtration. The purified protein is a dimer of Mr 160,000 apoproteins as shown by chemical cross-linking with dimethyl suberimidate. N-Terminal sequence analysis indicates that the two polypeptide chains are identical. The holoprotein contains 10% lipid by weight and 2.6% covalently bound carbohydrate. A native Mr 330,000 species was obtained by gel permeation chromatography. Antiserum directed against VHDL was used to show that VHDL is distinct from other hemolymph proteins and appears to constitute a novel lipoprotein of unknown function. However, the lipoprotein is present in high amounts in hemolymph only at the end of larval life, suggesting a potential role in lipid transport and/or storage protein metabolism during metamorphosis. PMID:3109474

  14. Mass Spectrometry-Based Proteomic Study Makes High-Density Lipoprotein a Biomarker for Atherosclerotic Vascular Disease

    PubMed Central

    Yang, Chao-Yuh; Tsai, Fuu-Jen; Lin, Shih-Yi

    2015-01-01

    High-density lipoprotein (HDL) is a lipid and protein complex that consists of apolipoproteins and lower level HDL-associated enzymes. HDL dysfunction is a factor in atherosclerosis and decreases patient survival. Mass spectrometry- (MS-) based proteomics provides a high throughput approach for analyzing the composition and modifications of complex HDL proteins in diseases. HDL can be separated according to size, surface charge, electronegativity, or apoprotein composition. MS-based proteomics on subfractionated HDL then allows investigation of lipoprotein roles in diseases. Herein, we review recent developments in MS-based quantitative proteomic techniques, HDL proteomics and lipoprotein modifications in diseases, and HDL subfractionation studies. We also discuss future directions and perspectives in MS-based proteomics on HDL. PMID:26090384

  15. A prominent large high-density lipoprotein at birth enriched in apolipoprotein C-I identifies a new group of infancts of lower birth weight and younger gestational age

    SciTech Connect

    Kwiterovich Jr., Peter O.; Cockrill, Steven L.; Virgil, Donna G.; Garrett, Elizabeth; Otvos, James; Knight-Gibson, Carolyn; Alaupovic, Petar; Forte, Trudy; Farwig, Zachlyn N.; Macfarlane, Ronald D.

    2003-10-01

    Because low birth weight is associated with adverse cardiovascular risk and death in adults, lipoprotein heterogeneity at birth was studied. A prominent, large high-density lipoprotein (HDL) subclass enriched in apolipoprotein C-I (apoC-I) was found in 19 percent of infants, who had significantly lower birth weights and younger gestational ages and distinctly different lipoprotein profiles than infants with undetectable, possible or probable amounts of apoC-I-enriched HDL. An elevated amount of an apoC-I-enriched HDL identifies a new group of low birth weight infants.

  16. Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

    PubMed Central

    Feitosa, Mary F.; Wojczynski, Mary K.; Straka, Robert; Kammerer, Candace M.; Lee, Joseph H.; Kraja, Aldi T.; Christensen, Kaare; Newman, Anne B.; Province, Michael A.; Borecki, Ingrid B.

    2014-01-01

    The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological

  17. Free cholesterol determines reassembled high-density lipoprotein phospholipid phase structure and stability.

    PubMed

    Auton, Matthew; Bassett, G Randall; Gillard, Baiba K; Pownall, Henry J

    2013-06-25

    Reassembled high-density lipoproteins (rHDL) of various sizes and compositions containing apo A-I or apo A-II as their sole protein, dimyristoylphosphatidylcholine (DMPC), and various amounts of free cholesterol (FC) have been isolated and analyzed by differential scanning calorimetry (DSC) and by circular dichroism to determine their stability and the temperature dependence of their helical content. Our data show that the multiple rHDL species obtained at each FC mole percent usually do not have the same FC mole percent as the starting mixture and that the size of the multiple species increases in a quantized way with their respective FC mole percent. DSC studies reveal multiple phases or domains that can be classified as virtual DMPC, which contains a small amount of DMPC that slightly reduces the melting temperature (Tm), a boundary phase that is adjacent to the apo A-I or apo A-II that circumscribes the discoidal rHDL, and a mixed FC/DMPC phase that has a Tm that increases with FC mole percent. Only the large rHDL contain virtual DMPC, whereas all contain boundary phase and various amounts of the mixed FC/DMPC phase according to increasing size and FC mole percent. As reported by others, FC stabilizes the rHDL. For rHDL (apo A-II) compared to rHDL (apo A-I), this occurs in spite of the reduced number of helical regions that mediate binding to the DMPC surface. This effect is attributed to the very high lipophilicity of apo A-II and the reduction in the polarity of the interface between DMPC and the aqueous phase with an increasing FC mole percent, an effect that is expected to increase the strength of the hydrophobic associations with the nonpolar face of the amphipathic helices of apo A-II. These data are relevant to the differential effects of FC and apolipoprotein species on intracellular and plasma membrane nascent HDL assembly and subsequent remodeling by plasma proteins. PMID:23721456

  18. High-density lipoproteins potentiate α1-antitrypsin therapy in elastase-induced pulmonary emphysema.

    PubMed

    Moreno, Juan-Antonio; Ortega-Gomez, Almudena; Rubio-Navarro, Alfonso; Louedec, Liliane; Ho-Tin-Noé, Benoit; Caligiuri, Giuseppina; Nicoletti, Antonino; Levoye, Angelique; Plantier, Laurent; Meilhac, Olivier

    2014-10-01

    Several studies report that high-density lipoproteins (HDLs) can carry α1-antitrypsin (AAT; an elastase inhibitor). We aimed to determine whether injection of exogenous HDL, enriched or not in AAT, may have protective effects against pulmonary emphysema. After tracheal instillation of saline or elastase, mice were randomly treated intravenously with saline, human plasma HDL (75 mg apolipoprotein A1/kg), HDL-AAT (75 mg apolipoprotein A1-3.75 mg AAT/kg), or AAT alone (3.75 mg/kg) at 2, 24, 48, and 72 hours. We have shown that HDL-AAT reached the lung and prevented the development of pulmonary emphysema by 59.3% at 3 weeks (alveoli mean chord length, 22.9 ± 2.8 μm versus 30.7 ± 4.5 μm; P < 0.001), whereas injection of HDL or AAT alone only showed a moderate, nonsignificant protective effect (28.2 ± 4.2 μm versus 30.7 ± 5 μm [P = 0.23] and 27.3 ± 5.66 μm versus 30.71 ± 4.96 μm [P = 0.18], respectively). Indeed, protection by HDL-AAT was significantly higher than that observed with HDL or AAT (P = 0.006 and P = 0.048, respectively). This protective effect was associated (at 6, 24, and 72 h) with: (1) a reduction in neutrophil and macrophage number in the bronchoalveolar lavage fluid; (2) decreased concentrations of IL-6, monocyte chemoattractant protein-1, and TNF-α in both bronchoalveolar lavage fluid and plasma; (3) a reduction in matrix metalloproteinase-2 and matrix metalloproteinase-9 activities; and (4) a reduction in the degradation of fibronectin, a marker of tissue damage. In addition, HDL-AAT reduced acute cigarette smoke-induced inflammatory response. Intravenous HDL-AAT treatment afforded a better protection against elastase-induced pulmonary emphysema than AAT alone, and may represent a significant development for the management of emphysema associated with AAT deficiency. PMID:24787644

  19. High-density lipoprotein subfractions and carotid plaque: The Northern Manhattan Study

    PubMed Central

    Tiozzo, Eduard; Gardener, Hannah; Hudson, Barry I.; Dong, Chuanhui; Della-Morte, David; Crisby, Milita; Goldberg, Ronald B.; Elkind, Mitchell S.V.; Cheung, Ying Kuen; Wright, Clinton B.; Sacco, Ralph L.; Rundek, Tatjana

    2016-01-01

    Objective The objective of this cross-sectional analysis was to investigate the relation between two major high-density lipoprotein cholesterol (HDL-C) subfractions (HDL2-C and HDL3-C) and carotid plaque in a population based cohort. Methods We evaluated 988 stroke-free participants (mean age 66±8 years; 40% men; 66% Hispanic and 34% Non-Hispanic) with available data on HDL subfractions using precipitation method and carotid plaque area and thickness assessed by a high-resolution 2D ultrasound. The associations between HDL-C subfractions and plaque measurements were analyzed by quantile regression. Results Plaque was present in 56% of the study population. Among those with plaque, the mean±SD plaque area was 19.40±20.46 mm2 and thickness 2.30±4.45 mm. The mean±SD total HDL-C was 46±14 mg/dl, HDL2-C 14±8 mg/dl, and HDL3-C 32±8 mg/dl. After adjusting for demographics and vascular risk factors, there was an inverse association between HDL3-C and plaque area (per mg/dl: beta= −0.26 at the 75th percentile, p=0.001 and beta= −0.32 at the 90th percentile, p=0.02). A positive association was observed between HDL2-C and plaque thickness (per mg/dl; beta= 0.02 at the 90% percentile, p=0.003). HDL-C was associated with plaque area (per mg/dl: beta= −0.18 at the 90th percentile, p=0.01), but only among Hispanics. Conclusion In our cohort we observed an inverse association between HDL3-C and plaque area and a positive association between HDL2-C and plaque thickness. HDL-C subfractions may have different contributions to the risk of vascular disease. More studies are needed to fully elucidate HDL-C anti-atherosclerotic functions in order to improve HDL-based treatments in prevention of vascular disease and stroke. PMID:25240111

  20. Synthesis and Characterization of Biomimetic High Density Lipoprotein Nanoparticles To Treat Lymphoma

    NASA Astrophysics Data System (ADS)

    Damiano, Marina Giacoma

    High density lipoproteins (HDLs), natural nanoparticles that function as vehicles for cholesterol transport, have enhanced uptake by several human cancers. This uptake is mediated, in part, by the high affinity HDL receptor, scavenger receptor B-1 (SR-B1). More specifically, studies show that the rate of cellular proliferation of lymphoma, a cancer of the lymphocytes, is directly proportional to the amount of HDL-cholesterol available. Thus, targeting of HDL-cholesterol uptake by these cells could be an effective therapeutic approach that may have lower toxicity to healthy cells compared to conventional therapies. Biomimetic HDL can be synthesized using a gold nanoparticle template (HDL-AuNPs), which provides control over size, shape, and surface chemistry. Like their natural counterparts, HDL-AuNPs sequester cholesterol. However, since the gold nanoparticle replaces the cholesterol core of natural HDL, HDL-AuNPs inherently deliver less cholesterol. We show that HDL-AuNPs are able to induce dose dependent apoptosis in B cell lymphoma cell lines and reduce tumor volume following systemic administration to mice bearing B cell lymphoma tumors. Furthermore, HDL-AuNPs are neither toxic to healthy human lymphocytes (SR-B1-), nor to hepatocytes and macrophages (SR-B1+), which are cells naturally encountered by HDLs. Manipulation of cholesterol flux and targeting of SR-B1 are responsible for the efficacy of HDL-AuNPs against B cell lymphoma. HDL-AuNPs could be used to treat B cell lymphomas and other diseases that involve pathologic accumulation of cholesterol. Titanium dioxide nanoparticle (TiO2 NP) core HDLs (HDL-TiO 2 NPs) have been synthesized for high resolution cellular localization studies and for future use as a therapeutic and imaging agent. In initial studies, HDL-TiO(2 NPs display maximum uptake in B cell lymphoma cell lines. X-ray fluorescence microscopy studies show interaction between HDL-TiO2 NPs and cells 10 minutes after treatment and internalization after

  1. Evidence for low high-density lipoprotein cholesterol levels in Australian indigenous peoples: a systematic review

    PubMed Central

    2014-01-01

    Background Low plasma high-density lipoprotein cholesterol (HDL-C) levels are a strong, independent, but poorly understood risk factor for cardiovascular disease (CVD). Although this atherogenic lipid abnormality has been widely reported in Australia’s Indigenous peoples, Aboriginal and Torres Strait Islanders, the evidence has not come under systematic review. This review therefore examines published data for Indigenous Australians reporting 1) mean HDL-C levels for both sexes and 2) factors associated with low HDL-C. Methods PubMed, Medline and Informit ATSI Health databases were systematically searched between 1950 and 2012 for studies on Indigenous Australians reporting mean HDL-C levels in both sexes. Retrieved studies were evaluated by standard criteria. Low HDL-C was defined as: <1.0 mmol/L. Analyses of primary data associating measures of HDL-C with other CVD risk factors were also performed. Results Fifteen of 93 retrieved studies were identified for inclusion. These provided 58 mean HDL-C levels; 29 for each sex, most obtained in rural/regional (20%) or remote settings (60%) and including 51–1641 participants. For Australian Aborigines, mean HDL-C values ranged between 0.81-1.50 mmol/L in females and 0.76-1.60 mmol/L in males. Two of 15 studies reported HDL-C levels for Torres Strait Islander populations, mean HDL-C: 1.00 or 1.11 mmol/L for females and 1.01 or 1.13 mmol/L for males. Low HDL-C was observed only in rural/regional and remote settings - not in national or urban studies (n = 3) in either gender. Diabetes prevalence, mean/median waist-to-hip ratio and circulating C-reactive protein levels were negatively associated with HDL-C levels (all P < 0.05). Thirty-four per cent of studies reported lower mean HDL-C levels in females than in males. Conclusions Very low mean HDL-C levels are common in Australian Indigenous populations living in rural and remote communities. Inverse associations between HDL-C and central obesity, diabetes

  2. Apolipoprotein A-I localization and dipalmitoylphosphatidylcholine dynamics in reconstituted high density lipoproteins.

    PubMed

    Dergunov, A D; Dobretsov, G E

    2000-02-01

    The structure and molecular dynamics of recombinant high density lipoproteins (rHDL) were studied by non-radiative energy transfer (NRET), fluorescence anisotropy and intensity measurements. The rHDL particles contained human plasma apolipoprotein (apo) A-I and dipalmitoylphosphatidylcholine (DPPC). Fluorescent cis- and trans-parinaric acids were used both as probes of molecular motion in the particle lipid phase and as acceptors in the Forster's energy transfer from apo A-I tryptophan residues to determine particle dimensions, apolipoprotein localization and lipid dynamics. The probes are sensitive to thermal wobbling (macromobility) and conformational deformations (micromobility) of phospholipid acyl chains. The experimental data fitted to various models of the particle structure are compatible with the following: (a) at T < Tt the particles appeared as lens-like discs with a radius of the lipid phase of 5 nm and a mean thickness of 4 nm, the value being more by 20% in the particle centre, the alpha-helices of about 1 nm thickness were located around the edge of the lipid core. Compared to liposomes, both macro- and micromobility of DPPC molecules in rHDL were more rapid due to a significant disorder of the boundary lipid molecules close to the apo A-I molecule. This disorder led to the increase of the specific surface area per one lipid molecule, S(o). The lipid phase can be divided into three regions: (i) zone I of the most tightly packed lipid (0-1.7 nm from the disc axis) with a S(o) value small as 0.5 nm2; (ii) intermediate zone II (from 1.7 to 4.0 nm); and (iii) boundary lipid zone III (4-5 nm) of significantly disordered lipid with a S(o) value large as 0.65 nm2. (b) at T> Tt the S(o) heterogeneity disappeared, the radius of the lipid phase did not increase significantly, not exceeding 5.2-5.4 nm, but protein-induced immobilization of lipid molecules which affected about half or more of the total lipid, became remarkable. The overall effect was the

  3. Simulation of High Density Lipoprotein Behavior on a Few Layer Graphene Undergoing Non-Uniform Mechanical Load.

    PubMed

    Glukhova, Olga E; Prytkova, Tatiana R; Savostyanov, George V

    2016-04-21

    Effect of a nonuniform external mechanical load on high density lipoprotein (HDL) in aqueous medium was investigated using course-grained molecular dynamics simulations. The nonuniform load was achieved by a few layer graphene on one side and closed single-walled carbon nanotube (SWNT) (7, 7) on the opposite side of lipoprotein. The tube had a diameter of 1 nm and was oriented perpendicularly to the graphene. HDL was located between them. The tube was approaching to HDL on graphene deforming it. We considered two cases of the tube movement with velocities of 20 and 5 m/s. Coarse-grained (CG) molecular dynamics with application of the MARTINI force field for HDL and coarse-grained model with an all-atom (AA)/CG mapping ratio of 1.5 for carbon nanotube (CNT) (each CG bead was modeled by the 4-site CG benzene) were used. Coarse-grained model of HDL was received by method of self-assembly. HDL was static but not fixed that gave the possibility to compensate its external influence in some way. It was established that in water medium HDL interacted with graphene substrate. It was established that in water HDL interacts with graphene substrate, slightly flattening but retaining its shape of the whole. It was also observed that during the calculations HDL partially dodged nanotube. Lipoprotein belts unfolded on the graphene substrate in the way of the best compensation for the impact of nanotubes. Finally, we observed that the approaching tube has passed through the less dense medium of dipalmitoylphosphatidylcholine (DPPC) and its pressure on the macromolecule decreased. Inhomogeneity of the external exposure deformed HDL at approximately 10-50%. The character of deformation demonstrated that lipoprotein has viscoelastic properties similar to a fluid. The discovered ability of lipoprotein may help to establish mechanism of interaction of lipoproteins with arterial walls and dynamic behavior of lipoproteins in arterial intima. PMID:27046673

  4. Lipoprotein-associated lysolipids are differentially involved in high-density lipoprotein- and its oxidized form-induced neurite remodeling in PC12 cells.

    PubMed

    Sato, Koichi; Tobo, Masayuki; Mogi, Chihiro; Murata, Naoya; Kotake, Mie; Kuwabara, Atsushi; Im, Dong-Soon; Okajima, Fumikazu

    2014-03-01

    Oxidatively damaged proteins and lipid peroxidation products have been shown to accumulate in the brain of neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, and oxidized lipoprotein is considered to be toxic and neurodegenerative. However, the role of lipoprotein and its oxidized form in neurite remodeling has not been well understood. In the present study, we have aimed to clarify whether and, if so, how high-density lipoprotein (HDL) and oxidized HDL (oxHDL) affect neuritogenesis. In the presence of nerve growth factor, exposure of PC12 cells to either HDL or oxHDL induces a rapid neurite retraction, which is followed by re-outgrowth of neurites in either case; however, oxHDL-treated cells exhibit much longer outgrowths than do basal and HDL-treated cells. Thus, processes in the morphological changes of neuronal cells after lipoprotein treatment are composed of two phases: the reversible retraction phase and the extension phase. Characterization of the active fractions of lipids and experiments with desensitization and knockdown of receptors have indicated that the reversible retraction phase involves mainly sphingosine 1-phosphate for HDL and lysophosphatidic acid for oxHDL. The change in the components responsible for the retraction response is comparable with the change in sphingosine 1-phosphate and lysophosphatidic acid contents by the oxidation of HDL. In the extension phase, lysophosphatidylcholine, which is increased by the oxidation of HDL, may play a stimulatory role in neurite outgrowth. We conclude that lipoprotein and its oxidized form differentially regulate neuritogenesis through lipoprotein-associated lysolipid molecules. PMID:24589770

  5. [A history and review of cholesterol ester transfer protein inhibitors and their contribution to the understanding of the physiology and pathophysiology of high density lipoprotein].

    PubMed

    Corral, Pablo; Schreier, Laura

    2014-01-01

    There is irrefutable evidence that statins reduce the risk of cardiovascular events in a magnitude proportional to the intensity of the decrease in cholesterol transport by the low density lipoproteins. Despite this great advance there is still a residual risk of cardiovascular events. For this reason, an increase in the levels of high density lipoprotein is considered in order to boost the main action of this lipoprotein, which is reverse cholesterol transport. Distinct classes of evidence (epidemiological, genetic, and pathophysiological) show that the inhibition and/or modulation of cholesterol ester transfer protein increases plasma high density lipoprotein-cholesterol levels. The main reason for presenting this review is to look at the physiology of cholesterol ester transfer protein, its interrelationship with high density lipoproteins, and to give an update on the development of different cholesterol ester transfer protein inhibitor/modulator molecules. PMID:24094503

  6. Very old adults with better memory function have higher low-density lipoprotein cholesterol levels and lower triglyceride to high-density lipoprotein cholesterol ratios: KOCOA project

    PubMed Central

    Katsumata, Yuriko; Todoriki, Hidemi; Higashiuesato, Yasushi; Yasura, Shotoku; Ohya, Yusuke; Willcox, D. Craig; Dodge, Hiroko H.

    2013-01-01

    We examined cross-sectionally which lipid profiles are associated with better cognitive function among those aged 80 and older-free of dementia (Clinical Dementia Rating ≤ 0.5), functionally independent and community-dwelling. Our cohort consisted of 193 participants from the “Keys to Optimal Cognitive Aging (KOCOA) Project”, a prospective cohort study in Okinawa, Japan. Higher low-density lipoprotein cholesterol levels and lower triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratios were associated with higher scores in memory performance after controlling for confounders. Further research is required to clarify the associations among LDL-C levels, TG/HDL-C ratios, and healthy cognitive aging. PMID:23207484

  7. Severe high-density lipoprotein deficiency associated with autoantibodies against lecithin:cholesterol acyltransferase in non-Hodgkin lymphoma.

    PubMed

    Simonelli, Sara; Gianazza, Elisabetta; Mombelli, Giuliana; Bondioli, Alighiero; Ferraro, Giovanni; Penco, Silvana; Sirtori, Cesare R; Franceschini, Guido; Calabresi, Laura

    2012-01-23

    An antibody against the lecithin:cholesterol acyltransferase (LCAT) enzyme, which negates cholesterol esterification in plasma, causing severe high-density lipoprotein deficiency (HD), was identified in a woman with a large-cell non-Hodgkin lymphoma. Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of the defective cholesterol esterification and HD. To our knowledge, an acquired LCAT deficiency leading to severe HD has not been reported previously in association with a malignant disease, and this patient represents the first such documented case. PMID:22271127

  8. Non-High-Density Lipoprotein Cholesterol in Children with Diabetes: Proposed Treatment Recommendations Based on Glycemic Control, Body Mass Index, Age, Sex, and Generally Accepted Cut Points.

    PubMed

    Schwab, K Otfried; Doerfer, Jürgen; Hungele, Andreas; Scheuing, Nicole; Krebs, Andreas; Dost, Axel; Rohrer, Tilman R; Hofer, Sabine; Holl, Reinhard W

    2015-12-01

    Percentile-based non-high-density lipoprotein cholesterol levels were analyzed by glycemic control, weight, age, and sex of children with type 1 diabetes (n = 26,358). Ten percent of all children and 25% of overweight adolescent girls require both immediate lipid-lowering medication and lifestyle changes to achieve non-high-density lipoprotein cholesterol levels <120 mg/dL and cardiovascular risk reduction. PMID:26427965

  9. Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients

    SciTech Connect

    Prenger, V.L.; Beaty, T.H.; Kwiterovich, P.O. )

    1992-11-01

    Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families. 27 refs., 3 figs., 5 tabs.

  10. Modified high-density lipoproteins by artificial sweetener, aspartame, and saccharin, showed loss of anti-atherosclerotic activity and toxicity in zebrafish.

    PubMed

    Kim, Jae-Yong; Park, Ki-Hoon; Kim, Jihoe; Choi, Inho; Cho, Kyung-Hyun

    2015-01-01

    Safety concerns have been raised regarding the association of chronic consumption of artificial sweeteners (ASs) with metabolic disorders, especially in the heart and brain. There has been no information on the in vivo physiological effects of AS consumption in lipoprotein metabolism. High-dosage treatment (final 25, 50, and 100 mM) with AS (aspartame, acesulfame K, and saccharin) to human high-density lipoprotein (HDL) induced loss of antioxidant ability along with elevated atherogenic effects. Aspartame-treated HDL3 (final 100 mM) almost all disappeared due to putative proteolytic degradation. Aspartame- and saccharin-treated HDL3 showed more enhanced cholesteryl ester transfer activity, while their antioxidant ability was disappeared. Microinjection of the modified HDL3 exacerbated the inflammatory death in zebrafish embryos in the presence of oxLDL. These results show that AS treatment impaired the beneficial functions of HDL, resulting in loss of antioxidant and anti-atherogenic activities. These results suggest that aspartame and saccharin could be toxic to the human circulation system as well as embryonic development via impairment of lipoprotein function. PMID:25142179

  11. Rosuvastatin Alters the Proteome of High Density Lipoproteins: Generation of alpha-1-antitrypsin Enriched Particles with Anti-inflammatory Properties.

    PubMed

    Gordon, Scott M; McKenzie, Benjamin; Kemeh, Georgina; Sampson, Maureen; Perl, Shira; Young, Neal S; Fessler, Michael B; Remaley, Alan T

    2015-12-01

    Statins lower plasma cholesterol by as much as 50%, thus reducing future cardiovascular events. However, the physiological effects of statins are diverse and not all are related to low density lipoprotein cholesterol (LDL-C) lowering. We performed a small clinical pilot study to assess the impact of statins on lipoprotein-associated proteins in healthy individuals (n = 10) with normal LDL-C (<130 mg/dL), who were treated with rosuvastatin (20 mg/day) for 28 days. Proteomic analysis of size-exclusion chromatography isolated LDL, large high density lipoprotein (HDL-L), and small HDL (HDL-S) fractions and spectral counting was used to compare relative protein detection before and after statin therapy. Significant protein changes were found in each lipoprotein pool and included both increases and decreases in several proteins involved in lipoprotein metabolism, complement regulation and acute phase response. The most dramatic effect of the rosuvastatin treatment was an increase in α-1-antirypsin (A1AT) spectral counts associated with HDL-L particles. Quantitative measurement by ELISA confirmed an average 5.7-fold increase in HDL-L associated A1AT. Molecular modeling predictions indicated that the hydrophobic reactive center loop of A1AT, the functional domain responsible for its protease inhibitor activity, is likely involved in lipid binding and association with HDL was found to protect A1AT against oxidative inactivation. Cell culture experiments, using J774 macrophages, demonstrated that the association of A1AT with HDL enhances its antiprotease activity, preventing elastase induced production of tumor necrosis factor α. In conclusion, we show that statins can significantly alter the protein composition of both LDL and HDL and our studies reveal a novel functional relationship between A1AT and HDL. The up-regulation of A1AT on HDL enhances its anti-inflammatory functionality, which may contribute to the non-lipid lowering beneficial effects of statins. PMID

  12. Effect of Extended-Release Niacin on High-Density Lipoprotein (HDL) Functionality, Lipoprotein Metabolism, and Mediators of Vascular Inflammation in Statin-Treated Patients

    PubMed Central

    Yadav, Rahul; Liu, Yifen; Kwok, See; Hama, Salam; France, Michael; Eatough, Ruth; Pemberton, Phil; Schofield, Jonathan; Siahmansur, Tarza J; Malik, Rayaz; Ammori, Basil A; Issa, Basil; Younis, Naveed; Donn, Rachelle; Stevens, Adam; Durrington, Paul; Soran, Handrean

    2015-01-01

    Background The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment. Methods and Results In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity. Conclusions ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL

  13. Comparing high density LIDAR and medium resolution GPS generated elevation data for predicting yield stability

    Technology Transfer Automated Retrieval System (TEKTRAN)

    High density light detection and ranging (LIDAR) imaging has been shown to be able to define yield stability areas of a field for multi-cropping. Since LIDAR imaging is expensive and not widely available, we hypothesized that medium resolution GPS elevation data which is commonly collected with var...

  14. Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: experimental animal models and clinical evidence.

    PubMed

    Ferri, Nicola; Corsini, Alberto; Macchi, Chiara; Magni, Paolo; Ruscica, Massimiliano

    2016-07-01

    Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the proprotein convertase family. Several studies have demonstrated its involvement in the regulation of low-density lipoprotein (LDL) cholesterol levels by inducing the degradation of the LDL receptor (LDLR). However, experimental, epidemiologic, and pharmacologic data provide important evidence on the role of PCSK9 also on high-density lipoproteins (HDLs). In mice, PCSK9 regulates the HDL cholesterol (HDL-C) levels by the degradation of hepatic LDLR, thus inhibiting the uptake of apolipoprotein (Apo)E-containing HDLs. Several epidemiologic and genetic studies reported positive relationship between PCSK9 and HDL-C levels, likely by reducing the uptake of the ApoE-containing HDL particles. PCSK9 enhances also the degradation of LDLR's closest family members, ApoE receptor 2, very low-density lipoprotein receptor, and LDLR-related protein 1. This feature provides a molecular mechanism by which PCSK9 may affect HDL metabolism. Experimental studies demonstrated that PCSK9 directly interacts with HDL by modulating PCSK9 self-assembly and its binding to the LDLR. Finally, the inhibition of PCSK9 by means of monoclonal antibodies directed to PCSK9 (ie, evolocumab and alirocumab) determines an increase of HDL-C fraction by 7% and 4.2%, respectively. Thus, the understanding of the role of PCSK9 on HDL metabolism needs to be elucidated with a particular focus on the effect of PCSK9 on HDL-mediated reverse cholesterol transport. PMID:26548330

  15. Consistently high plasma high-density lipoprotein-cholesterol levels in children in Spain, a country with low cardiovascular mortality.

    PubMed

    Garcés, Carmen; Gil, Angel; Benavente, Mercedes; Viturro, Enrique; Cano, Beatriz; de Oya, Manuel

    2004-08-01

    Coronary heart disease (CHD) mortality is relatively low in Spain compared with other developed countries and has remained low despite an apparent increase in mean plasma cholesterol concentration in adults over the last several years. It is accepted that pathologic processes related to arteriosclerosis development begin in childhood and seem to be related to the presence of cardiovascular risk factors at this age. High-density lipoprotein-cholesterol (HDL-C) levels in children have been inversely correlated with the incidence of coronary heart disease in the different countries studied. Childhood plasma lipoprotein profile might contribute to the low coronary heart disease mortality in Spain. Thus, we analyzed data on lipid levels over time in schoolchildren in Spain in the last decade. Plasma lipid levels were analyzed in prepuberal children (6 to 8 years) in 3 school-based surveys performed by our group in Madrid in 1987, 1993, and 1999. A significant increase in plasma total cholesterol (P < .05) and low-density lipoprotein-cholesterol (LDL-C) (P < .01) levels in prepuberal children was observed over the last decade. However, the mean concentration of plasma HDL-C remained stable and very high. These high levels of plasma HDL-C in Spanish school children may help to explain why the coronary heart disease mortality rate in Spain is low compared with that in other developed countries. PMID:15281016

  16. Fast and Simplified Method for High Through-put Isolation of miRNA from Highly Purified High Density Lipoprotein

    PubMed Central

    Seneshaw, Mulugeta; Mirshahi, Faridoddin; Min, Hae-Ki; Asgharpour, Amon; Mirshahi, Shervin; Daita, Kalyani; Boyett, Sherry; Santhekadur, Prasanna K.; Fuchs, Michael; Sanyal, Arun J.

    2016-01-01

    Small non-coding RNAs (miRNAs) have been implicated in a variety of human diseases including metabolic syndromes. They may be utilized as biomarkers for diagnosis and prognosis or may serve as targets for drug development, respectively. Recently it has been shown that miRNAs are carried in lipoproteins, particularly high density lipoproteins (HDL) and are delivered to recipient cells for uptake. This raises the possibility that miRNAs play a critical and pivotal role in cellular and organ function via regulation of gene expression as well as messenger for cell-cell communications and crosstalk between organs. Current methods for miRNA isolation from purified HDL are impractical when utilizing small samples on a large scale. This is largely due to the time consuming and laborious methods used for lipoprotein isolation. We have developed a simplified approach to rapidly isolate purified HDL suitable for miRNA analysis from plasma samples. This method should facilitate investigations into the role of miRNAs in health and disease and in particular provide new insights into the variety of biological functions, outside of the reverse cholesterol transport, that have been ascribed to HDL. Also, the miRNA species which are present in HDL can provide valuable information of clinical biomarkers for diagnosis of various diseases. PMID:27501005

  17. Specific high-affinity binding of high density lipoproteins to cultured human skin fibroblasts and arterial smooth muscle cells.

    PubMed

    Biesbroeck, R; Oram, J F; Albers, J J; Bierman, E L

    1983-03-01

    Binding of human high density lipoproteins (HDL, d = 1.063-1.21) to cultured human fibroblasts and human arterial smooth muscle cells was studied using HDL subjected to heparin-agarose affinity chromatography to remove apoprotein (apo) E and B. Saturation curves for binding of apo E-free 125I-HDL showed at least two components: low-affinity nonsaturable binding and high-affinity binding that saturated at approximately 20 micrograms HDL protein/ml. Scatchard analysis of high-affinity binding of apo E-free 125I-HDL to normal fibroblasts yielded plots that were significantly linear, indicative of a single class of binding sites. Saturation curves for binding of both 125I-HDL3 (d = 1.125-1.21) and apo E-free 125I-HDL to low density lipoprotein (LDL) receptor-negative fibroblasts also showed high-affinity binding that yielded linear Scatchard plots. On a total protein basis, HDL2 (d = 1.063-1.10), HDL3 and very high density lipoproteins (VHDL, d = 1.21-1.25) competed as effectively as apo E-free HDL for binding of apo E-free 125I-HDL to normal fibroblasts. Also, HDL2, HDL3, and VHDL competed similarly for binding of 125I-HDL3 to LDL receptor-negative fibroblasts. In contrast, LDL was a weak competitor for HDL binding. These results indicate that both human fibroblasts and arterial smooth muscle cells possess specific high affinity HDL binding sites. As indicated by enhanced LDL binding and degradation and increased sterol synthesis, apo E-free HDL3 promoted cholesterol efflux from fibroblasts. These effects also saturated at HDL3 concentrations of 20 micrograms/ml, suggesting that promotion of cholesterol efflux by HDL is mediated by binding to the high-affinity cell surface sites. PMID:6826722

  18. Effects of high density lipoprotein subfractions on cholesterol homeostasis in human fibroblasts and arterial smooth muscle cells.

    PubMed

    Oram, J F

    1983-01-01

    Ultracentrifugally isolated high density lipoprotein (HDL) particles of d greater than 1.125 g/ml promote net transport of cholesterol from cultured cells. Consequently, when cultured human fibroblasts and arterial smooth muscle cells were incubated with HDL3 (d = 1.125-1.21 g/ml) and "very high" density lipoprotein (VHDL, d = 1.21-1.25 g/ml), low density lipoprotein (LDL) receptor activity was induced and the rate of LDL degradation by the cells was increased. Enhancement of LDL degradation by HDL3 and VHDL was sustained over incubation periods of 5 days at medium LDL concentrations greater than needed to saturate the LDL receptors. Even during these long-term incubations with LDL, HDL3 and VHDL caused marked reductions in cellular cholesterol content. Thus, an increase in the rate of cholesterol transport from cells may lead to a steady-state decrease in cellular cholesterol content and a sustained increase in the rate of clearance of LDL from the extracellular fluid. In contrast to the effects of HDL3 and VHDL, the major subclasses of HDL2 (HDL2b, d = 1.063-1.100 g/ml; HDL2a, d = 1.100-1.125 g/ml) did not promote net cholesterol transport from cells. Moreover, by apparent direct blockage of the effects that HDL3 and VHDL had on cholesterol transport, HDL2 reversed the increased rate of LDL degradation induced by HDL3 and VHDL. These results suggest that the relative proportion of HDL subfractions in the extracellular fluid may be an important determinant of both the rate of cholesterol transport from cells and the rate of receptor-mediated catabolism of LDL. PMID:6312947

  19. Dietary Squalene Increases High Density Lipoprotein-Cholesterol and Paraoxonase 1 and Decreases Oxidative Stress in Mice

    PubMed Central

    Gabás-Rivera, Clara; Barranquero, Cristina; Martínez-Beamonte, Roberto; Navarro, María A.; Surra, Joaquín C.; Osada, Jesús

    2014-01-01

    Background and Purpose Squalene, the main hydrocarbon in the unsaponifiable fraction of virgin olive oil, is involved in cholesterol synthesis and it has been reported to own antiatherosclerotic and antiesteatosic effects. However, the squalene's role on lipid plasma parameters and the influence of genotype on this effect need to be addressed. Experimental Approaches Three male mouse models (wild-type, Apoa1- and Apoe- deficient) were fed chow semisynthetic diets enriched in squalene to provide a dose of 1 g/kg during 11 weeks. After this period, their plasma parameters and lipoprotein profiles were analyzed. Key Results Squalene administration at a dose of 1 g/kg showed decreased reactive oxygen species in lipoprotein fractions independently of the animal background and caused an specific increase in high density lipoprotein (HDL)-cholesterol levels, accompanied by an increase in phosphatidylcholine and paraoxonase 1 and no changes in apolipoproteins A1 and A4 in wild-type mice. In these mice, the cholesterol increase was due to its esterified form and associated with an increased hepatic expression of Lcat. These effects were not observed in absence of apolipoprotein A1. The increases in HDL- paraoxonase 1 were translated into decreased plasma malondialdehyde levels depending on the presence of Apolipoprotein A1. Conclusions and Implications Dietary squalene promotes changes in HDL- cholesterol and paraoxonase 1 and decreases reactive oxygen species in lipoproteins and plasma malondialdehyde levels, providing new benefits of its intake that might contribute to explain the properties of virgin olive oil, although the phenotype related to apolipoproteins A1 and E may be particularly relevant. PMID:25117703

  20. Biochemical and Functional Characterization of Charge-defined Subfractions of High-density Lipoprotein From Normal Adults

    PubMed Central

    Huang, Max T.; Chang, Chia-Ming; Chen, Chia-Ying; Shen, Ming-Yi; Liao, Hsin-Yi; Wang, Guei-Jane; Chen, Chu-Huang; Chen, Chao-Jung; Yang, Chao-Yuh

    2013-01-01

    High-density lipoprotein (HDL) is regarded as atheroprotective because it provides antioxidant and anti-inflammatory benefits and plays an important role in reverse cholesterol transport. In this paper, we outline a novel methodology for studying the heterogeneity of HDL. Using anion-exchange chromatography, we separated HDL from 6 healthy individuals into 5 subfractions (H1 through H5) with increasing charge and evaluated the composition and biologic activities of each subfraction. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis showed that apolipoprotein (apo) AI and apoAII were present in all 5 subfractions; apoCI was present only in H1; and apoCIII and apoE were most abundantly present in H4 and H5. HDL-associated antioxidant enzymes such as lecithin-cholesterol acyltransferase, lipoprotein-associated phospholipase A2, and paraoxonase 1 were most abundant in H4 and H5. Lipoprotein isoforms were analyzed in each subfraction by using matrix-assisted laser desorption–time of flight mass spectrometry. To quantify other proteins in the HDL subfractions, we used the isobaric tags for relative and absolute quantitation approach followed by nanoflow liquid chromatography–tandem mass spectrometry analysis. Most antioxidant proteins detected were found in H4 and H5. The ability of each subfraction to induce cholesterol efflux from macrophages increased with increasing HDL electronegativity, with the exception of H5, which promoted the least efflux activity. In conclusion, anion-exchange chromatography is an attractive method for separating HDL into subfractions with distinct lipoprotein compositions and biologic activities. By comparing the properties of these subfractions, it may be possible to uncover HDL-specific proteins that play a role in disease. PMID:24171625

  1. Modifications in high-density lipoprotein lipid composition and structure alter the plasma distribution of free and liposomal annamycin.

    PubMed

    Wasan, K M; Ng, S; Cassidy, S M

    1997-07-01

    Recent studies have shown that changes in lipoprotein cholesterol and triglyceride concentration alters the plasma distribution of free (Ann.) and liposomal annamycin (LAnn) and that the majority of Ann. is associated with high-density lipoproteins (HDL) following the incubation in plasma of LAnn. To demonstrate that alterations in HDL lipid composition and HDL structure may influence the plasma distribution of Ann. and LAnn, Ann. and LAnn (20 micrograms/mL) were incubated in plasma pretreated with dithionitrobenzoate (DTNB, a compound which inhibits the conversion of free cholesterol to esterified cholesterol) 18 h prior to the experiment or in untreated plasma for 60 min at 37 degrees C. In addition, Ann. and LAnn were co-incubated with DTNB in plasma for 60 min at 37 degrees C. Following incubation the plasma was separated into its HDL, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and lipoprotein-deficient plasma (LPDP) fractions by ultracentrifugation and assayed for Ann. by fluorimetry. The HDL plasma cholesterol:triglyceride concentration ratio was significantly decreased following 18 h of DTNB pretreatment compared to untreated plasma controls. No significant differences in LDL/VLDL plasma cholesterol:triglyceride concentration ratio following 18 h of DTNB pretreatment was observed. An increased number of discoidal HDL particles were observed following 18 h of DTNB pretreatment. When Ann. was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL, LDL, and VLDL fractions significantly increased. However, the percentage of Ann. recovered within the LPDP fraction was significantly decreased. When LAnn was incubated in plasma pretreated with DTNB for 18 h the percentage of Ann. recovered in the HDL fraction significantly decreased. The percentage of Ann. recovered in the LPDP fraction significantly increased when LAnn was incubated in plasma pretreated with DTNB for 18 h. No significant differences

  2. High density lipoproteins and prevention of experimental atherosclerosis with special reference to tree shrews.

    PubMed

    She, M P; Xia, R Y; Ran, B F; Wong, Z L

    1990-01-01

    According to data obtained from epidemiological and experimental survey, serum HDL level is known to be correlated conversely with the incidence of atherosclerosis. Experimental data collected in this article explained part of its mechanism, which is described in four parts as follows: 1. The result of 3 successive experiments on experimental atherosclerosis in tree shrews (total of 96 animals available including 40 as the controls) showed that the serum HDL level had been kept persistantly to 69-88% of the total serum lipoproteins even after a high cholesterol intake for 32 weeks. The incidence of atheromatous lesions developed was only 0-9%, but the incidence of gall stone was very high, 48-84% by gross examination by the end of these experiments. 2. HDL are also capable of (1) promotion of monocyte migration activity; (2) enhancement of cholesterol clearance rate of aortic smooth muscle cells originally isolated from either rabbits or tree shrews; (3) inhibition of 20% of LDL degradation but with no inhibitory effect obtained on Ac-LDL degradation in the endothelial cells; (4) presence of specific binding sites for apo E free HDL on the surface of aortic smooth muscle cells from either rabbits or tree shrews which recognizes apo A1 as a ligand. 3. Data from 2 successive experiments in rabbits showed that HDL lipoproteins (mainly apo A1) possess an inhibitory effect on the development of atheromatous plaques, but not a very strong one. 4. The colesterol clearance effect of smooth muscle cells was markedly enhanced by apo A1/phospholipid liposomes (the apo A1 used was isolated from either rabbit's or tree shrew's serum) in vitro. PMID:2123379

  3. The structure of human high density lipoprotein and the levels of apolipoprotein A-I in plasma as determined by radioimmunoassay.

    PubMed

    Schonfeld, G; Pfleger, B

    1974-08-01

    The major apoprotein of high density lipoprotein is apolipoprotein A-I (ApoA-I). In addition to being a structural component of this class of lipoproteins, ApoA-I also has a physiologic role as an activator of lecithin-cholesterol acyl transferase, an enzyme important in the metabolism of all lipoproteins. To measure ApoA-I content in human plasma, to assess its immunologic activity in hyperlipoproteinemia, and to carry out certain structural studies of high density lipoproteins, we have developed a double antibody radioimmunoassay. ApoA-I, isolated by gel filtration, was used to produce monospecific antisera. ApoA-I was iodinated by chloramine-T and the resulting [(125)I]-ApoA-I was purified by gel filtration. > 85% of [(125)I]-ApoA-I was precipitated by antibody, and 90% of bound [(125)I]ApoA-I was displaced by "cold" ApoA-I. Other lipoproteins and apoproteins did not react. Plasma and high density lipoprotein from normals and subjects with hyperlipoproteinemia displaced counts in parallel with ApoA-I, suggesting that the same antigenic determinants were reacting with antibody on lipid-free and lipid-associated ApoA-I. However, less than 5% of ApoA-I of high density lipoprotein reacted in the assay. Removal of the lipid by extraction increased the reactivity of ApoA-I in high density lipoprotein 15-20-fold; thus more than 95% of the ApoA-I molecules in "intact" high density lipoprotein are unreactive with antibody. Normal and hyperlipoproteinemic plasma and high density lipoproteins isolated from the same subjects continued to display parallelism with ApoA-I standard after lipid extraction, suggesting that ApoA-I of normal and hyperliproteinemic subjects are immunologically identical. About 90% of ApoA-I was in the d 1.063-1.21 fractions of normal plasma, trace quantities were found in the lipoproteins of d < 1.063, and the rest (about 10%) was in the d > 1.21 fraction. Normal plasma levels, assessed in extracted plasmas with a precision of 8%, were 100+/-35 mg

  4. Beneficial effects of omega-3 fatty acids in the proteome of high-density lipoprotein proteome

    PubMed Central

    2012-01-01

    Background Omega-3 poly-unsaturated fatty acids (ω-3 PUFAs) have demonstrated to be beneficial in the prevention of cardiovascular disease, however, the mechanisms by which they perform their cardiovascular protection have not been clarified. Intriguingly, some of these protective effects have also been linked to HDL. The hypothesis of this study was that ω-3 PUFAs could modify the protein cargo of HDL particle in a triglyceride non-dependent mode. The objective of the study was to compare the proteome of HDL before and after ω-3 PUFAs supplemented diet. Methods A comparative proteomic analysis in 6 smoker subjects HDL before and after a 5 weeks ω-3 PUFAs enriched diet has been performed. Results Among the altered proteins, clusterin, paraoxonase, and apoAI were found to increase, while fibronectin, α-1-antitrypsin, complement C1r subcomponent and complement factor H decreased after diet supplementation with ω-3 PUFAs. Immunodetection assays confirmed these results. The up-regulated proteins are related to anti-oxidant, anti-inflammatory and anti-atherosclerotic properties of HDL, while the down-regulated proteins are related to regulation of complement activation and acute phase response. Conclusions Despite the low number of subjects included in the study, our findings demonstrate that ω-3 PUFAs supplementation modifies lipoprotein containing apoAI (LpAI) proteome and suggest that these protein changes improve the functionality of the particle. PMID:22978374

  5. A biosensor of high-density lipoprotein of human serum on a liquid crystal and polymer composite film

    NASA Astrophysics Data System (ADS)

    Lin, Yi-Hsin; Chang, Kai-Han; Chu, Wei-Lin; Tsou, Yu-Shih; Wu, Li-Ching; Li, Chien-Feng

    2013-10-01

    A biosensor for the concentration of high-density lipoprotein (HDL) in human serum on a liquid crystal and polymer composite film (LCPCF) is demonstrated. The sensing mechanism is based on a polar-polar interaction between orientation of LC directors and HDL in human serum. The concentration of polar HDL in human serum affects the orientations of LC directors at the interface between LCPCF and the human serum. In addition, the surface free energy of LCPCF changes with the applied voltage due to the electrically tunable orientations of LC directors anchored among the polymer grains of LCPCF. As a result, the droplet motion of human serum on LCPCF under applied voltages can sense the concentration of HDL in human serum.

  6. Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport.

    PubMed

    Annema, Wijtske; Tietge, Uwe J F

    2011-06-01

    Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease. PMID:21424685

  7. Antioxidative Activity after Rosuvastatin Treatment in Patients with Stable Ischemic Heart Disease and Decreased High Density Lipoprotein Cholesterol

    PubMed Central

    Park, Do-Sim; Park, Hyun Young; Rhee, Sang Jae; Kim, Nam-Ho; Oh, Seok Kyu; Jeong, Jin-Won

    2016-01-01

    Background and Objectives The clinical significance of statin-induced high-density lipoprotein cholesterol (HDL-C) changes is not well known. We investigated whether rosuvastatin-induced HDL-C changes can influence the anti-oxidative action of high-density lipoprotein particle. Subjects and Methods A total of 240 patients with stable ischemic heart disease were studied. Anti-oxidative property was assessed by paraoxonase 1 (PON1) activity. We compared the lipid profile and PON1 activity at baseline and at 8 weeks after rosuvastatin 10 mg treatment. Results Rosuvastatin treatment increased the mean HDL-C concentration by 1.9±9.2 mg/dL (6.4±21.4%). HDL-C increased in 138 patients (57.5%), but decreased in 102 patients (42.5%) after statin treatment. PON1 activity increased to 19.1% in all patients. In both, the patients with increased HDL-C and with decreased HDL-C, PON1 activity significantly increased after rosuvastatin treatment (+19.3% in increased HDL-C responder; p=0.018, +18.8% in decreased HDL-C responder; p=0.045 by paired t-test). Baseline PON1 activity modestly correlated with HDL-C levels (r=0.248, p=0.009); however, the PON1 activity evaluated during the course of the treatment did not correlate with HDL-C levels (r=0.153, p=0.075). Conclusion Rosuvastatin treatment improved the anti-oxidative properties as assessed by PON1 activity, regardless of on-treatment HDL-C levels, in patients with stable ischemic heart disease. PMID:27275167

  8. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study.

    PubMed Central

    Lindenstrøm, E.; Boysen, G.; Nyboe, J.

    1994-01-01

    OBJECTIVE--To estimate the influence of plasma total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease. DESIGN--The Copenhagen City Heart Study is a prospective observational survey with two cardiovascular examinations at five year intervals. Non-fasting plasma lipids were measured in participants once at each examination, along with other variables. The Cox regression model was used to establish the effect of the factors recorded on cerebrovascular events of mostly, but not exclusively, ischaemic origin. SUBJECTS--19,698 women and men at least 20 years old, randomly selected after age stratification from an area of central Copenhagen. MAIN OUTCOME MEASURES--Initial cases of stroke and transient ischaemic attack recorded from hospital records and death certificates from 1976 through 1988. RESULTS--660 non-haemorrhagic and 33 haemorrhagic events were recorded. Total cholesterol was positively associated with risk of non-haemorrhagic events, but only for levels > 8 mmol/l, corresponding to the upper 5% of the distribution in the study population. For lower plasma cholesterol values the relative risk remained nearly constant. Plasma triglyceride concentration was significantly, positively associated with risk of non-haemorrhagic events. The relative risk corresponding to an increase of 1 mmol/l was 1.12 (95% confidence interval 1.07 to 1.16). There was a negative, log linear association between high density lipoprotein cholesterol and risk of non-haemorrhagic events (0.53 (0.34 to 0.83)). There was no indication that the effects of plasma lipids were different in women and men. CONCLUSIONS--The pattern of the association between plasma cholesterol and risk of ischaemic cerebrovascular disease was not log linear, and the increased risk was confined to the upper 5% of the cholesterol distribution. Further studies should concentrate on the association between plasma cholesterol and verified haemorrhagic stroke. PMID

  9. 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

  10. The clinical significance of preoperative serum cholesterol and high-density lipoprotein-cholesterol levels in hepatocellular carcinoma

    PubMed Central

    Jiang, Shan-Shan; Weng, De-Sheng; Jiang, Long; Zhang, Yao-Jun; Pan, Ke; Pan, Qiu-Zhong; Chen, Chang-Long; Zhao, Jing-Jing; Zhang, Xiao-Fei; Zhang, Hong-Xia; Tang, Yan; Zhou, Zi-Qi; Chen, Min-Shan; Xia, Jian-Chuan

    2016-01-01

    Purpose: To evaluate the prognostic role of the preoperative plasma lipid profile, including low-density lipoprotein -cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], cholesterol, and triglycerides, in hepatocellular carcinoma patients undergoing radical resection. Methods: Clinical data, including the preoperative plasma profile levels, were retrospectively collected and reviewed in 1411 hepatocellular carcinoma patients, who underwent operation between 2001 and 2010. Kaplan-Meier method and the Cox proportional hazards regression model were used in analyzing the DFS and OS. Results: We found that HDL-C ≤ 0.88 mmol/L and cholesterol ≤ 4.420 mmol/L were preoperative risk factors of disease-free survival (DFS) and overall survival (OS). A decreased CHO level was significantly associated with decreased OS (HR, 0.800; 95% CI, (0.691-0.926), P =0.003) and decreased DFS (HR, 0.844; 95% CI, 0.737-0.966, P=0.012). Additionally, an increased HDL-C level was shown significant association with increased OS (HR, 0.679; 95% CI, 0.570-0.808, P<0.01) and DFS (HR, 2.085; 95% CI, 1.271- 3.422, P = 0.002). In the univariate and multivariate analyses involving OS and DFS, no significant relativity were observed between the LDL-C and TG groups. Conclusions: Decreased levels of CHO and HDL might predict worse outcomes both DFS and OS for hepatocellular carcinoma patients. PMID:27076843

  11. 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

  12. Biochemistry of the evolution of Triatoma infestans. XII. Biosynthesis and secretion of a very high density lipoprotein.

    PubMed

    Rimoldi, O J; González, M S; Brenner, R R

    1997-01-01

    Biosynthetic processes related to the production of an insect hexamerin, very high density lipoprotein (VHDL), have been examined in the fat body of fifth-instar nymph and adult Triatoma infestans. Fat bodies were incubated in vitro with [3H]leucine and the incubation media were precipitated using a specific antiserum. The SDS-polyacrylamide gel electrophoresis followed by blotting on nitrocellulose showed that both larval and adult fat body secreted the VHDL subunit. Moreover, the radiolabel recovered in this subunit is indicative of the de novo synthesis. When the incubation medium was subjected to density gradient ultracentrifugation, a radiolabeled fraction was found at density 1.27 g/ml, value identical to the hemolymph circulating VHDL, indicating that the secreted apoprotein is combined with lipids. The SDS-polyacrylamide gel electrophoresis and immunoblotting of this fraction corroborated the presence of the VHDL-apoprotein. These results demonstrate that the fat body of T. infestans is able to synthesize the protein subunit which is associated to lipids as a lipoprotein particle that is released into the medium as VHDL. PMID:9339237

  13. Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice.

    PubMed

    Ru, Ding; Zhiqing, He; Lin, Zhu; Feng, Wu; Feng, Zhang; Jiayou, Zhang; Yusheng, Ren; Min, Fan; Chun, Liang; Zonggui, Wu

    2015-05-01

    High density lipoprotein (HDL) dysfunction has been widely reported in clinic, and oxidation of HDL (ox-HDL) was shown to be one of the most common modifications in vivo and participate in the progression of atherosclerosis. But the behind mechanisms are still elusive. In this study, we firstly analyzed and found strong relationship between serum ox-HDL levels and risk factors of coronary artery diseases in clinic, then the effects of ox-HDL in initiation and progression of atherosclerosis in LDLR knockout mice were investigated by infusion of ox-HDL dissolved in chitosan hydrogel before the formation of lesions in vivo. Several new evidence were shown: (i) the serum levels of ox-HDL peaked early before the formation of lesions in LDLR mice fed with high fat diet similar to oxidative low density lipoprotein, (ii) the formation of atherosclerotic lesions could be accelerated by infusion of ox-HDL, (iii) the pro-atherosclerotic effects of ox-HDL were accompanied by imbalanced levels of effector and regulatory T cells and relative gene expressions, which implied that imbalance of teff and treg might contribute to the pro-atherosclerosis effects of ox-HDL. PMID:25912129

  14. Streptococcal serum opacity factor increases the rate of hepatocyte uptake of human plasma high-density lipoprotein cholesterol.

    PubMed

    Gillard, Baiba K; Rosales, Corina; Pillai, Biju K; Lin, Hu Yu; Courtney, Harry S; Pownall, Henry J

    2010-11-16

    Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasma high-density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, a small discoidal HDL-like particle, and a large cholesteryl ester-rich microemulsion (CERM) that contains the cholesterol esters (CE) of up to ∼400000 HDL particles and apo E as its major protein. Similar SOF reaction products are obtained with HDL, total plasma lipoproteins, and whole plasma. We hypothesized that hepatic uptake of CERM-CE via multiple apo E-dependent receptors would be faster than that of HDL-CE. We tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamster ovary (CHO) cells. The uptake of [(3)H]CE by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was 2.4 and 4.5 times faster, respectively, than from control HDL. CERM-[(3)H]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptor (LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-R and SR-BI confirmed CERM-[(3)H]CE uptake by both receptors. RAP and heparin inhibit CERM-[(3)H]CE but not HDL-[(3)H]CE uptake, thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases the rate of CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase the level of hepatic disposal of plasma cholesterol in a way that is therapeutically useful. PMID:20879789

  15. Roles of High-Density Lipoprotein Cholesterol in Patients With Acute Myocardial Infarction

    PubMed Central

    Lee, Cheol Hyun; Woo, Jong Shin; Park, Chang Bum; Cho, Jin Man; Ahn, Young Keun; Kim, Chong Jin; Jeong, Myung Ho; Kim, Weon

    2016-01-01

    Abstract Many observational studies showed hogh-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular (CV) outcome. However, recent large clinical trials evaluating therapies to raise HDL-C level in those already on statin therapy have been discouraging. This complexity is not well-known. A total of 28,357 acute myocardial infarction (AMI) patients were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR), which was a prospective, multicenter, nationwide, web-based database of AMI in Korea. From this registry, we evaluated 3574 patients with AMI who have follow-up HDL-C level to investigate its association with clinical outcomes. The primary endpoint was the relationship between follow-up change in HDL-C and a 12-month composite of major adverse cardiac events (MACEs). Patients with initial HDL-C ≥ 40 mg/dL showed significantly lower rates of 12-month MACEs, especially cardiac and all-cause mortalities (P < 0.001). When patients were stratified into 4 groups according to the change of HDL-C, patients with decreasing HDL-C showed significantly higher rates of 12-month MACEs as comparable with patients with increasing HLD-C. A multivariate analysis indicated that HDL-C level was a significant predictor of CV events (hazard ratio, 1.38; 95% confidence interval, 1.12–1.71) after correcting for confounding variables. The follow-up change in HDL-C level was significantly related with CV outcomes in patients with AMI. PMID:27149442

  16. Relation of Combined Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B With Atherosclerosis in Adults With Type 1 Diabetes Mellitus.

    PubMed

    Bjornstad, Petter; Eckel, Robert H; Pyle, Laura; Rewers, Marian; Maahs, David M; Snell-Bergeon, Janet K

    2015-10-01

    Apolipoprotein B (apoB) and non-high-density lipoprotein cholesterol (non-HDL-C) are cardiovascular disease risk markers, although data in adults with type 1 diabetes mellitus (DM) are limited. We hypothesized that elevated apoB and non-HDL-C would be associated with greater odds of coronary artery calcification progression (CACp), a measure of coronary atherosclerosis, than either category alone in adults with type 1 DM. We grouped subjects with type 1 DM (n = 652) into 4 groups: elevated apoB (≥90 mg/dl) and elevated non-HDL-C (≥130 mg/dl), elevated non-HDL-C alone, elevated apoB alone, and normal apoB and non-HDL-C. We used logistic regression to examine the associations between the groups and CACp for a period of 6 years. We performed sensitivity analyses with elevated apoB and non-HDL-C redefined as at or more than the cohort means (91.4 and 119.0 mg/dl, respectively). Subjects with elevated apoB and non-HDL-C had greater odds of CACp compared with those with normal apoB and non-HDL-C (odds ratio 1.90, 95% confidence interval 1.15 to 3.15) and compared with subjects with elevated apoB alone (odds ratio 2.86, 95% confidence interval 1.43 to 5.74) adjusting for age, gender, duration, hemoglobin A1c, and statins. Similar results were obtained with elevated apoB and non-HDL-C defined as at or more than the cohort means. In conclusion, elevated apoB and non-HDL-C carry a greater risk of atherosclerosis than elevated apoB in the absence of elevated non-HDL-C in adults with type 1 DM. These data suggest that apoB and non-HDL-C should be viewed as complementary rather than competitive indexes of cardiovascular disease risk in type 1 DM. PMID:26251001

  17. Add-on rosiglitazone therapy improves plasminogen activity and high-density lipoprotein cholesterol in type 2 diabetes mellitus.

    PubMed

    Mustaffa, Nazri; Ibrahim, Suhairi; Abdullah, Wan Zaidah; Yusof, Zurkurnai

    2011-09-01

    Rosiglitazone is an oral hypoglycaemic agent of the thiazolidinedione group. This study aimed to assess changes in the diabetic prothrombotic state via plasminogen activity and changes in surrogate markers of atherosclerotic burden via ankle-brachial pressure index (ABPI) measurements after rosiglitazone was added to a pre-existing type 2 diabetes mellitus treatment regime. A nonblinded interventional study was designed. Fifty-nine patients were enrolled. Rosiglitazone-naïve patients were prescribed oral rosiglitazone 4 mg daily for 10 weeks. ABPI, plasminogen activity, glycosylated haemoglobin (HbA1c) and fasting lipid profile were measured pretreatment and post-treatment. Forty-eight patients completed the study. At the end of this study, mean plasminogen activity improvement was nearly 16% (P<0.05), mean ABPI improvement was 0.01 (P=0.439), mean HbA1c reduction was 0.51% (P<0.05), mean total cholesterol (TC) increase was 0.36 mmol/l (P<0.05), mean high-density lipoprotein cholesterol (HDL-C) increase was 0.15 mmol/l (P<0.05) and mean low-density lipoprotein cholesterol increased by 0.19 mmol/l (P=0.098). Rosiglitazone significantly improved plasminogen activity. There was also significant HbA1c reduction, and rise in both TC and HDL-C. Thus, rosiglitazone potentially improves the atherosclerotic burden and prothrombotic state. In future, more studies are needed to confirm the relationship between rosiglitazone, fibrinolytic system and atheromatous reduction in type 2 diabetes mellitus. PMID:21537159

  18. Mechanism of the hepatic lipase induced accumulation of high-density lipoprotein cholesterol by cells in culture

    SciTech Connect

    Bamberger, M.; Lund-Katz, S.; Phillips, M.C.; Rothblat, G.H.

    1985-07-02

    Hepatic lipase can enhance the delivery of high-density lipoprotein (HDL) cholesterol to cells by a process which does not involve apoprotein catabolism. The incorporation of HDL-free (unesterified) cholesterol, phospholipid, and cholesteryl ester by cells has been compared to establish the mechanism of this delivery process. Human HDL was reconstituted with /sup 3/H-free cholesterol and (/sup 14/C)sphingomyelin, treated with hepatic lipase in the presence of albumin to remove the products of lipolysis, reisolated, and then incubated with cultured rat hepatoma cells. Relative to control HDL, modification of HDL with hepatic lipase stimulated both the amount of HDL-free cholesterol taken up by the cell and the esterification of HDL-free cholesterol but did not affect the delivery of sphingomyelin. Experiments utilizing HDL reconstituted with /sup 14/C-free cholesterol and (/sup 3/H)cholesteryl oleoyl ether suggest that hepatic lipase enhances the incorporation of HDL-esterified cholesterol. However, the amount of free cholesterol delivered as a result of treatment with hepatic lipase was 4-fold that of esterified cholesterol. On the basis of HDL composition, the cellular incorporation of free cholesterol was about 10 times that which would occur by the uptake and degradation of intact particles. The preferential incorporation of HDL-free cholesterol did not require the presence of lysophosphatidylcholine. To correlate the events observed at the cellular level with alterations in lipoprotein structure, high-resolution, proton-decoupled /sup 13/C nuclear magnetic resonance spectroscopy (90.55 MHz) was performed on HDL3 in which the cholesterol molecules were replaced with (4-/sup 13/C)cholesterol by particle reconstitution.

  19. Current status and future directions in lipid management: emphasizing low-density lipoproteins, high-density lipoproteins, and triglycerides as targets for therapy

    PubMed Central

    Lin, Yun; Mousa, Shaymaa S; Elshourbagy, Nabil; Mousa, Shaker A

    2010-01-01

    Current lipid management guidelines are focused on decreasing low-density lipoprotein (LDL-C) levels as the primary target for reducing coronary heart disease (CHD) risk. Yet, many recent studies suggest that low levels of high-density lipoprotein (HDL-C) are a major independent risk factor for cardiovascular diseases. According to several clinical trials, a 1% increase in HDL-C is associated with a 0.7%–3% decrease in CHD events. The direct link between high levels of triglycerides (TG) and CHD, on the other hand, is less well defined. A large reduction in TG is needed to show a difference in CHD events, especially in men. Evidence for a shift in lipid management toward targeting both LDL-C and HDL-C as primary targets for therapy is presented. Currently, the 3-hydroxy-3-methylgutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors) have proven to significantly decrease LDL-C levels, reduce CHD morbidity/mortality and improve overall survival. However, improvement of survival with statins may be due to other pleiotropic effects beyond LDL-C lowering. Fibric acid derivatives and niacin are primarily used to increase HDL-C levels, although with side effects. Future therapies targeting HDL-C may have profound results on reducing CHD morbidity and mortality. This article highlights existing and future targets in lipid management and is based on available clinical data. There is an urgent need for new treatments using a combination of drugs targeting both LDL-C and HDL-C. Such treatments are expected to have a superior outcome for dyslipidemia therapy, along with TG management. PMID:20234782

  20. Lack of Association between High-Density Lipoprotein Cholesterol and Angiographic Coronary Lesion Severity in Chinese Patients with Low Background Low-Density Lipoprotein Cholesterol

    PubMed Central

    Su, Chieh-Shou; Chen, Kuan-Ju; Sheu, Wayne Huey-Herng; Yang, Ya-Ling; Liu, Tsun-Jui; Chang, Wei-Chun; Wang, Kuo-Yang; Lee, Wen-Lieng

    2015-01-01

    Background The atheroprotective role of high-density lipoprotein (HDL-C) particles as measured by HDL-C level in coronary arterial disease (CAD) remains unsettled. The aim of our study was to ascertain whether HDL-C was associated with the development and severity of coronary artery disease in Chinese patients who underwent coronary angiogram with low background Low-density lipoprotein (LDL-C) levels, which has not been previously investigated. Methods Between March 1995 and May 2000, 566 consecutive patients (408 males, 66.7 ± 11.3 years of age) with background LDL-C less than 100 mg/dl who underwent coronary artery angiography at our cath lab for suspected CAD were retrospectively recruited into the study. The severity of coronary lesions was measured by conventional coronary angiography and modified Gensini scores. Results In those subjects with significant coronary lesions, there were more males and conventional CAD risk factors of diabetes mellitus, smoking, and chronic renal disease. They were also older compared to those in the control group. However, total cholesterol, LDL-C, HDL-C, triglyceride levels and use of statins were similar in both groups. In those subjects with significant coronary lesions, there was no difference in conventional coronary lesion severity or modified Gensini score between the quartered HDL-C subgroups. Furthermore, there was no significant correlation between serum HDL-C level and modified Gensini scores. In linear regression analysis, HDL-C was not an independent predictor for modified Gensini scores. Furthermore, HDL-C was also not an independent risk factor for the presence of significant coronary lesions in low LDL-C patients in logistic regression analysis. Conclusions In Chinese patients with low background LDL-C, serum HDL-C was not associated with development of CAD or lesion severity in patients with suspected CAD. Therefore, HDL-C did not appear to be atheroprotective in these patients. PMID:27122918

  1. The Effect of Aerobic Exercise on Total Cholesterol, High-Density Lipoprotein, Apolipoprotein B, Apolipoprotein A-I, and Percent Body Fat in Adolescent Females.

    ERIC Educational Resources Information Center

    Lungo, Diane; And Others

    The effect of aerobic exercise on total cholesterol (TC), high-density lipoprotein (HDL), apolipoprotein B (Apo B), apolioprotein A-I (Apo A-I), and percent body fat in adolescent females was studied. The control subjects (n=86) were volunteers who had completed a physical education class at least six months prior to the commencement of the study,…

  2. Correction of Apolipoprotein A-I-mediated Lipid Efflux and High Density Lipoprotein Particle Formation in Human Niemann-Pick Type C Disease Fibroblasts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Impaired cell cholesterol trafficking in Niemann-Pick type C (NPC) disease results in the first known instance of impaired regulation of the ATP-binding cassette transporter A1 (ABCA1), a lipid transporter mediating the rate-limiting step in high density lipoprotein (HDL) formation, as a cause of lo...

  3. Characterization of High Density Lipoprotein Particles in Familial Apolipoprotein A-I Deficiency With Premature Coronary Atherosclerosis, Corneal Arcus and Opacification, and Tubo-Eruptive and Planar Xanthomas

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We describe two male siblings with homozygous familial apolipoprotein (apo) A-I deficiency, markedly decreased high density lipoprotein (HDL) cholesterol levels, undetectable plasma apoA-1, tubo-eruptive and planar xanthomas, and mild corneal arcus and opacification. Sequencing of the apoA-I gene re...

  4. The effect of a high-intensity interval training program on high-density lipoprotein cholesterol in young men.

    PubMed

    Musa, Danladi I; Adeniran, Samuel A; Dikko, A U; Sayers, Stephen P

    2009-03-01

    This study examined the impact of an 8-week program of high-intensity interval training on high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and the atherogenic index (TC/HDL-C) in 36 untrained men ages 21-36 years. Participants were randomly assigned to an interval training group (n = 20) or a control group (n = 16). Participants in the experimental group performed 3.2 km of interval running (1:1 work:rest ratio) 3 times a week for 8 weeks at an intensity of 90% of maximal heart rate ( approximately 423 kcal per session). Results indicated significant pre- to posttraining changes in HDL-C (1.1 vs. 1.3 mmolxL, p < 0.0001) and TC/HDL-C (3.8 vs. 3.1, p < 0.0001) but no significant changes in TC (3.9 vs. 3.8 mmolxL, p > 0.05) with interval training. It was concluded that an 8-week program of high-intensity interval training is effective in eliciting favorable changes in HDL-C and TC/HDL-C but not TC in young adult men with normal TC levels. Our findings support the recommendations of high-intensity interval training as an alternative mode of exercise to improve blood lipid profiles for individuals with acceptable physical fitness levels. PMID:19209073

  5. Variability in the components of high density lipoprotein particles measured in human ovarian follicular fluid - A cross-sectional analysis

    PubMed Central

    Bloom, Michael S.; Kim, Keewan; Fujimoto, Victor Y.; Browne, Richard W.

    2014-01-01

    Objective Assess the variability of follicular fluid (FF) high-density lipoprotein (HDL) particle components. Design FF specimens were collected from two contralateral follicles on the day of oocyte retrieval and analyzed for HDL components. We characterized analytes by age, body mass index (BMI), race and smoking using a cross-sectional design. Biological variability was assessed using two-stage nested analysis of variance. Setting Reproductive health center. Patients One-hundred eighty in vitro fertilization (IVF) patients. Interventions None. Main Outcome Measures Nineteen HDL components including HDL-cholesterol and free (unesterified) and esterified forms, phospholipids, triglycerides, apolipoproteins A-1 and A-2, paraoxonase 1 (PON1) activities, and seven lipophilic vitamins and micronutrients. Results For some analytes, a majority of total measurement variability was attributed to sources between-follicles, suggesting an important role for the integrity of the blood-follicle-barrier and in situ remodeling of plasma derived constituents. For other analytes, variability was mostly attributed to sources between-women, likely indicative of plasma levels. Variability between-follicles decreased with increasing age, differed by BMI and smoking, and generally were lower for Asians and women with diminished ovarian reserve. Conclusions Substantial variability in FF HDL components exist between-follicles among women undergoing IVF, as well as between-women by age, BMI, race, smoking and by infertility diagnosis. PMID:24581578

  6. High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion.

    PubMed

    Chung, Dominic W; Chen, Junmei; Ling, Minhua; Fu, Xiaoyun; Blevins, Teri; Parsons, Scott; Le, Jennie; Harris, Jeff; Martin, Thomas R; Konkle, Barbara A; Zheng, Ying; López, José A

    2016-02-01

    The ability of von Willebrand factor (VWF) to initiate platelet adhesion depends on the number of monomers in individual VWF multimers and on the self-association of individual VWF multimers into larger structures. VWF self-association is accelerated by shear stress. We observed that VWF self-association occurs during adsorption of VWF onto surfaces, assembly of secreted VWF into hyperadhesive VWF strings on the endothelial surface, and incorporation of fluid-phase VWF into VWF fibers. VWF adsorption under static conditions increased with increased VWF purity and was prevented by a component of plasma. We identified that component as high-density lipoprotein (HDL) and its major apolipoprotein ApoA-I. HDL and ApoA-I also prevented VWF on the endothelium from self-associating into longer strands and inhibited the attachment of fluid-phase VWF onto vessel wall strands. Platelet adhesion to VWF fibers was reduced in proportion to the reduction in self-associated VWF. In a mouse model of thrombotic microangiopathy, HDL also largely prevented the thrombocytopenia induced by injection of high doses of human VWF. Finally, a potential role for ApoA-I in microvascular occlusion associated with thrombotic thrombocytopenic purpura and sepsis was revealed by the inverse relationship between the concentration of ApoA-I and that of hyperadhesive VWF. These results suggest that interference with VWF self-association would be a new approach to treating thrombotic disorders. PMID:26552698

  7. Defining specific goals of therapy in treating dyslipidemia in the patient with low high-density lipoprotein cholesterol.

    PubMed

    Belalcazar, L M; Ballantyne, C M

    1998-01-01

    Because patients with low high-density lipoprotein (HDL) cholesterol (HDL-C) are at high risk for clinical coronary artery disease (CAD) events, these patients require aggressive treatment with lifestyle modifications-increased exercise, smoking cessation, and weight loss in overweight patients-and available pharmacological agents. Drugs that raise HDL-C include nicotinic acid, fibric acid derivatives, estrogens, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), alpha-blockers, and alcohol. However, all agents that increase HDL-C may not have the same clinical benefit, just as, as shown in genetic studies in humans and mice, genetic causes of high HDL-C do not always protect against CAD, nor do genetic causes of low HDL-C always increase risk for CAD. Better understanding of the complexities of HDL metabolism and the mechanisms by which HDL protects against CAD is needed to enable the development of new therapeutic strategies--novel drugs or gene delivery systems--to increase HDL-C and reduce CAD events. The statins are the agents with the greatest evidence for slowing progression of CAD and reducing clinical events in patients with low HDL-C, but additional research is needed to determine the potential benefits of additional interventions that increase HDL-C, including combination therapy, which may provide greater improvements in the entire lipid profile. PMID:9790415

  8. Serum amyloid A changes high density lipoprotein's cellular affinity. A clue to serum amyloid A's principal function.

    PubMed

    Kisilevsky, R; Subrahmanyan, L

    1992-06-01

    The affinity of high density lipoproteins (HDL), or HDL carrying serum amyloid A (HDL/SAA), for hepatocytes or peritoneal macrophages was examined, as part of an investigation exploring the principal function of SAA and how this may be related to amyloidogenesis. The binding results in conjunction with SAA's existence primarily on HDL during inflammation, and HDL's known "reverse cholesterol transport" function suggest a clear role for SAA in the afferent arm of the reverse cholesterol transport pathway during the process of inflammation. The presence of SAA reduced HDL's affinity for normal hepatocytes by a factor of 2. In contrast, HDL/SAA had a 3- to 4-fold higher affinity for macrophages than HDL alone. Furthermore, the number of binding sites for HDL/SAA increased on macrophages during inflammation, while decreasing on hepatocytes. The net effect was a significant shift in HDL cholesterol carrying capacity towards the macrophage. Competition experiments demonstrated that HDL/SAA is only half as effective as HDL in inhibiting radiolabeled HDL binding to macrophages. This is in keeping with the reduced apolipoprotein A-1 content in HDL/SAA. Strikingly, although HDL contains twice as much apolipoprotein A-1 as HDL/SAA, it is only one-tenth as effective as HDL/SAA in inhibiting radiolabeled HDL/SAA binding to macrophages. The latter results suggest that there is a specific SAA binding site on macrophages. PMID:1602745

  9. Comparative analysis of oestrogen and raloxifene effects on the phospholipid composition of high density lipoproteins in healthy postmenopausal women.

    PubMed

    Piperi, C; Kalofoutis, C; Papapanagiotou, A; Skenderi, C; Kalofoutis, A

    2004-01-01

    The beneficial effect of selective oestrogen receptor modulators such as raloxifene in cardiovascular disease may be mediated partly by favourable changes in the phospholipid composition of high density lipoprotein (HDL) subclasses. In Group A (oestrogen alone) HDL2 phosphatidylcholine increased (P<0.001), while there was a decrease in HDL2 phosphatidylinositol (P<0.05) and HDL2 phosphatidylethanolamine (P<0.05) compared to controls (baseline). In the same group, HDL3 phosphatidylcholine increased (P<0.001) and HDL3 phosphatidylethanolamine decreased (P<0.01). In Group B (raloxifene) HDL2 phosphatidylcholine increased (P<0.001) as well as HDL2 diphosphatidylglycerol (P<0.01) while there were decreases in HDL2 sphingomyelin (P<0.01) and HDL2 phosphatidylethanolamine (P<0.05). In the same group, an increase in HDL3 phosphatidylcholine (P<0.001) and a reduction in HDL3 phosphatidylinositol (P<0.05) were observed as well as a decrease in HDL3 phosphatidylethanolamine (P<0.01) and HDL3 diphosphatidylglycerol (P<0.05). The significance of these results is discussed. PMID:14675982

  10. A Biocompatible Reconstituted High-Density Lipoprotein Nano-System as a Probe for Lung Cancer Detection

    PubMed Central

    Lu, Hongxiu; Zhang, Hongguang; Zhang, Dong; Lu, Hongwang; Ma, Dedong

    2015-01-01

    Background Early detection of cancer is critical and is expected to contribute significantly to the success of cancer therapy and improvement of patient survival rates. Material/Methods A biocompatible, reconstituted, high-density lipoprotein (rHDL)-based nano-system containing calcium carbonate and near-infrared fluorescence dye (NIRF), methylene blue (MB), was fabricated and characterized by particle size, zeta potential, and morphology observation. The safety profile was confirmed by bovine serum albumin (BSA) challenge assay, hemolysis test, MTT assay, and in vivo long-term toxicity assay. The tumor targetability was assessed by cellular uptake, competitive inhibition experiments, and in vivo imaging assay. Results The self-assembled rHDL/MB/CCPs exhibited desirable and homogenous particle size, neutral surface charges, high bovine serum albumin stability, low hemolytic activity, and negligible cytotoxicity in vitro. The results obtained from confocal scanning laser microscopy and flow cytometry indicated that SR-BI coating exerted tumor-targeting function, which induced high and specific cellular uptake of rHDL/MB/CCPs. In vivo investigation in an A549 tumor xenografts-bearing mouse model revealed that rHDL/MB/CCPs possessed strong tumor targetability. Conclusions rHDL/MB/CCPs could be a safe tumor-targeting probe for cancer detection. PMID:26365043

  11. Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein.

    PubMed

    Yao, Zhili; Mates, Jessica M; Cheplowitz, Alana M; Hammer, Lindsay P; Maiseyeu, Andrei; Phillips, Gary S; Wewers, Mark D; Rajaram, Murugesan V S; Robinson, John M; Anderson, Clark L; Ganesan, Latha P

    2016-09-15

    During Gram-negative bacterial infections, excessive LPS induces inflammation and sepsis via action on immune cells. However, the bulk of LPS can be cleared from circulation by the liver. Liver clearance is thought to be a slow process mediated exclusively by phagocytic resident macrophages, Kupffer cells (KC). However, we discovered that LPS disappears rapidly from the circulation, with a half-life of 2-4 min in mice, and liver eliminates about three quarters of LPS from blood circulation. Using microscopic techniques, we found that ∼75% of fluor-tagged LPS in liver became associated with liver sinusoidal endothelial cells (LSEC) and only ∼25% with KC. Notably, the ratio of LSEC-KC-associated LPS remained unchanged 45 min after infusion, indicating that LSEC independently processes the LPS. Most interestingly, results of kinetic analysis of LPS bioactivity, using modified limulus amebocyte lysate assay, suggest that recombinant factor C, an LPS binding protein, competitively inhibits high-density lipoprotein (HDL)-mediated LPS association with LSEC early in the process. Supporting the previous notion, 3 min postinfusion, 75% of infused fluorescently tagged LPS-HDL complex associates with LSEC, suggesting that HDL facilitates LPS clearance. These results lead us to propose a new paradigm of LSEC and HDL in clearing LPS with a potential to avoid inflammation during sepsis. PMID:27534554

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

    PubMed

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

    2005-10-01

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

  13. The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering.

    PubMed

    Wu, Zhiping; Gogonea, Valentin; Lee, Xavier; May, Roland P; Pipich, Vitaliy; Wagner, Matthew A; Undurti, Arundhati; Tallant, Thomas C; Baleanu-Gogonea, Camelia; Charlton, Francesca; Ioffe, Alexander; DiDonato, Joseph A; Rye, Kerry-Anne; Hazen, Stanley L

    2011-04-01

    Spherical high density lipoprotein (sHDL), a key player in reverse cholesterol transport and the most abundant form of HDL, is associated with cardiovascular diseases. Small angle neutron scattering with contrast variation was used to determine the solution structure of protein and lipid components of reconstituted sHDL. Apolipoprotein A1, the major protein of sHDL, forms a hollow structure that cradles a central compact lipid core. Three apoA1 chains are arranged within the low resolution structure of the protein component as one of three possible global architectures: (i) a helical dimer with a hairpin (HdHp), (ii) three hairpins (3Hp), or (iii) an integrated trimer (iT) in which the three apoA1 monomers mutually associate over a portion of the sHDL surface. Cross-linking and mass spectrometry analyses help to discriminate among the three molecular models and are most consistent with the HdHp overall architecture of apoA1 within sHDL. PMID:21292766

  14. Characterization and purification of proteins which bind high-density lipoprotein. A putative cell-surface receptor.

    PubMed Central

    Bond, H M; Morrone, G; Venuta, S; Howell, K E

    1991-01-01

    High-density lipoprotein (HDL) is shown by ligand blotting to bind membrane-associated polypeptides with sizes of 60, 100 and 210 kDa. Binding was concentration-dependent and competed by excess unlabelled HDL. All the major apolipoproteins of HDL, apoA-I, apoA-II and apoA-IV, bound independently. The 100 kDa and 210 kDa HDL-binding activities were purified from membranes of Hep3B tumour cells by ion-exchange chromatography and gel filtration. The binding activities at 100 kDa and 210 kDa co-purified. After treatment with disulphide-reducing reagent, the 210 kDa band was no longer present and an increase was observed in the amount and binding ability of the 100 kDa polypeptide. The 100 kDa binding protein labelled at the cell surface with 125I could be immunoprecipitated after cross-linking to cell-surface-bound HDL. It is proposed that this HDL-binding activity, a putative cell-surface receptor for HDL, exists totally or in part as a high-molecular-mass complex composed of 100 kDa subunits. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7. Fig. 8. PMID:1659384

  15. High-density lipoprotein contribute to G0-G1/S transition in Swiss NIH/3T3 fibroblasts

    PubMed Central

    Angius, Fabrizio; Spolitu, Stefano; Uda, Sabrina; Deligia, Stefania; Frau, Alessandra; Banni, Sebastiano; Collu, Maria; Accossu, Simonetta; Madeddu, Clelia; Serpe, Roberto; Batetta, Barbara

    2015-01-01

    High density lipoproteins (HDLs) play a crucial role in removing excess cholesterol from peripheral tissues. Although their concentration is lower during conditions of high cell growth rate (cancer and infections), their involvement during cell proliferation is not known. To this aim, we investigated the replicative cycles in synchronised Swiss 3T3 fibroblasts in different experimental conditions: i) contact-inhibited fibroblasts re-entering cell cycle after dilution; ii) scratch-wound assay; iii) serum-deprived cells induced to re-enter G1 by FCS, HDL or PDGF. Analyses were performed during each cell cycle up to quiescence. Cholesterol synthesis increased remarkably during the replicative cycles, decreasing only after cells reached confluence. In contrast, cholesteryl ester (CE) synthesis and content were high at 24 h after dilution and then decreased steeply in the successive cycles. Flow cytometry analysis of DiO-HDL, as well as radiolabeled HDL pulse, demonstrated a significant uptake of CE-HDL in 24 h. DiI-HDL uptake, lipid droplets (LDs) and SR-BI immunostaining and expression followed the same trend. Addition of HDL or PDGF partially restore the proliferation rate and significantly increase SR-BI and pAKT expression in serum-deprived cells. In conclusion, cell transition from G0 to G1/S requires CE-HDL uptake, leading to CE-HDL/SR-BI pathway activation and CEs increase into LDs. PMID:26640042

  16. High-density lipoprotein contribute to G0-G1/S transition in Swiss NIH/3T3 fibroblasts.

    PubMed

    Angius, Fabrizio; Spolitu, Stefano; Uda, Sabrina; Deligia, Stefania; Frau, Alessandra; Banni, Sebastiano; Collu, Maria; Accossu, Simonetta; Madeddu, Clelia; Serpe, Roberto; Batetta, Barbara

    2015-01-01

    High density lipoproteins (HDLs) play a crucial role in removing excess cholesterol from peripheral tissues. Although their concentration is lower during conditions of high cell growth rate (cancer and infections), their involvement during cell proliferation is not known. To this aim, we investigated the replicative cycles in synchronised Swiss 3T3 fibroblasts in different experimental conditions: i) contact-inhibited fibroblasts re-entering cell cycle after dilution; ii) scratch-wound assay; iii) serum-deprived cells induced to re-enter G1 by FCS, HDL or PDGF. Analyses were performed during each cell cycle up to quiescence. Cholesterol synthesis increased remarkably during the replicative cycles, decreasing only after cells reached confluence. In contrast, cholesteryl ester (CE) synthesis and content were high at 24 h after dilution and then decreased steeply in the successive cycles. Flow cytometry analysis of DiO-HDL, as well as radiolabeled HDL pulse, demonstrated a significant uptake of CE-HDL in 24 h. DiI-HDL uptake, lipid droplets (LDs) and SR-BI immunostaining and expression followed the same trend. Addition of HDL or PDGF partially restore the proliferation rate and significantly increase SR-BI and pAKT expression in serum-deprived cells. In conclusion, cell transition from G0 to G1/S requires CE-HDL uptake, leading to CE-HDL/SR-BI pathway activation and CEs increase into LDs. PMID:26640042

  17. Is the serum amyloid A protein in acute phase plasma high density lipoprotein the precursor of AA amyloid fibrils?

    PubMed Central

    Baltz, M L; Rowe, I F; Caspi, D; Turnell, W G; Pepys, M B

    1986-01-01

    Serum amyloid A protein (SAA), an apolipoprotein of high density lipoprotein (HDL), is generally considered to be the precursor of AA protein, which forms the fibrils in reactive systemic amyloidosis in man and animals. This view is based on amino acid sequence identity between AA and the amino-terminal portion of SAA. However, in extensive and well-controlled studies of experimentally induced murine AA amyloidosis, we were unable to demonstrate a direct precursor-product relationship between SAA, in SAA-rich HDL preparations from acute phase or amyloidotic mouse or human serum, and AA protein in the amyloid deposits. This raises the possibility that SAA in its usual form, as an apolipoprotein of HDL synthesized during the acute phase response, may not be the major precursor of AA fibrils. The amyloidogenic forms of circulating SAA molecules may not be isolated during the preparation of HDL. Alternatively, particularly in the light of recent evidence that SAA mRNA is expressed in many different tissues throughout the body of appropriately stimulated animals, amyloidogenic SAA may be derived from sources other than the liver cells in which SAA-rich HDL is synthesized. PMID:3105937

  18. Isoferulic Acid Action against Glycation-Induced Changes in Structural and Functional Attributes of Human High-Density Lipoprotein.

    PubMed

    Jairajpuri, D S; Jairajpuri, Z S

    2016-03-01

    Glycation-induced high-density lipoprotein (HDL) modification by aldehydes can result in loss of its antiinflammatory/antioxidative properties, contributing to diabetes-associated cardiovascular diseases. Isoferulic acid, a major active ingredient of Cimicifuga heracleifolia, shows antiinflammatory, antiviral, antioxidant, and antidiabetic properties. Thus, this study investigated the antiglycation effect of isoferulic acid against compositional modifications of HDL and loss of biological activity of HDL-paraoxonase induced on incubation with different aldehydes. Protective effect of isoferulic acid was assessed by subjecting purified HDL from human plasma to glycation with methylglyoxal, glyoxal, or glycolaldehyde and varying concentrations of isoferulic acid. The effect of isoferulic acid was analyzed by determining amino group number, tryptophan and advanced glycation end-product fluorescence, thermal denaturation studies, carboxymethyl lysine content, and activity of HDL-paraoxonase. Concentration-dependent inhibitory action of isoferulic acid was observed against extensive structural perturbations, decrease in amino group number, increase in carboxymethyl lysine content, and decrease in the activity of HDL-paraoxonase caused by aldehyde-associated glycation in the HDL molecule. Isoferulic acid, when taken in concentration equal to that of aldehydes, was most protective, as 82-88% of paraoxonase activity was retained for all studied aldehydes. Isoferulic acid shows antiglycation action against aldehyde-associated glycation in HDL, which indicates its therapeutic potential for diabetic patients, especially those with micro-/macrovascular complications. PMID:27262199

  19. Steroid hormone 20-hydroxyecdysone regulation of the very-high-density lipoprotein (VHDL) receptor phosphorylation for VHDL uptake.

    PubMed

    Dong, Du-Juan; Liu, Wen; Cai, Mei-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2013-04-01

    During the metamorphic stage of holometabolous insects, the biosynthetic precursors needed for the synthesis of a large number of adult proteins are acquired from the selective absorption of storage proteins. The very-high-density lipoprotein (VHDL), a non-hexameric storage protein, is consumed by the fat body from the hemolymph through VHDL receptor (VHDL-R)-mediated endocytosis. However, the mechanism of the uptake of VHDL by a VHDL-R remains unclear. In this study, a VHDL-R from Helicoverpa armigera was found to be involved in 20E-regulated VHDL uptake through the regulation of steroid hormone 20-hydroxyecdysone (20E). The transcripts of VHDL-R were detected mainly in the fat body and integument during the wandering stage. The transcription of VHDL-R was upregulated by 20E through the ecdysteroid receptor (EcRB1) and Ultraspiracle (USP1). In addition, 20E stimulates the phosphorylation of VHDL-R through protein kinase C for ligand binding. VHDL-R knockdown in larvae results the inhibition of development to adulthood. These data imply that 20E regulates VHDL-R on both transcriptional and posttranslational levels for VHDL absorption. PMID:23416133

  20. Near-infrared fluorescent imaging of metastatic ovarian cancer using folate receptor-targeted high-density lipoprotein nanocarriers

    PubMed Central

    Corbin, Ian R; Ng, Kenneth K; Ding, Lili; Jurisicova, Andrea; Zheng, Gang

    2013-01-01

    Aim The targeting efficiency of folate receptor-α (FR-α)-targeted high-density lipoprotein nanoparticles (HDL NPs) was evaluated in a syngeneic mouse model of ovarian cancer. Materials & methods Folic acid was conjugated to the surface of fluorescent-labeled HDL NPs. In vivo tumor targeting of folic acid-HDL NPs and HDL NPs were evaluated in mice with metastatic ovarian cancer following intravenous or intraperitoneal (ip.) administration. Results & discussion Intravenous FR-α-targeted HDL resulted in high uptake of the fluorescent nanoparticle in host liver and spleen. The ip. injection of fluorescent HDL produced moderate fluorescence throughout the abdomen. Conversely, animals receiving the ip. FR-α-targeted HDL showed a high fluorescence signal in ovarian tumors, surpassing that seen in all of the host tissues. Conclusion The authors' findings demonstrate that the combination of local–regional ip. administration and FR-α-directed nanoparticles provides an enhanced approach to selectively targeting ovarian cancer cells for drug treatment. PMID:23067398

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

    PubMed Central

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

    2014-01-01

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

  2. Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents.

    PubMed

    Khetarpal, Sumeet A; Schjoldager, Katrine T; Christoffersen, Christina; Raghavan, Avanthi; Edmondson, Andrew C; Reutter, Heiko M; Ahmed, Bouhouche; Ouazzani, Reda; Peloso, Gina M; Vitali, Cecilia; Zhao, Wei; Somasundara, Amritha Varshini Hanasoge; Millar, John S; Park, YoSon; Fernando, Gayani; Livanov, Valentin; Choi, Seungbum; Noé, Eric; Patel, Pritesh; Ho, Siew Peng; Kirchgessner, Todd G; Wandall, Hans H; Hansen, Lars; Bennett, Eric P; Vakhrushev, Sergey Y; Saleheen, Danish; Kathiresan, Sekar; Brown, Christopher D; Abou Jamra, Rami; LeGuern, Eric; Clausen, Henrik; Rader, Daniel J

    2016-08-01

    Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss of function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2-deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals. PMID:27508872

  3. Lysine residues direct the chlorination of tyrosines in YXXK motifs of apolipoprotein A-I when hypochlorous acid oxidizes high density lipoprotein.

    PubMed

    Bergt, Constanze; Fu, Xiaoyun; Huq, Nabiha P; Kao, Jeff; Heinecke, Jay W

    2004-02-27

    Oxidized lipoproteins may play an important role in the pathogenesis of atherosclerosis. Elevated levels of 3-chlorotyrosine, a specific end product of the reaction between hypochlorous acid (HOCl) and tyrosine residues of proteins, have been detected in atherosclerotic tissue. Thus, HOCl generated by the phagocyte enzyme myeloperoxidase represents one pathway for protein oxidation in humans. One important target of the myeloperoxidase pathway may be high density lipoprotein (HDL), which mobilizes cholesterol from artery wall cells. To determine whether activated phagocytes preferentially chlorinate specific sites in HDL, we used tandem mass spectrometry (MS/MS) to analyze apolipoprotein A-I that had been oxidized by HOCl. The major site of chlorination was a single tyrosine residue located in one of the protein's YXXK motifs (where X represents a nonreactive amino acid). To investigate the mechanism of chlorination, we exposed synthetic peptides to HOCl. The peptides encompassed the amino acid sequences YKXXY, YXXKY, or YXXXY. MS/MS analysis demonstrated that chlorination of tyrosine in the peptides that contained lysine was regioselective and occurred in high yield if the substrate was KXXY or YXXK. NMR and MS analyses revealed that the N(epsilon) amino group of lysine was initially chlorinated, which suggests that chloramine formation is the first step in tyrosine chlorination. Molecular modeling of the YXXK motif in apolipoprotein A-I demonstrated that these tyrosine and lysine residues are adjacent on the same face of an amphipathic alpha-helix. Our observations suggest that HOCl selectively targets tyrosine residues that are suitably juxtaposed to primary amino groups in proteins. This mechanism might enable phagocytes to efficiently damage proteins when they destroy microbial proteins during infection or damage host tissue during inflammation. PMID:14660678

  4. Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle-aged men.

    PubMed

    Talmud, P J; Hawe, E; Robertson, K; Miller, G J; Miller, N E; Humphries, S E

    2002-03-01

    The effects of common variants of cholesteryl ester transfer protein (CETP) (TaqIB), hepatic lipase (HL) (-514C>T), lipoprotein lipase (LPL) (S447X) and lecithin cholesterol acyl transferase (LCAT) (S208T) on the determination of high density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoAI) levels were examined in 2773 healthy middle-aged men participating in the second Northwick Park Heart Study. The extent of gene:gene, gene:smoking and gene:alcohol interactions were determined. For HDL-C levels, only CETP genotype was associated with significant effects (p&0.0001), with the B2 allele being associated with higher levels in both smokers and non-smokers. This interaction was significant at the lowest tertile of TG, suggesting that TG levels were rate limiting. As previously reported, CETP, LPL and HL genotypes were all associated with significant effects on apoAI levels (all p&0.01), with carriers of the rare alleles having higher levels and with no evidence of heterogeneity of effects in smokers and non-smokers. LCAT genotype was not associated with significant effects on either trait. There was no significant interaction between any of the genotypes and alcohol consumption on either HDL-C or apoAI levels. All genotypic effects were additive for HDL-C and apoAI. Environmental and TG levels explained more than 20% and 5.5% of the variance in HDL-C and apoAI, respectively. The novel aspect of this finding is that genetic variation at these loci explained in total only 2.5% of the variance in HDL-C and 1.89% of the variance in apoAI levels. Thus despite the key roles played by these enzymes in HDL metabolism, variation at these loci, at least as detected by these common genotypes, contributes minimally to the variance in HDL-C and apoAI levels in healthy men, highlighting the polygenic and multifactorial control of HDL-C. PMID:12174215

  5. Direct Selective Laser Sintering/Melting of High Density Alumina Powder Layers at Elevated Temperatures

    NASA Astrophysics Data System (ADS)

    Deckers, J.; Meyers, S.; Kruth, J. P.; Vleugels, J.

    Direct selective laser sintering (SLS) or selective laser melting (SLM) are additive manufacturing techniques that can be used to produce three-dimensional ceramic parts directly, without the need for a sacrificial binder. In this paper, a low laser energy density is applied to SLS/SLM high density powder layers of sub-micrometer alumina at elevated temperatures (up to 800̊C). In order to achieve this, a furnace was designed and built into a commercial SLS machine. This furnace was able to produce a homogeneously heated cylindrical zone with a height of 60 mm and a diameter of 32 mm. After optimizing the layer deposition and laser scanning parameters, two ceramic parts with a density up to 85% and grain sizes as low as 5 μm were successfully produced.

  6. Analysis by enzyme-linked immunosorbent assay and 2-dimensional electrophoresis of haptoglobin in the high-density lipoprotein fraction in cows.

    PubMed

    Kanno, H; Katoh, N

    2001-01-01

    Haptoglobin (Hp) is a hemoglobin (Hb)-binding acute-phase protein. Besides its relevance in inflammation, Hp is involved in the regulation of lipid metabolism. In cattle, in addition to the lipoprotein-deficient fraction, Hp is distributed in high-density lipoprotein (HDL) and very high-density lipoprotein (VHDL) fractions. The purpose of this study was to determine Hp concentrations in the lipoprotein fractions using an enzyme-linked immunosorbent assay (ELISA) based on the affinity with Hb, and also to detect structural differences of HDL Hp from that in the lipoprotein-deficient fraction using 2-dimensional electrophoresis. When purified Hp was used as the antigen for the ELISA, the detection limit was 7.4 ng/ml and linearity was obtained from 14.8 to 475 ng/ml. The correlation coefficient between the ELISA and single radial immunodiffusion was 0.884. The ELISA was shown to be applicable to evaluate Hp concentrations in the lipoprotein fractions. Hp concentrations in the lipoprotein fractions were in the range of 0.94 to 8.77 microg of Hp/ml (n = 4), and concentration ratios were 0.2 to 0.3% of whole serum Hp. Of the lipoprotein fractions, Hp was most abundant in HDL, moderate in VHDL and faint in chylomicrons, the very low-density lipoprotein fraction and low-density lipoprotein fraction. By 2-dimensional electrophoresis, alpha- and beta-chains of serum Hp were each separated into 5 spots, and their isoelectric point (pI) values were from 5.05 to 6.28 in the alpha-chain and from 5.92 to 6.95 in the beta-chain. The pI values of HDL Hp were indistinguishable from those of serum Hp. These results indicate that the ELISA based on the affinity with Hb is useful for evaluating Hp concentrations in lipoprotein fractions, and also suggest that HDL Hp is structurally similar to that in the lipoprotein-deficient fraction. PMID:11217066

  7. Exclusive photothermal heat generation by a gadolinium bis(naphthalocyanine) complex and inclusion into modified high-density lipoprotein nanocarriers for therapeutic applications.

    PubMed

    Mathew, Simon; Murakami, Tatsuya; Nakatsuji, Hirotaka; Okamoto, Haruki; Morone, Nobuhiro; Heuser, John E; Hashida, Mitsuru; Imahori, Hiroshi

    2013-10-22

    A hydrophobic gadolinium bis(naphthalocyanine) sandwich complex (GdSand) possessing several absorbances across visible and infrared wavelengths (up to 2500 nm) was solubilized in aqueous solution by uptake into a nascent mutant high-density lipoprotein (HDL) nanocarrier. The HDL nanocarrier was additionally functionalized with a trans-activator of transcription peptide sequence to promote efficient cell penetration of the drug delivery system (cpHDL). The dye-loaded nanocarrier (GdSand@cpHDL) exhibited photothermal heat generation properties upon irradiation with near-infrared (NIR) laser light, with controllable heat generation abilities as a function of the incident laser light power. Comparison of the photothermal behavior of the dyes GdSand and the well-explored molecular photothermal agent indocyanine green (ICG) in the cpHDL nanocarrier (i.e., ICG@cpHDL) revealed two significant advantages of GdSand@cpHDL: (1) the ability to maintain elevated temperatures upon light absorption for extended periods of time, with a reduced degree of self-destruction of the dye, and (2) exclusive photothermal heat generation with no detectable singlet oxygen production leading to improved integrity of the cpHDL nanocarrier after irradiation. Finally, GdSand@cpHDL was successfully subjected to an in vitro study against NCI-H460 human lung cancer cells, demonstrating the proof-of-principle utility of lanthanide sandwich complexes in photothermal therapeutic applications. PMID:24053139

  8. WDR1 and CLNK gene polymorphisms correlate with serum glucose and high-density lipoprotein levels in Tibetan gout patients.

    PubMed

    Lan, Bing; Chen, Peng; Jiri, Mutu; He, Na; Feng, Tian; Liu, Kai; Jin, Tianbo; Kang, Longli

    2016-03-01

    Current evidence suggests heredity and metabolic syndrome contributes to gout progression. Specifically, the WDR1 and CLNK genes may play a role in gout progression in European ancestry populations. However, no studies have focused on Chinese populations, especially Tibetan individuals. This study aims to determine whether variations in these two genes correlate with gout-related indices in Chinese-Tibetan gout patients. Eleven single-nucleotide polymorphisms in the WDR1 and CLNK genes were detected in 319 Chinese-Tibetan gout patients and 318 controls. We used one-way analysis of variance to evaluate the polymorphisms' effects on gout based on mean serum levels of metabolism indicators, such as albumin, glucose (GLU), triglycerides, cholesterol, high-density lipoproteins (HDL-C), creatinine, and uric acid, from fasting venous blood samples. All p values were Bonferroni corrected. Polymorphisms of the WDR1 and CLNK genes affected multiple risk factors for gout development. Significant differences in serum GLU levels were detected between different genotypic groups with WDRI polymorphisms rs4604059 (p = 0.005) and rs12498927 (p = 0.005). In addition, significant differences in serum HDL-C levels were detected between different genotypic groups with the CLNK polymorphism rs2041215 (p = 0.001). Polymorphisms of CLNK also affected levels of albumin, triglycerides, and creatinine. This study is the first to investigate and identify positive correlations between WDR1 and CLNK gene polymorphisms in Chinese-Tibetan populations. Our findings provide significant evidence for the effect of genetic polymorphisms on gout-related factors in Chinese-Tibetan populations. PMID:26438387

  9. Apolipoprotein AI Deficiency Inhibits Serum Opacity Factor Activity against Plasma High Density Lipoprotein via a Stabilization Mechanism

    PubMed Central

    Rosales, Corina; Patel, Niket; Gillard, Baiba K.; Yelamanchili, Dedipya; Yang, Yaliu; Courtney, Harry S.; Santos, Raul D.; Gotto, Antonio M.; Pownall, Henry J.

    2016-01-01

    The reaction of Streptococcal serum opacity factor (SOF) against plasma high-density lipoproteins (HDL) produces a large cholesteryl ester-rich microemulsion (CERM), a smaller neo HDL that is apolipoprotein (apo) AI-poor, and lipid-free apo AI. SOF is active vs. both human and mouse plasma HDL. In vivo injection of SOF into mice reduces plasma cholesterol ~40% in 3 hours while forming the same products observed in vitro, but at different ratios. Previous studies supported the hypothesis that labile apo AI is required for the SOF reaction vs. HDL. Here we further tested that hypothesis by studies of SOF against HDL from apo AI-null mice. When injected into apo AI-null mice, SOF reduced plasma cholesterol ~35% in three hours. The reaction of SOF vs. apo AI-null HDL in vitro produced a CERM and neo HDL, but no lipid-free apo. Moreover, according to the rate of CERM formation, the extent and rate of the SOF reaction vs. apo AI-null mouse HDL was less than that against wild-type (WT) mouse HDL. Chaotropic perturbation studies using guanidine hydrochloride showed that apo AI-null HDL was more stable than WT HDL. Human apo AI added to apo AI-null HDL was quantitatively incorporated, giving reconstituted HDL. Both SOF and guanidine hydrochloride displaced apo AI from the reconstituted HDL. These results support the conclusion that apo AI-null HDL is more stable than WT HDL because it lacks apo AI, a labile protein that is readily displaced by physico-chemical and biochemical perturbations. Thus, apo AI-null HDL is less SOF-reactive than WT HDL. The properties of apo AI-null HDL can be partially restored to those of WT HDL by the spontaneous incorporation of human apo AI. It remains to be determined what other HDL functions are affected by apo AI deletion. PMID:25790332

  10. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    PubMed Central

    An, Ping; Straka, Robert J.; Pollin, Toni I.; Feitosa, Mary F.; Wojczynski, Mary K.; Daw, E. Warwick; O'Connell, Jeffrey R.; Gibson, Quince; Ryan, Kathleen A.; Hopkins, Paul N.; Tsai, Michael Y.; Lai, Chao-Qiang; Province, Michael A.; Ordovas, Jose M.; Shuldiner, Alan R; Arnett, Donna K.; Borecki, Ingrid B.

    2014-01-01

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted. PMID:24604477

  11. Liver Gene Transfer of Interkeukin-15 Constructs That Become Part of Circulating High Density Lipoproteins for Immunotherapy

    PubMed Central

    Ochoa, Maria C.; Fioravanti, Jessica; Duitman, Erwin H.; Medina-Echeverz, Jose; Palazon, Asis; Arina, Ainhoa; Dubrot, Juan; Alfaro, Carlos; Morales-Kastresana, Aizea; Murillo, Oihana; Hervas-Stubbs, Sandra; Prieto, Jesus

    2012-01-01

    Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding a chimeric molecule encompassing interleukin-15 (IL-15) and Apo A-I (pApo-hIL15) that was tested by hydrodynamic injections into mice and was co-administered with a plasmid encoding the sushi domain of IL-15Rα (pSushi) in order to enhance IL-15 trans-presentation and thereby bioactivity. The pharmacokinetics of the Apo A-I chimeric protein were much longer than non-stabilized IL-15 and its bioactivity was enhanced in combination with IL-15Rα Sushi. Importantly, the APO-IL-15 fusion protein was incorporated in part into circulating HDL. Liver gene transfer of these constructs increased NK and memory-phenotype CD8 lymphocyte numbers in peripheral blood, spleen and liver as a result of proliferation documented by CFSE dilution and BrdU incorporation. Moreover, the gene transfer procedure partly rescued the NK and memory T-cell deficiency observed in IL-15Rα−/− mice. pApo-hIL15+ pSushi gene transfer to the liver showed a modest therapeutic activity against subcutaneously transplanted MC38 colon carcinoma tumors, that was more evident when tumors were set up as liver metastases. The improved pharmacokinetic profile and the strong biological activity of APO-IL-15 fusion protein holds promise for further development in combination with other immunotherapies. PMID:23285013

  12. Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

    PubMed Central

    Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

    2013-01-01

    Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

  13. Regulation of high density lipoprotein receptors in cultured macrophages: role of acyl-CoA:cholesterol acyltransferase.

    PubMed Central

    Schmitz, G; Niemann, R; Brennhausen, B; Krause, R; Assmann, G

    1985-01-01

    The interaction of human serum high density lipoproteins (HDL) with mouse peritoneal macrophages and human blood monocytes was studied. Saturation curves for binding of apolipoprotein E-free [125I]HDL3 showed at least two components: non-specific binding and specific binding that saturated at approximately 40 micrograms HDL protein/ml. Scatchard analysis of specific binding of apo E-free [125I]-HDL3 to cultured macrophages yielded linear plots indicative of a single class of specific binding sites. Pretreatment of [125I]HDL3 with various apolipoprotein antibodies (anti apo A-I, anti apo A-II, anti apo C-II, anti apo C-III and anti apo E) and preincubation of the cells with anti-idiotype antibodies against apo A-I and apo A-II prior to the HDL binding studies revealed apolipoprotein A-I as the ligand involved in specific binding of HDL. Cellular cholesterol accumulation via incubation with acetylated LDL led to an increase in HDL binding sites as well as an increase in the activity of the cytoplasmic cholesterol esterifying enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Incubation of the cholesterol-loaded cells in the presence of various ACAT inhibitors (Sandoz 58.035, Octimibate-Nattermann, progesterone) revealed a time- and dose-dependent amplification in HDL binding and HDL-mediated cholesterol efflux. It is concluded that the homeostasis of cellular cholesterol in macrophages is regulated in part by the number of HDL binding sites and that ACAT inhibitors enhance HDL-mediated cholesterol efflux from peripheral cells. Images Fig. 4. PMID:2998754

  14. Distinct Roles of Apolipoproteins A1 and E in the Modulation of High-Density Lipoprotein Composition and Function.

    PubMed

    Filou, Serafoula; Lhomme, Marie; Karavia, Eleni A; Kalogeropoulou, Christina; Theodoropoulos, Vassilis; Zvintzou, Evangelia; Sakellaropoulos, George C; Petropoulou, Peristera-Ioanna; Constantinou, Caterina; Kontush, Anatol; Kypreos, Kyriakos E

    2016-07-12

    In addition to high-density lipoprotein cholesterol (HDL-C) levels, HDL quality also appears to be very important for atheroprotection. Analysis of various clinical paradigms suggests that the lipid and apolipoprotein composition of HDL defines its size, shape, and functions and may determine its beneficial effects on human health. Previously, we reported that like apolipoprotein A-I (Apoa1), apolipoprotein E (Apoe) is also capable of promoting the de novo biogenesis of HDL with the participation of ATP binding cassette A lipid transporter member 1 (Abca1) and plasma enzyme lecithin:cholesterol acyltransferase (Lcat), in a manner independent of a functional Apoa1. Here, we performed a comparative analysis of the functions of these HDL subpopulations. Specifically, Apoe and Apoa1 double-deficient (Apoe(-/-) × Apoa1(-/-)) mice were infected with APOA1- or APOE3-expressing adenoviruses, and APOA1-containing HDL (APOA1-HDL) and APOE3-containing HDL (APOE3-HDL), respectively, were isolated and analyzed by biochemical and physicochemical methods. Western blot and lipidomic analyses indicated significant differences in the apolipoprotein and lipid composition of the two HDL species. Moreover APOE3-HDL presented a markedly reduced antioxidant potential and Abcg1-mediated cholesterol efflux capacity. Surprisingly, APOE3-HDL but not APOA1-HDL attenuated LPS-induced production of TNFα in RAW264.7 cells, suggesting that the anti-inflammatory effects of APOA1 are dependent on APOE expression. Taken together, our data indicate that APOA1 and APOE3 recruit different apolipoproteins and lipids on the HDL particle, leading to structurally and functionally distinct HDL subpopulations. The distinct role of these two apolipoproteins in the modulation of HDL functionality may pave the way toward the development of novel pharmaceuticals that aim to improve HDL functionality. PMID:27332083

  15. Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice.

    PubMed

    Robert, Jérôme; Stukas, Sophie; Button, Emily; Cheng, Wai Hang; Lee, Michael; Fan, Jianjia; Wilkinson, Anna; Kulic, Iva; Wright, Samuel D; Wellington, Cheryl L

    2016-05-01

    Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aβ40 and Aβ42 levels were significantly reduced within 24h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aβ levels in animals assessed 7days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aβ levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aβ pool. That systemic administration of rHDL can acutely modify brain Aβ levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26454209

  16. Harnessing high density lipoproteins to block transforming growth factor beta and to inhibit the growth of liver tumor metastases.

    PubMed

    Medina-Echeverz, José; Fioravanti, Jessica; Díaz-Valdés, Nancy; Frank, Kathrin; Aranda, Fernando; Gomar, Celia; Ardaiz, Nuria; Dotor, Javier; Umansky, Viktor; Prieto, Jesús; Berraondo, Pedro

    2014-01-01

    Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2-/-IL2rγ-/- immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. PMID:24797128

  17. Liver gene transfer of interkeukin-15 constructs that become part of circulating high density lipoproteins for immunotherapy.

    PubMed

    Ochoa, Maria C; Fioravanti, Jessica; Duitman, Erwin H; Medina-Echeverz, Jose; Palazon, Asis; Arina, Ainhoa; Dubrot, Juan; Alfaro, Carlos; Morales-Kastresana, Aizea; Murillo, Oihana; Hervas-Stubbs, Sandra; Prieto, Jesus; Berraondo, Pedro; Melero, Ignacio

    2012-01-01

    Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding a chimeric molecule encompassing interleukin-15 (IL-15) and Apo A-I (pApo-hIL15) that was tested by hydrodynamic injections into mice and was co-administered with a plasmid encoding the sushi domain of IL-15Rα (pSushi) in order to enhance IL-15 trans-presentation and thereby bioactivity. The pharmacokinetics of the Apo A-I chimeric protein were much longer than non-stabilized IL-15 and its bioactivity was enhanced in combination with IL-15Rα Sushi. Importantly, the APO-IL-15 fusion protein was incorporated in part into circulating HDL. Liver gene transfer of these constructs increased NK and memory-phenotype CD8 lymphocyte numbers in peripheral blood, spleen and liver as a result of proliferation documented by CFSE dilution and BrdU incorporation. Moreover, the gene transfer procedure partly rescued the NK and memory T-cell deficiency observed in IL-15Rα(-/-) mice. pApo-hIL15+ pSushi gene transfer to the liver showed a modest therapeutic activity against subcutaneously transplanted MC38 colon carcinoma tumors, that was more evident when tumors were set up as liver metastases. The improved pharmacokinetic profile and the strong biological activity of APO-IL-15 fusion protein holds promise for further development in combination with other immunotherapies. PMID:23285013

  18. Effect of obesity on the association between MYL2 (rs3782889) and high-density lipoprotein cholesterol among Korean men.

    PubMed

    Cho, Eo Rin; Jee, Yon Ho; Kim, Sang Won; Sull, Jae Woong

    2016-05-01

    High-density lipoprotein (HDL) cholesterol levels are associated with a decreased risk of coronary artery disease. Several genome-wide association studies that have examined HDL cholesterol levels have implicated myosin light chain 2 regulatory cardiac slow (MYL2) as a possible causal factor. Herein, the association between the rs3782889 single-nucleotide polymorphism (SNP) in the MYL2 gene and HDL cholesterol levels was tested in the Korean population. A total of 4294 individuals were included in a replication study with MYL2 SNP rs3782889. SNP rs3782889 in the MYL2 gene was associated with mean HDL cholesterol level (effect per allele, -1.055 mg dl(-1), P=0.0005). Subjects with the CT/CC genotype had a 1.43-fold (range 1.19-1.73-fold) higher risk of an abnormal HDL cholesterol level (<40 mg dl(-1)) than subjects with the TT genotype. When analyzed by sex, the MYL2 association was stronger in men than that in women. When analyzed by body mass index (BMI), the MYL2 association was much stronger in male subjects with BMI ⩾26.44 kg m(-2) (odds ratio (OR)=2.68; 95% confidence interval (CI)=1.87-3.84; P<0.0001) than that in male subjects with BMI <26.44 kg m(-2). When compared with subjects having the TT genotype and BMI <26.44 kg m(-2), ORs (95% CI) were 3.30 (2.41-4.50) in subjects having the CT/CC genotype and BMI ⩾26.44 kg m(-2) (P for interaction <0.0001). Our results clearly demonstrate that genetic variants in MYL2 influence HDL cholesterol levels in Korean obese male subjects. PMID:26763873

  19. Apolipoprotein AI deficiency inhibits serum opacity factor activity against plasma high density lipoprotein via a stabilization mechanism.

    PubMed

    Rosales, Corina; Patel, Niket; Gillard, Baiba K; Yelamanchili, Dedipya; Yang, Yaliu; Courtney, Harry S; Santos, Raul D; Gotto, Antonio M; Pownall, Henry J

    2015-04-14

    The reaction of Streptococcal serum opacity factor (SOF) against plasma high-density lipoproteins (HDL) produces a large cholesteryl ester-rich microemulsion (CERM), a smaller neo HDL that is apolipoprotein (apo) AI-poor, and lipid-free apo AI. SOF is active versus both human and mouse plasma HDL. In vivo injection of SOF into mice reduces plasma cholesterol ∼40% in 3 h while forming the same products observed in vitro, but at different ratios. Previous studies supported the hypothesis that labile apo AI is required for the SOF reaction vs HDL. Here we further tested that hypothesis by studies of SOF against HDL from apo AI-null mice. When injected into apo AI-null mice, SOF reduced plasma cholesterol ∼35% in 3 h. The reaction of SOF vs apo AI-null HDL in vitro produced a CERM and neo HDL, but no lipid-free apo. Moreover, according to the rate of CERM formation, the extent and rate of the SOF reaction versus apo AI-null mouse HDL were less than that against wild-type (WT) mouse HDL. Chaotropic perturbation studies using guanidine hydrochloride showed that apo AI-null HDL was more stable than WT HDL. Human apo AI added to apo AI-null HDL was quantitatively incorporated, giving reconstituted HDL. Both SOF and guanidine hydrochloride displaced apo AI from the reconstituted HDL. These results support the conclusion that apo AI-null HDL is more stable than WT HDL because it lacks apo AI, a labile protein that is readily displaced by physicochemical and biochemical perturbations. Thus, apo AI-null HDL is less SOF-reactive than WT HDL. The properties of apo AI-null HDL can be partially restored to those of WT HDL by the spontaneous incorporation of human apo AI. It remains to be determined what other HDL functions are affected by apo AI deletion. PMID:25790332

  20. Oxidized High-Density Lipoprotein Impairs Endothelial Progenitor Cells' Function by Activation of CD36-MAPK-TSP-1 Pathways

    PubMed Central

    Wu, Jianxiang; He, Zhiqing; Gao, Xiang; Wu, Feng; Ding, Ru; Ren, Yusheng; Jiang, Qijun; Fan, Min

    2015-01-01

    Abstract Aims: High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms. Results: ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-κB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal. Innovation: This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum. Conclusion: Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease. Antioxid. Redox Signal. 22, 308–324. PMID:25313537

  1. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol.

    PubMed

    Roman, Tamara S; Marvelle, Amanda F; Fogarty, Marie P; Vadlamudi, Swarooparani; Gonzalez, Arlene J; Buchkovich, Martin L; Huyghe, Jeroen R; Fuchsberger, Christian; Jackson, Anne U; Wu, Ying; Civelek, Mete; Lusis, Aldons J; Gaulton, Kyle J; Sethupathy, Praveen; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L

    2015-12-01

    Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID:26637976

  2. Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol

    PubMed Central

    Roman, Tamara S.; Marvelle, Amanda F.; Fogarty, Marie P.; Vadlamudi, Swarooparani; Gonzalez, Arlene J.; Buchkovich, Martin L.; Huyghe, Jeroen R.; Fuchsberger, Christian; Jackson, Anne U.; Wu, Ying; Civelek, Mete; Lusis, Aldons J.; Gaulton, Kyle J.; Sethupathy, Praveen; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Kuusisto, Johanna; Collins, Francis S.; Laakso, Markku; Boehnke, Michael; Mohlke, Karen L.

    2015-01-01

    Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r2 > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10−12). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT– haplotype] versus 16-fold [CC+ haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID:26637976

  3. Harnessing High Density Lipoproteins to Block Transforming Growth Factor Beta and to Inhibit the Growth of Liver Tumor Metastases

    PubMed Central

    Medina-Echeverz, José; Fioravanti, Jessica; Díaz-Valdés, Nancy; Frank, Kathrin; Aranda, Fernando; Gomar, Celia; Ardaiz, Nuria; Dotor, Javier; Umansky, Viktor; Prieto, Jesús; Berraondo, Pedro

    2014-01-01

    Transforming growth factor β (TGF-β) is a powerful promoter of cancer progression and a key target for antitumor therapy. As cancer cells exhibit active cholesterol metabolism, high density lipoproteins (HDLs) appear as an attractive delivery system for anticancer TGFβ-inhibitory molecules. We constructed a plasmid encoding a potent TGF-β-blocking peptide (P144) linked to apolipoprotein A-I (ApoA-I) through a flexible linker (pApoLinkerP144). The ApoLinkerP144 sequence was then incorporated into a hepatotropic adeno-associated vector (AAVApoLinkerP144). The aim was to induce hepatocytes to produce HDLs containing a modified ApoA-I capable of blocking TGF-β. We observed that transduction of the murine liver with pApoLinkerP144 led to the appearance of a fraction of circulating HDL containing the fusion protein. These HDLs were able to attenuate TGF-β signaling in the liver and to enhance IL-12 -mediated IFN-γ production. Treatment of liver metastasis of MC38 colorectal cancer with AAVApoLinkerP144 resulted in a significant reduction of tumor growth and enhanced expression of IFN-γ and GM-CSF in cancerous tissue. ApoLinkerP144 also delayed MC38 liver metastasis in Rag2−/−IL2rγ−/− immunodeficient mice. This effect was associated with downregulation of TGF-β target genes essential for metastatic niche conditioning. Finally, in a subset of ret transgenic mice, a model of aggressive spontaneous metastatic melanoma, AAVApoLinkerP144 delayed tumor growth in association with increased CD8+ T cell numbers in regional lymph nodes. In conclusion, modification of HDLs to transport TGF-β-blocking molecules is a novel and promising approach to inhibit the growth of liver metastases by immunological and non-immunological mechanisms. PMID:24797128

  4. Plasma-derived and synthetic high-density lipoprotein inhibit tissue factor in endothelial cells and monocytes.

    PubMed

    Ossoli, Alice; Remaley, Alan T; Vaisman, Boris; Calabresi, Laura; Gomaraschi, Monica

    2016-01-15

    HDL (high-density lipoproteins) exert anti-thrombotic activities by preventing platelet adhesion and activation and by stimulating the protein C pathway and fibrinolysis. The aim of the present study was to assess the effect of plasma-derived and synthetic HDL on endothelial and monocyte expression of TF (tissue factor), the primary initiator of coagulation. HDL inhibited TF expression and activity in stimulated endothelial cells and monocytes in a dose-dependent way. Synthetic HDL fully retain the ability to inhibit TF expression in a dose-dependent manner; lipid-free apoA-I (apolipoprotein A-I) was not effective and neither was sphingosine 1-phosphate involved. HDL-mediated TF inhibition was due to a modulation of cellular cholesterol content through the interaction with SR-BI (scavenger receptor BI); downstream, HDL inhibited the activation of p38 MAPK (mitogen-activated protein kinase) and the repression of the PI3K (phosphoinositide 3-kinase) pathway responsible for TF expression. In vivo, human apoA-I-transgenic mice displayed a reduced aortic TF expression compared with wild-type animals and TF plasma levels were increased in subjects with low HDL-C (HDL-cholesterol) levels compared with high HDL-C subjects. Thus the anti-thrombotic activity of HDL could also be mediated by the inhibition of TF expression and activity in endothelial cells and monocytes; synthetic HDL retain the inhibitory activity of plasma-derived HDL, supporting the hypothesis that synthetic HDL infusion may be beneficial in the setting of acute coronary syndrome. PMID:26556891

  5. 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

  6. Thyroid function modifies the association between ratio of triglyceride to high-density lipoprotein cholesterol and renal function: a multicenter cross-sectional study

    PubMed Central

    Yuan, Zhongshang; Zhao, Meng; Zhang, Bingchang; Zhang, Haiqing; Zhang, Xu; Guan, Qingbo; Ning, Guang; Gao, Ling; Xue, Fuzhong; Zhao, Jiajun

    2015-01-01

    Hypothyroidism was confirmed to be associated with both dyslipidemia and renal dysfunction. However, the impact of thyroid function on the relationship between serum lipid levels and renal function has never been given sufficient attention. In this large-scale multicenter cross-sectional study, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL) and the prevalence of hypothyroidism in CKD subjects were significantly higher than those in non-CKD ones (P < 0.001). After adjustment for potential confounding factors, TG/HDL was shown to be significantly associated with serum Cr levels (β = 0.551; 95%CI, 0.394–0.708), and eGFR (β = −0.481; 95%CI, −0.731–−0.230). The risk for CKD was significantly increased as TG/HDL ratio was elevated (adjusted odds ratio = 1.20; 95%CI, 1.11–1.27). These significant associations were found among subjects with euthyroidism and hypothyroidism rather than hyperthyroidism. Furthermore, the associations between TG/HDL and Cr or CKD status were significantly greater in hypothyroidism than those in euthyroidism (P < 0.05). These results suggested that elevated TG/HDL ratio was associated with renal dysfunction; it exhibited a significantly stronger association with Cr and CKD in hypothyroidism than in euthyroidism. Therefore, more attention should be paid on lipid profile to prevent or delay the occurrence and progression of renal dysfunction, especially for those with hypothyroidism. PMID:26179571

  7. Thyroid function modifies the association between ratio of triglyceride to high-density lipoprotein cholesterol and renal function: a multicenter cross-sectional study.

    PubMed

    Yuan, Zhongshang; Zhao, Meng; Zhang, Bingchang; Zhang, Haiqing; Zhang, Xu; Guan, Qingbo; Ning, Guang; Gao, Ling; Xue, Fuzhong; Zhao, Jiajun

    2015-01-01

    Hypothyroidism was confirmed to be associated with both dyslipidemia and renal dysfunction. However, the impact of thyroid function on the relationship between serum lipid levels and renal function has never been given sufficient attention. In this large-scale multicenter cross-sectional study, the ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL) and the prevalence of hypothyroidism in CKD subjects were significantly higher than those in non-CKD ones (P < 0.001). After adjustment for potential confounding factors, TG/HDL was shown to be significantly associated with serum Cr levels (β = 0.551; 95%CI, 0.394-0.708), and eGFR (β = -0.481; 95%CI, -0.731--0.230). The risk for CKD was significantly increased as TG/HDL ratio was elevated (adjusted odds ratio = 1.20; 95%CI, 1.11-1.27). These significant associations were found among subjects with euthyroidism and hypothyroidism rather than hyperthyroidism. Furthermore, the associations between TG/HDL and Cr or CKD status were significantly greater in hypothyroidism than those in euthyroidism (P < 0.05). These results suggested that elevated TG/HDL ratio was associated with renal dysfunction; it exhibited a significantly stronger association with Cr and CKD in hypothyroidism than in euthyroidism. Therefore, more attention should be paid on lipid profile to prevent or delay the occurrence and progression of renal dysfunction, especially for those with hypothyroidism. PMID:26179571

  8. Clinical significance of high-density lipoproteins and the development of atherosclerosis: focus on the role of the adenosine triphosphate-binding cassette protein A1 transporter.

    PubMed

    Brewer, H Bryan; Santamarina-Fojo, Silvia

    2003-08-21

    Low levels of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary artery disease, and there is evidence that increasing HDL cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is at least as common in patients hospitalized for cardiovascular disease as is hypercholesterolemia, and it is characteristic of diabetes and the metabolic syndrome, conditions associated with increased cardiovascular risk. Recent studies have elucidated mechanisms by which HDL acts to reduce cardiovascular risk, bolstering the rationale for targeting of HDL in lipid-modifying therapy. In particular, HDL (1) carries excess cholesterol from peripheral cells to the liver for removal in the process termed reverse cholesterol transport, (2) reduces oxidative modification of low-density lipoproteins (LDL), and (3) inhibits cytokine-induced expression of cellular adhesion molecules on endothelial cells. Studies of the newly described adenosine triphosphate-binding cassette protein A1 (ABCA1) transporter have established a crucial role for this transporter in modulating the levels of plasma HDL and intracellular cholesterol in the liver as well as in peripheral cells. Elevated levels of intracellular cholesterol stimulate the liver X receptor pathway, enhancing the expression of ABCA1, which increases intracellular trafficking of excess cholesterol to the cell surface for interaction with lipid-poor apolipoprotein A-I to form nascent HDL. Nascent HDL facilitates the removal of additional excess cellular cholesterol, which is esterified by lecithin-cholesterol acyltransferase with conversion of the nascent HDL to mature spherical HDL. Overexpression of ABCA1 in mice on a regular chow or Western diet results in a marked increase in plasma HDL, increased LDL, and increased transport of cholesterol to the liver. On a high cholesterol/cholate diet, transgenic mice overexpressing ABCA1 have increased HDL

  9. Direct cytosolic siRNA delivery by reconstituted high density lipoprotein for target-specific therapy of tumor angiogenesis.

    PubMed

    Ding, Yang; Wang, Yazhe; Zhou, Jianping; Gu, Xiaochen; Wang, Wei; Liu, Congyan; Bao, Xiuli; Wang, Cheng; Li, Yuanru; Zhang, Qiang

    2014-08-01

    We described here the mechanisms by which small interfering RNA (siRNA) molecules incorporated in reconstituted high density lipoprotein (rHDL) were efficiently transferred into the cytoplasm of cells to perform target-specific therapy of tumor angiogenesis. Using fluorescent-tagged apolipoprotein A-I (apoA-I) and cholesterol-conjugated siRNA (Chol-siRNA), it was confirmed with FACS and confocal microscopic measurements that Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were successfully established and apoA-I certainly was attached to the surface of Chol-siRNA-loaded lipoplexes (Lipos/Chol-siRNA complexes). Stably assembled rHDL/Chol-siRNA complexes demonstrated proper nanosize, quasi-spherical shape and improved nuclease protection over naked Chol-siRNA. It was also interesting to note that rHDL provided a highly effective approach to transfer Chol-siRNA across the membrane directly into the cytoplasm via the scavenger receptor BI (SR-BI)-mediated non-endocytotic mechanism, thereby bypassing endo-lysosomal trapping. We also showed clear evidence that the in vitro implementation of rHDL for Chol-siRNA-VEGF (Chol-siRNA targeting vascular endothelial growth factor gene) delivery markedly promoted RNA interference (RNAi)-mediated degradation of VEGF mRNA, resulting in down-regulation of secreted VEGF protein. In vivo fluorescence imaging indicated that near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-siRNA complexes) displayed long circulation time, SR-BI positive tumor-selective targeting, and efficient cytosolic delivery capabilities. Furthermore, intravenous administration of Chol-siRNA-VEGF-loaded rHDL nanoparticles (rHDL/Chol-siRNA-VEGF complexes) significantly enhanced anti-tumor efficacy against breast cancer, decreased VEGF expression level, and inhibited formation of intratumoral microvessels at the tumor tissue. It was concluded that rHDL possessed therapeutic potential and versatility in mediating

  10. PET Imaging of Tumor-Associated Macrophages with 89Zr-Labeled High-Density Lipoprotein Nanoparticles

    PubMed Central

    Pérez-Medina, Carlos; Tang, Jun; Abdel-Atti, Dalya; Hogstad, Brandon; Merad, Miriam; Fisher, Edward A.; Fayad, Zahi A.; Lewis, Jason S.; Mulder, Willem J.M.; Reiner, Thomas

    2015-01-01

    Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)–facilitated TAM PET imaging in a breast cancer model. Methods Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide 89Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. 89Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate 89Zr-PL-HDL and 89Zr-AI-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of 89Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry. Results The phospholipid- and apoA-I–labeled rHDL were produced at 79% ± 13% (n = 6) and 94% ± 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 percentage injected dose per gram for apoA-I– and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and

  11. Antibodies to high-density lipoproteins are associated with inflammation and cardiovascular disease in rheumatoid arthritis patients.

    PubMed

    Rodríguez-Carrio, Javier; Alperi-López, Mercedes; López, Patricia; Ballina-García, Francisco J; Abal, Francisco; Suárez, Ana

    2015-12-01

    Several lines of evidence suggest that chronic inflammation and immune dysregulation are related to altered lipid profiles in rheumatoid arthritis (RA), but the actual mechanisms are still unclear. We wondered whether the development of antibodies against high-density lipoprotein (HDL) can be found in RA patients linked to clinical and cardiovascular (CV) risk factors. To this end, immunoglobulin G (IgG) anti-HDL antibodies and total IgG serum levels were quantified in 212 RA patients, 131 sex- and age-matched healthy controls (HC), and 52 subjects with traditional CV risk factors (tCVRs). A subgroup of 13 RA patients was prospectively followed on TNFα-blockade. TNFα, interferon (IFN)α, MIP1α, IFNγ, IL-8, VEGF, GM-CSF, IL-17, MCP-1, SDF-1α, resistin, and leptin serum levels were quantified by immunoassays. IgG anti-HDL levels were higher in RA patients compared with HC (P < 0.0001) and tCVR subjects (P = 0.015). Differences with HC remained after correction for total IgG levels (P < 0.003). Anti-HDL/IgG were negatively associated with HDL levels in RA (-1.182 [-1.823 to -0.541], P = 0.0003) after adjusting for demographical, clinical, inflammatory parameters, and treatments. RA patients with high levels of anti-HDL/IgG (n = 40, 18.8%) were more likely to have experienced a CV event (P < 0.0001) and exhibited increased levels of several proinflammatory mediators (C-reactive protein, IFNα, MIP1α, IFNγ, IL-8, GM-CSF, IL-17 and MCP-1). Finally, change in anti-HDL antibodies on TNFα-blockade was independently associated with increasing HDL levels. Overall, IgG anti-HDL antibodies are increased in RA independently of tCVRs and associated with a proinflammatory milieu and impaired lipid blood profile, which may contribute to the increased rate of CV events in these patients. PMID:26279255

  12. Multidrug resistance P-glycoprotein dampens SR-BI cholesteryl ester uptake from high density lipoproteins in human leukemia cells

    PubMed Central

    Spolitu, Stefano; Uda, Sabrina; Deligia, Stefania; Frau, Alessandra; Collu, Maria; Angius, Fabrizio; Batetta, Barbara

    2016-01-01

    Tumor cells are characterised by a high content of cholesterol esters (CEs), while tumor-bearing patients show low levels of high-density lipoproteins (HDLs). The origin and significance of high CE levels in cancer cell biology has not been completely clarified. Recent evidence that lymphoblastic cells selectively acquire exogenous CE from HDL via the scavenger receptor SR-BI has drawn attention to the additional membrane proteins involved in this pathway. P-glycopotein-MDR1 (P-gp) is a product of the MDR1 gene and confers resistance to antitumor drugs. Its possible role in plasma membrane cholesterol trafficking and CE metabolism has been suggested. In the present study this aspect was investigated in a lymphoblastic cell line selected for MDR1 resistance. CEM were made resistant by stepwise exposure to low (LR) and high (HR) doses of vincristine (VCR). P-gp activity (3H-vinblastine), CE content, CE and triglycerides (TG) synthesis (14C-oleate), neutral lipids and Dil-HDL uptake (fluorescence), SR-BI, ABCA1 and P-gp protein expression (western blotting) were determined. To better evaluate the relationship between CE metabolism and P-gp activity, the ACAT inhibitor Sandoz-58035 and the P-gp inhibitors progesterone, cyclosporine and verapamil were used. CE content and synthesis were similar in the parental and resistant cells. However, in the latter population, SR-BI protein expression increased, whereas CE-HDL uptake decreased. These changes correlated with the degree of VCR-resistance. As well as reverting MDR1-resistance, the inhibitors of P-gp activity induced the CE-HDL/SR-BI pathway by reactivating membrane cholesterol trafficking. Indeed, CE-HDL uptake, SRBI expression and CE content increased, whereas there was a decrease in cholesterol esterification. These results demonstrated that P-gp overexpression impairs anticancer drug uptake as well as the SR-BI mediated selective CE-HDL uptake. This suggests that these membrane proteins act in an opposite manner on

  13. Multidrug resistance P-glycoprotein dampens SR-BI cholesteryl ester uptake from high density lipoproteins in human leukemia cells.

    PubMed

    Spolitu, Stefano; Uda, Sabrina; Deligia, Stefania; Frau, Alessandra; Collu, Maria; Angius, Fabrizio; Batetta, Barbara

    2016-01-01

    Tumor cells are characterised by a high content of cholesterol esters (CEs), while tumor-bearing patients show low levels of high-density lipoproteins (HDLs). The origin and significance of high CE levels in cancer cell biology has not been completely clarified. Recent evidence that lymphoblastic cells selectively acquire exogenous CE from HDL via the scavenger receptor SR-BI has drawn attention to the additional membrane proteins involved in this pathway. P-glycopotein-MDR1 (P-gp) is a product of the MDR1 gene and confers resistance to antitumor drugs. Its possible role in plasma membrane cholesterol trafficking and CE metabolism has been suggested. In the present study this aspect was investigated in a lymphoblastic cell line selected for MDR1 resistance. CEM were made resistant by stepwise exposure to low (LR) and high (HR) doses of vincristine (VCR). P-gp activity ((3)H-vinblastine), CE content, CE and triglycerides (TG) synthesis ((14)C-oleate), neutral lipids and Dil-HDL uptake (fluorescence), SR-BI, ABCA1 and P-gp protein expression (western blotting) were determined. To better evaluate the relationship between CE metabolism and P-gp activity, the ACAT inhibitor Sandoz-58035 and the P-gp inhibitors progesterone, cyclosporine and verapamil were used. CE content and synthesis were similar in the parental and resistant cells. However, in the latter population, SR-BI protein expression increased, whereas CE-HDL uptake decreased. These changes correlated with the degree of VCR-resistance. As well as reverting MDR1-resistance, the inhibitors of P-gp activity induced the CE-HDL/SR-BI pathway by reactivating membrane cholesterol trafficking. Indeed, CE-HDL uptake, SRBI expression and CE content increased, whereas there was a decrease in cholesterol esterification. These results demonstrated that P-gp overexpression impairs anticancer drug uptake as well as the SR-BI mediated selective CE-HDL uptake. This suggests that these membrane proteins act in an opposite

  14. Anti-Aging and Tissue Regeneration Ability of Policosanol Along with Lipid-Lowering Effect in Hyperlipidemic Zebrafish via Enhancement of High-Density Lipoprotein Functionality.

    PubMed

    Lee, Eun-Young; Yoo, Jeong-Ah; Lim, So-Mang; Cho, Kyung-Hyun

    2016-04-01

    We investigated the tissue regeneration and lipid-lowering effects of policosanol (PCO) by employing a hyperlipidemic zebrafish model. A reconstituted high-density lipoprotein containing policosanol (PCO-rHDL) facilitated greater cell growth and replication with less apoptosis and reactive oxygen species (ROS) production in BV-2 microglial cell lines. From in vivo study, injection of rHDL containing apolipoprotein A-I (ApoA-I) caused 76 ± 4% (p = 0.01) greater tissue regeneration activity than the phosphate-buffered saline (PBS) control, whereas PCO-rHDL caused 94 ± 7% (p = 0.002) increased regeneration. PCO in ethanol (EtOH) showed lower cholesteryl ester transfer protein (CETP) inhibitory ability than did anacetrapib, whereas PCO-rHDL showed higher inhibitory ability than anacetrapib, suggesting a synergistic effect between PCO and rHDL. Following 9 weeks of PCO consumption, the PCO group (0.003% PCO in Tetrabit) showed the highest survivability (80%), whereas normal diet (ND) and high-cholesterol diet (HCD) control groups showed 67% and 70% survival rates, respectively. Supplementation with a HCD resulted in two-fold elevation of CETP activity along with 3- and 2.5-fold increases in serum total cholesterol (TC) and triglycerides (TGs) levels, respectively. Consumption of PCO for 9 weeks resulted in 40 ± 5% (p = 0.01 vs. HCD) and 33 ± 4% (p = 0.02 vs. HCD) reduction of TC and TGs levels, respectively. Serum high-density lipoprotein cholesterol (HDL-C) level increased up to 37 ± 2 mg/dL (p = 0.004), whereas the percentage of HDL-C/TC increased up to 20 ± 2% from 5 ± 1% compared to the HCD control. The serum glucose level was reduced to 47 ± 2% (p = 0.002) compared to the HCD control. Fatty liver change and hepatic inflammation levels were remarkably increased upon HCD consumption and were two-fold higher than that under ND. However, the PCO group showed 58 ± 5% (p = 0.001) and 50 ± 3

  15. Anti-Aging and Tissue Regeneration Ability of Policosanol Along with Lipid-Lowering Effect in Hyperlipidemic Zebrafish via Enhancement of High-Density Lipoprotein Functionality

    PubMed Central

    Lee, Eun-Young; Yoo, Jeong-Ah; Lim, So-Mang

    2016-01-01

    Abstract We investigated the tissue regeneration and lipid-lowering effects of policosanol (PCO) by employing a hyperlipidemic zebrafish model. A reconstituted high-density lipoprotein containing policosanol (PCO-rHDL) facilitated greater cell growth and replication with less apoptosis and reactive oxygen species (ROS) production in BV-2 microglial cell lines. From in vivo study, injection of rHDL containing apolipoprotein A-I (ApoA-I) caused 76 ± 4% (p = 0.01) greater tissue regeneration activity than the phosphate-buffered saline (PBS) control, whereas PCO-rHDL caused 94 ± 7% (p = 0.002) increased regeneration. PCO in ethanol (EtOH) showed lower cholesteryl ester transfer protein (CETP) inhibitory ability than did anacetrapib, whereas PCO-rHDL showed higher inhibitory ability than anacetrapib, suggesting a synergistic effect between PCO and rHDL. Following 9 weeks of PCO consumption, the PCO group (0.003% PCO in Tetrabit) showed the highest survivability (80%), whereas normal diet (ND) and high-cholesterol diet (HCD) control groups showed 67% and 70% survival rates, respectively. Supplementation with a HCD resulted in two-fold elevation of CETP activity along with 3- and 2.5-fold increases in serum total cholesterol (TC) and triglycerides (TGs) levels, respectively. Consumption of PCO for 9 weeks resulted in 40 ± 5% (p = 0.01 vs. HCD) and 33 ± 4% (p = 0.02 vs. HCD) reduction of TC and TGs levels, respectively. Serum high-density lipoprotein cholesterol (HDL-C) level increased up to 37 ± 2 mg/dL (p = 0.004), whereas the percentage of HDL-C/TC increased up to 20 ± 2% from 5 ± 1% compared to the HCD control. The serum glucose level was reduced to 47 ± 2% (p = 0.002) compared to the HCD control. Fatty liver change and hepatic inflammation levels were remarkably increased upon HCD consumption and were two-fold higher than that under ND. However, the PCO group showed 58 ± 5% (p = 0.001) and 50

  16. Lipolytic surface remnants of triglyceride-rich lipoproteins are cytotoxic to macrophages but not in the presence of high density lipoprotein. A possible mechanism of atherogenesis?

    PubMed Central

    Chung, B H; Segrest, J P; Smith, K; Griffin, F M; Brouillette, C G

    1989-01-01

    Hypertriglyceridemic (HTG) serum, lipolyzed in vitro by purified bovine milk lipoprotein lipase, was found to be cytotoxic to cultured macrophages. Surviving macrophages contained numerous lipid inclusions similar to those found in foam cells. Individual lipoprotein fractions isolated from the lipolyzed HTG serum, including HDL, were also cytotoxic. Lipolysis of isolated lipoprotein fractions (either HTG or normal) allowed localization of cytotoxicity to postlipolysis remnant VLDL and chylomicron particles. The presence of a critical concentration of HDL in either the lipolysis mixture or the culture dishes inhibited the cytotoxicity. Below this critical concentration HDL itself became cytotoxic, producing lipid inclusions in surviving macrophages. The lipid fraction of the cytotoxic remnants contained the cytotoxic factor(s); neither FFA nor lysolecithin alone could account for this cytotoxicity. Postprandial lipemic sera from subjects with a brisk chylomicron response, when lipolyzed in vitro, were cytotoxic to cultured macrophages; neither fasted sera from these subjects, nor postprandial sera from normolipidemic subjects with a normal chylomicron response, were cytotoxic. Postheparin (in vivo lipolyzed) serum and its isolated lipoprotein fractions obtained 30 min after heparin injection in subjects with HTG were shown to be cytotoxic to macrophages; by 60 min most of the cytotoxicity had disappeared. The postprandial and postheparin observations support an in vivo significance for remnant-associated cytotoxicity. We hypothesize that cytotoxic remnants of lipolyzed VLDL and chylomicrons may be one of the major atherogenic lipoproteins. Further, we suggest that inhibition of the cytotoxicity of these remnants may be one important way that HDL prevents atherosclerosis. Images PMID:2703536

  17. Uptake of (/sup 3/H)vitamin D/sub 3/ from low and high density lipoproteins by cultured human fibroblasts

    SciTech Connect

    Shireman, R.B.; Williams, D.; Remsen, J.F.

    1986-03-01

    The plasma distribution and cellular uptake of (/sup 3/H)vitamin D/sub 3/ was studied in vitro using cultured human fibroblasts. Incubation of (/sup 3/H)vitamin D/sub 3/ (cholecalciferol) with plasma followed by sequential ultracentrifugal fractionation of the lipoproteins indicated that 2-4% of the radioactivity associated with the very low density lipoprotein (VLDL), 12% with low density lipoprotein (LDL), and approximately 60% with the high density lipoprotein (HDL). The remaining radioactivity, 25%, was associated with the sedimented plasma fractions. By comparison, an average of 86% of the radioactivity from (/sup 3/H) 1,25-dihydroxycholecalciferol associated with the sedimented plasma fractions. The uptake of (/sup 3/H)vitamin D/sub 3/ from plasma, LDL, or HDL was studied in cultured human cells; uptake by normal fibroblasts was greatest from LDL and least from plasma. The cellular association of vitamin D/sub 3/ was time, concentration, and temperature dependent. At a concentration of 50 ..mu..g LDL/ml of medium, the uptake of (/sup 3/H)vitamin D/sub 3/ from LDL at 37/sup 0/C was rapid and reached a maximum at approximately 4 hr; it was slower from HDL but continued to increase slowly up to 24 hr. The significance of these in vitro findings is uncertain since much of the vitamin D/sub 3/ absorbed from the intestine reportedly associates with chylomicrons and is rapidly taken up by the liver.

  18. Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters.

    PubMed

    Zong, Chuanlong; Song, Guohua; Yao, Shutong; Li, Luqin; Yu, Yang; Feng, Lei; Guo, Shoudong; Luo, Tian; Qin, Shucun

    2012-06-01

    Hydrogen (dihydrogen; H(2)) has an antiatherosclerotic effect in apolipoprotein (apo) E knockout mice. The goals of this study were to further characterize the effects of H(2) on the content, composition, and biological activities of plasma lipoproteins in golden hamsters. Plasma analysis by enzymatic method and fast protein liquid chromatography showed that 4-week intraperitoneal injection of hydrogen-saturated saline remarkably decreased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels in high-fat diet-fed hamsters. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of apolipoproteins from ultracentrifugally isolated plasma lipoproteins revealed a marked decrease of apo B100 and apo B48 in LDL. A profound decrease of apo E level in very low-density lipoprotein was also observed. Besides, we determined the functional quality of high-density lipoprotein (HDL) particles isolated from H(2)-treated and control mice. H(2) significantly improved HDL functionality assessed in 2 independent ways, namely, (1) stimulation of cholesterol efflux from macrophage foam cells by measuring HDL-induced [(3)H]cholesterol efflux and (2) protection against LDL oxidation as a measure of Cu(2+)-induced thiobarbituric acid reactive substances formation. Administration of hydrogen-saturated saline decreases plasma LDL cholesterol and apo B levels and improves hyperlipidemia-injured HDL functions, including the capacity of enhancing cellular cholesterol efflux and playing antioxidative properties, in high-fat diet-fed hamsters. PMID:22153840

  19. Lipid transfer protein I facilitated transfer of cyclosporine from low- to high-density lipoproteins is only partially dependent on its cholesteryl ester transfer activity.

    PubMed

    Wasan, K M; Ramaswamy, M; Wong, W; Pritchard, P H

    1998-02-01

    The purpose of this study was to determine if lipid transfer protein (LTP I) regulates the plasma lipoprotein distribution of cyclosporine (CSA). Experimental strategies that involved the supplementation and inhibition of LTP I were used to test these hypotheses. Incubation of CSA with human plasma supplemented with exogenous LTP I resulted in a significantly greater percentage of CSA recovered in the high-density lipoprotein (HDL)/lipoprotein deficient plasma (LPDP) fraction than in the low-density lipoprotein (LDL)/very low-density lipoprotein (VLDL) fraction compared to plasma which had no exogenous LTP I added. Incubation of radiolabeled cholesteryl ester (CE) or CSA-enriched HDL or LDL in T150 buffer supplemented with LTP I resulted in a significantly greater percentage of CE than CSA being transferred from HDL to LDL and LDL to HDL. However, the percent transfer from LDL to HDL was significantly lower for CE than CSA when these particles were incubated in LPDP that contained endogenous LTP I. The percent transfer of CE from HDL to LDL and LDL to HDL was significantly decreased in the presence of TP2, a monoclonal antibody directed against LTP I, compared to controls. The percent transfer of CSA from LDL to HDL was significantly decreased in the presence of TP2. However, the percent transfer of CSA from HDL to LDL in the presence of TP2 was not significantly different compared to controls. These findings suggest that the transfer of CSA between HDL and LDL is only partially facilitated through LTP I CE transfer activity. PMID:9454803

  20. High-Density and Very-Low-Density Lipoprotein Have Opposing Roles in Regulating Tumor-Initiating Cells and Sensitivity to Radiation in Inflammatory Breast Cancer

    SciTech Connect

    Wolfe, Adam R.; Atkinson, Rachel L.; Reddy, Jay P.; Debeb, Bisrat G.; Larson, Richard; Li, Li; Masuda, Hiroko; Brewer, Takae; Atkinson, Bradley J.; Brewster, Abeena; Ueno, Naoto T.; Woodward, Wendy A.

    2015-04-01

    Purpose: We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. Methods and Materials: Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. Results: VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015). Conclusions: This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients

  1. Effects of Triton WR 1339 and heparin on the transfer of surface lipids from triglyceride-rich emulsions to high density lipoproteins in rats

    SciTech Connect

    Maranhao, R.C.; Roland, I.A.; Hirata, M.H. )

    1990-11-01

    The influence of lipolytic mechanisms on the transfer of phospholipids and unesterified cholesterol from artificial emulsions, serving as chylomicron models to other plasma lipoproteins, mainly high density lipoproteins (HDL) were tested in vivo. The emulsions labeled with radioactive lipids were injected into the bloodstream of rats (controls) and the results were compared with those obtained from rats that had previously been treated with Triton WR 1339 or heparin. Plasma clearance and the distribution of cholesteryl esters, phospholipids and unesterified cholesterol in the different plasma lipoprotein fractions were then determined. Whereas virtually no cholesteryl esters were found in d greater than 1.006 g/mL density fraction of the three experimental groups, 2.8 +/- 1.3% of the injected phospholipids were in the 1.063-1.210 g/L density fraction of the Triton treated rats, and 12.6 +/- 5.4% of the heparin treated rats, as compared to 10.1 +/- 1.7% in controls. This indicates that lipolysis directly influences phospholipid transfer to HDL. In contrast, free-cholesterol transfer to HDL, besides being less pronounced than phospholipid transfer, was enhanced by Triton and diminished by heparin, indicating that lipolytic mechanisms were not important determinants in this process.

  2. Interaction of high-density and low-density lipoproteins to solid surfaces coated with cholesterol as determined by an optical fiber-based biosensor

    NASA Astrophysics Data System (ADS)

    Singh, Bal R.; Poirier, Michelle A.

    1993-05-01

    In recent years, the use of fiber optics has become an important tool in biomedicine and biotechnology. We are involved in developing and employing a new system which, through the use of fiber optics, may be capable of measuring the content of cholesterol and lipoproteins in blood samples in real time. In the optical fiber-based biosensor, a laser beam having a wavelength of 512 nm (green light) is launched into an optical fiber, which transmits the light to its distal end. An evanescent wave (travelling just outside the fiber core) is used to excite rhodamine-labelled HDL or LDL which become bound to the fiber or to fiber-bound molecules. The fluorescence (red light) is coupled back into the fiber and detected with a photodiode. Preliminary work has involved testing of high density lipoprotein (HDL) binding to a cholesterol-coated fiber and to a bare fiber and low density lipoprotein (LDL) binding to a cholesterol-coated fiber. A significant difference was observed in the binding rate of HDL (5 (mu) g/mL and lower) to a bare fiber as opposed to a cholesterol-coated fiber. The binding rate of HDL (5 (mu) g/mL) to a bare fiber was 7.5 (mu) V/sec and to a cholesterol-coated fiber was 3.5 (mu) V/sec. We have calculated the binding affinity of LDL to a cholesterol- coated fiber as 1.4 (mu) M-1. These preliminary results suggest that the optical fiber-based biosensor can provide a unique and promising approach to the analysis of lipoprotein interaction with solid surfaces and with cholesterol. More importantly, the results suggest that this technique may be used to assess the binding of blood proteins to artificial organs/tissues, and to measure the amount of cholesterol, HDL and LDL in less than a minute.

  3. Identification of high-density lipoprotein in serum to determine anti-cancer efficacy of doxorubicin in HeLa cells.

    PubMed

    Yung, B Y; Bor, A M

    1992-04-01

    The cytotoxic effects of doxorubicin (DOX) and daunorubicin (DAU) on HeLa cells cultured under different serum conditions were analyzed by the "nucleophosmin translocation" assay using immunofluorescence. Bright nucleolar fluorescence was observed in untreated cells. A shift from nucleolar to nuclear fluorescence was observed with increasing doses of DOX or DAU, with longer incubation times. A lesser degree of nucleophosmin translocation from nucleoli to nucleoplasm was observed in serum-deprived cells under the same DOX or DAU treatment. These results correlated well with those of cell-growth-reversibility and colony-formation studies, showing decreased inhibitory effects of growth on cells cultured in medium without serum. Furthermore, cells cultured in medium supplemented with the lipoprotein-free serum responded to DOX in a similar way to cells cultured without serum. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) were then added to the lipoprotein-free serum. Cells cultured in medium with the HDL-supplemented, serum showed increased sensitivity to DOX. Inhibition of cell growth and colony formation was observed in such HDL-supplemented cells upon DOX treatment (30 min). LDL, on the other hand, did not show an increase in the anti-cancer response. These results suggested that the variation in response of cells to DOX anti-cancer treatment under different growth conditions may be due to their varied concentrations of HDL. "Nucleophosmin translocation", which is useful for monitoring and ensuring the efficacy of the drug during anti-cancer treatment, provides an improved potential for successful chemotherapy. PMID:1555894

  4. Effects of hypophysectomy and administration of pituitary hormones on luteal function and uptake of high density lipoproteins by luteinized ovaries and adrenals of the rat

    SciTech Connect

    Murphy, B.D.; Rajkumar, K.; McKibbin, P.E.; Macdonald, G.J.; Buhr, M.M.; Grinwich, D.L.

    1985-04-01

    The role of plasma lipoproteins and hypophyseal hormones in the maintenance of progesterone secretion by the rat corpus luteum was investigated. In the first experiment, rats were treated daily from days 1-6 of pregnancy with 5 mg/kg 4-aminopyrozolopyramidine (4APP), a blocker of hepatic lipoprotein secretion, or with 5 mg/kg 4APP and 1 or 2 mg ovine PRL or 0.1 ml 0.5% phosphoric acid (4APP vehicle). The administration of 4APP reduced serum cholesterol and progesterone levels on days 2-6 of pregnancy and ovarian progesterone on day 6. The reduced progesterone secretion had no effect on embryo implantation. PRL, in the doses used, was incapable of abrogating the effects of 4APP on circulating or ovarian progesterone levels. Ovaries and adrenals, but not kidneys, of pseudopregnant rats exhibited specific and saturable uptake of porcine high density lipoprotein (HDL). Time-course studies indicated that the uptake of HDL was rapid in ovaries compared to that in adrenals. Ovaries from rats not only exhibited uptake of porcine HDL, but also were capable of using it for progesterone synthesis. Treatment with 4APP increased the adrenal uptake of HDL, but ovarian uptake was not different from that in the control group. Hypophysectomy reduced both adrenal and ovarian uptake of HDL. In adrenals only ACTH at the dose employed ameliorated reduction of HDL uptake induced by hypophysectomy, while in the ovaries, both PRL and LH reversed the effect of hypophysectomy. The effect of PRL on uptake was specific to (/sup 125/I)HDL and did not alter (/sup 125/I)albumin uptake. It is concluded that: 1) hypophysectomy reduces HDL uptake in the luteinized rat ovary; and 2) PRL and LH replacement therapy maintain ovarian uptake of HDL, suggesting a direct effect of these luteotropins on lipoprotein uptake.

  5. Comparison of the intravascular metabolism of cholesteryl esters and apoproteins of plasma low- and high-density lipoproteins in the rat (Rattus norvegicus), an animal species without plasma cholesteryl ester transfer activity.

    PubMed

    Terpstra, A H

    1993-12-01

    1. The intravascular metabolism of the cholesteryl esters (CE) and apoproteins of low density lipoproteins (LDL) and high density lipoproteins (HDL) was compared in the rat, an animal species without plasma cholesteryl ester transfer activity (CETA). 2. The apoproteins and the CE of LDL had identical catabolic rates, and there was no transfer of LDL CE to other lipoprotein classes. 3. The CE of the HDL, however, had higher catabolic rates than the apoproteins, and there was transfer of HDL CE to LDL but not to very low density lipoproteins. PMID:8299346

  6. Postprandial cholesteryl ester transfer and high density lipoprotein composition in normotriglyceridemic non-insulin-dependent diabetic patients.

    PubMed

    Durlach, V; Attia, N; Zahouani, A; Leutenegger, M; Girard-Globa, A

    1996-02-01

    Altered postprandial HDL metabolism is a possible cause of defective reverse cholesterol transport and increased cardiovascular risk in diabetic patients with a normal fasting lipoprotein profile. Ten normolipidemic, normoponderal non-insulin dependent diabetes mellitus (NIDDM) patients and seven controls received a 980 kcal meal containing 78 g lipids with 100 000 IU vitamin A. Chylomicron clearance was not different, but area under the curve (AUC) for retinyl palmitate in chylimicron-free serum (remnant clearance) was greater in patients (P < 0.02). LCAT activity increased postprandially to the same extent in both groups. In control subjects, cholesteryl ester transfer protein (CETP) activity (CETA) also increased by 20% (P < 0.01 at 6 h) in parallel with a 20% decrease in HDL2-CE (r = -0.55, P = 0.009). In NIDDM patients, on the contrary, CETA which was 35% higher in the fasting state (P < 0.005), decreased postprandially yet HDL2-CE remained unchanged. Postprandial HDL3 of controls were enriched with phospholipid (PL) (30.3 +/- 2.6% at 6 h) with respect to fasting (25.6 +/- 2.5%, P < 0.01) and to NIDDM-HDL3 (25.8 +/- 1.7% at 6 h, P < 0.01). These results show that variation in plasma CETA has little impact on HDL2-CE in NIDDH subjects. They support the concept that, in controls, the combined enrichment of HDL3 with PL, increased LCAT and CETA create the conditions for stimulation of cell cholesterol efflux and CE transfer to apo B lipoproteins. In NIDDM, because of the lesser HDL3 enrichment with PL and of the inverse trend of CETA, these conditions fail to occur, depriving the patients of a potentially efficient mechanism of unesterified cholesterol (UC) clearance, despite their strictly normal preprandial profile. PMID:8645357

  7. Evidence for Two Distinct Binding Sites for Lipoprotein Lipase on Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1)*

    PubMed Central

    Reimund, Mart; Larsson, Mikael; Kovrov, Oleg; Kasvandik, Sergo; Olivecrona, Gunilla; Lookene, Aivar

    2015-01-01

    GPIHBP1 is an endothelial membrane protein that transports lipoprotein lipase (LPL) from the subendothelial space to the luminal side of the capillary endothelium. Here, we provide evidence that two regions of GPIHBP1, the acidic N-terminal domain and the central Ly6 domain, interact with LPL as two distinct binding sites. This conclusion is based on comparative binding studies performed with a peptide corresponding to the N-terminal domain of GPIHBP1, the Ly6 domain of GPIHBP1, wild type GPIHBP1, and the Ly6 domain mutant GPIHBP1 Q114P. Although LPL and the N-terminal domain formed a tight but short lived complex, characterized by fast on- and off-rates, the complex between LPL and the Ly6 domain formed more slowly and persisted for a longer time. Unlike the interaction of LPL with the Ly6 domain, the interaction of LPL with the N-terminal domain was significantly weakened by salt. The Q114P mutant bound LPL similarly to the N-terminal domain of GPIHBP1. Heparin dissociated LPL from the N-terminal domain, and partially from wild type GPIHBP1, but was unable to elute the enzyme from the Ly6 domain. When LPL was in complex with the acidic peptide corresponding to the N-terminal domain of GPIHBP1, the enzyme retained its affinity for the Ly6 domain. Furthermore, LPL that was bound to the N-terminal domain interacted with lipoproteins, whereas LPL bound to the Ly6 domain did not. In summary, our data suggest that the two domains of GPIHBP1 interact independently with LPL and that the functionality of LPL depends on its localization on GPIHBP1. PMID:25873395

  8. Effects of human follicular fluid and high-density lipoproteins on early spermatozoa hyperactivation and cholesterol efflux

    PubMed Central

    Hamdi, Safouane M.; Vieitez, Gérard; Jaspard, Béatrice; Barbaras, Ronald; Perret, Bertrand; Mieusset, Roget; Parinaud, Jean; Collet, Xavier

    2010-01-01

    The preovulatory human follicular fluid contains only HDLs as a lipoprotein class with a typically high proportion of preβ HDL. We first examined the role of follicular fluid and HDL subfractions on human spermatozoa capacitation, a process characterized by a hyperactivation of the flagellar movement and a depletion of plasma membrane cholesterol. Whole follicular fluid and isolated HDL, used at constant free cholesterol concentration, were both able to promote an early flagellar hyperactivation. Moreover, incubation of [3H]cholesterol-labeled spermatozoa with follicular fluid induced a rapid cholesterol efflux from spermatozoa that was confirmed by mass measurements of cholesterol transfer. Using isolated HDL, the cholesterol efflux had a similar time course and represented 70% of that mediated by whole follicular fluid. We then analyzed the time course of radioactive labeling of HDL subfractions. In the first minute of incubation, we found that the preβ HDL fraction incorporated the main part of the radioactivity (60%), with the rest being found in α-HDL, but strikingly, the labeling of α-HDL increased with time at the expense of preβ HDL.Thus, our results indicate that HDLs are involved in both spermatozoa hyperactivation and cholesterol effl ux and suggest the role of preβ-HDL particles as fi rst cellular cholesterol acceptors. PMID:19965575

  9. Very low levels of high density lipoprotein cholesterol in four sibs of a family with non-neuropathic Niemann-Pick disease and sea-blue histiocytosis.

    PubMed Central

    Viana, M B; Giugliani, R; Leite, V H; Barth, M L; Lekhwani, C; Slade, C M; Fensom, A

    1990-01-01

    Very low serum levels of high density lipoprotein cholesterol ranging from 8.6 to 13.9 mg/dl were detected in four out of 12 sibs of a Brazilian kindred with the non-neuropathic form of Niemann-Pick disease. Hepatosplenomegaly, interstitial infiltration of the lungs, absence of neurological signs, sea-blue histiocytes in the bone marrow and liver, and high values for serum acid phosphatase (18 to 32 U/l) were common to all affected children. Leucocyte acid sphingomyelinase activity ranged from 3.6 to 6.5% of mean control values, and fibroblast activity from 9 to 13% of mean controls. The parents had low-normal levels. The relationship between these findings is unclear and deserves further investigation. Images PMID:2120445

  10. The Effect of Residing Altitude on Levels of High-Density Lipoprotein Cholesterol: A Pilot Study From the Omani Arab Population.

    PubMed

    Al Riyami, Nafila B; Banerjee, Yajnavalka; Al-Waili, Khalid; Rizvi, Syed G; Al-Yahyaee, Said; Hassan, Mohammed O; Albarwani, Sulayma; Al-Rasadi, Khalid; Bayoumi, Riad A

    2015-07-01

    Lower mortality rates from coronary heart disease and higher levels of serum high-density lipoprotein cholesterol (HDL-C) have been observed in populations residing at high altitude. However, this effect has not been investigated in Arab populations, which exhibit considerable genetic homogeneity. We assessed the relationship between residing altitude and HDL-C in 2 genetically similar Omani Arab populations residing at different altitudes. The association between the levels of HDL-C and other metabolic parameters was also investigated. The levels of HDL-C were significantly higher in the high-altitude group compared with the low-altitude group. Stepwise regression analysis showed that altitude was the most significant factor affecting HDL-C, followed by gender, serum triglycerides, and finally the 2-hour postprandial plasma glucose. This finding is consistent with previously published studies from other populations and should be taken into consideration when comparing cardiovascular risk factors in populations residing at different altitudes. PMID:25078070

  11. Characterization of human plasma apolipoprotein E-containing lipoproteins in the high density lipoprotein size range: focus on pre-beta1-LpE, pre-beta2-LpE, and alpha-LpE.

    PubMed

    Krimbou, L; Tremblay, M; Davignon, J; Cohn, J S

    1997-01-01

    We have used two-dimensional gel electrophoresis to separate and characterize human plasma apolipoprotein (apo) E-containing lipoproteins in the high density lipoprotein (HDL) size range. Lipoproteins were separated from whole plasma by electrophoresis (according to charge) in a 0.75% agarose gel, and then in the second dimension (according to size) in a 2-15% non-denaturing polyacrylamide gradient gel. ApoE-containing lipoproteins were detected by radiography after electrotransfer of lipoproteins to nitrocellulose membranes and incubation with 125I-labeled affinity-purified polyclonal apoE antibody. ApoE-containing lipoproteins in the HDL size range had a particle size ranging from 9 to 18.5 nm in diameter and could be characterized as having either gamma, pre-beta1-, pre-beta2- or alpha-electrophoretic mobility (designated gamma-LpE, pre-beta1-LpE, pre-beta2LpE, and alpha-LpE respectively). gamma-LpE and a substantial proportion of pre-beta1- and pre-beta2-LpE did not co-migrate with apoA-I, apoA-II, apoC-III, or apoB-100. Subsequent experiments focused on the pre-beta1-LpE, pre-beta2LpE, and alpha-LpE subfractions, which represented > 95% of apoE in HDL-sized lipoproteins. Storage of plasma at 4 degrees C or in vitro incubation of plasma at 37 degrees C caused a relative decrease in pre-beta1-LpE and increase in alpha-LpE. Normolipidemic patients with an apoE 2/2 phenotype tended to have increased levels of alpha-LpE, whereas apoE 4/4 subjects tended to have a greater proportion of HDL-apoE as pre-beta1-LpE. Decrease in plasma HDL apoE concentration after an oral fat load was associated with a reduction in the plasma concentration of all HDL-apoE subfractions. These results demonstrate that: 1) apoE-containing HDL are heterogeneous in size and charge; 2) pre-beta1-LpE is a relatively labile HDL subfraction; 3) HDL-apoE subfraction distribution is dependent on apoE phenotype; and 4) all apoE-containing HDL subfractions participate in the plasma transfer of apo

  12. High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway.

    PubMed

    Song, Guohua; Wu, Xia; Zhang, Pu; Yu, Yang; Yang, Mingfeng; Jiao, Peng; Wang, Ni; Song, Haiming; Wu, You; Zhang, Xiangjian; Liu, Huaxia; Qin, Shucun

    2016-01-01

    Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation. PMID:27468698

  13. High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway

    PubMed Central

    Song, Guohua; Wu, Xia; Zhang, Pu; Yu, Yang; Yang, Mingfeng; Jiao, Peng; Wang, Ni; Song, Haiming; Wu, You; Zhang, Xiangjian; Liu, Huaxia; Qin, Shucun

    2016-01-01

    Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation. PMID:27468698

  14. High density lipoprotein deficiency with xanthomas. A defect in reverse cholesterol transport caused by a point mutation in the apolipoprotein A-I gene.

    PubMed Central

    Lackner, K J; Dieplinger, H; Nowicka, G; Schmitz, G

    1993-01-01

    A 7-yr-old girl with high density lipoprotein (HDL) deficiency and xanthomas has been identified in a Turkish kindred with repetitive consanguinity. She has severely reduced HDL-cholesterol and no apolipoprotein (apo) A-I. ApoA-II is reduced, whereas apoA-IV and apoC-III are normal. ApoB and low density lipoprotein (LDL)-cholesterol are increased. This is reflected in hypercholesterolemia. VLDL and IDL particles are low, and serum triglycerides are normal. The genetic defect could be identified as a base insertion into the third exon of the apoA-I gene. This leads to a nonsense peptide sequence beginning at amino acid 5 of the mature plasma protein and early termination of translation. The patient is homozygous for this mutation. Pedigree analysis indicated an autosomal dominant inheritance with no evidence of another genetic defect of lipoprotein metabolism in the kindred. In HDL deficiency, HDL binding to leukocytes was increased compared to normal. In the postprandial state, binding of labeled HDL3 to leukocytes is unchanged. This is in contrast to results with postprandially isolated leukocytes from controls or Tangier patients, which have a reduced binding capacity for HDL3. These results indicate that postprandial HDL precursors may compete the binding of labeled HDL3. The metabolic consequences of HDL deficiency were analyzed. There is only a small number of HDL-like particles containing apoA-II, apoA-IV, apoE, and lecithin/cholesteryl acyl transferase. The C-apolipoproteins were normal in the proband. Due to the lack of HDL they can only associate with apoB-containing particles, where they may interfere with cellular uptake. Thus, pure apoA-I deficiency leads to a complex metabolic derangement. Images PMID:7693760

  15. Primary Low Level of High-Density Lipoprotein Cholesterol and Risks of Coronary Heart Disease, Cardiovascular Disease, and Death: Results From the Multi-Ethnic Study of Atherosclerosis.

    PubMed

    Ahmed, Haitham M; Miller, Michael; Nasir, Khurram; McEvoy, John W; Herrington, David; Blumenthal, Roger S; Blaha, Michael J

    2016-05-15

    Prior studies observing associations between low levels of high-density lipoprotein (HDL) cholesterol and cardiovascular disease (CVD) have often been conducted among persons with metabolic or other lipid abnormalities. In this study, we investigated the association between primary low HDL cholesterol and coronary heart disease (CHD), CVD, and all-cause death after adjustment for confounders in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants who were free of clinical CVD were recruited from 6 US research centers from 2000 to 2002 and followed for a median duration of 10.2 years. We defined "primary low HDL cholesterol" as HDL cholesterol level <40 mg/dL (men) or <50 mg/dL (women), triglyceride level <100 mg/dL, and low-density lipoprotein cholesterol level <100 mg/dL (n = 158). We defined an "optimal" lipid profile as HDL cholesterol ≥40 mg/dL (men) or ≥50 mg/dL (women) and triglycerides and low-density lipoprotein cholesterol <100 mg/dL (n = 780). For participants with primary low HDL cholesterol versus those with an optimal lipid profile, adjusted hazard ratios for total CHD, CVD, and death were 2.25 (95% confidence interval (CI): 1.20, 4.21; P = 0.011), 1.93 (95% CI: 1.11, 3.34; P = 0.020), and 1.11 (95% CI: 0.67, 1.84; P = 0.69), respectively. Participants with primary low HDL cholesterol had higher risks of CHD and CVD than participants with optimal lipid profiles but no difference in survival after a median 10.2 years of follow-up. PMID:27189327

  16. Brazil nut ingestion increased plasma selenium but had minimal effects on lipids, apolipoproteins, and high-density lipoprotein function in human subjects.

    PubMed

    Strunz, Célia C; Oliveira, Tatiane V; Vinagre, Juliana C M; Lima, Adriana; Cozzolino, Silvia; Maranhão, Raul C

    2008-03-01

    The Brazil nut (Bertholletia excelsa) of the Amazon region is consumed worldwide. It is rich in both monounsaturated fatty acids and polyunsaturated fatty acids and is known for its high selenium content. This study tested the hypothesis whether the consumption of this nut could affect the plasma lipids and apolipoproteins and some functional properties of the antiatherogenic high-density lipoprotein (HDL). Fifteen normolipidemic subjects aged 27.3 +/- 3.9 years and with body mass index of 23.8 +/- 2.8 kg/m(2) consumed 45 g of Brazil nuts per day during a 15-day period. On days 0 and 15, blood was collected for biochemical analysis, determination of HDL particle size, paraoxonase 1 activity, and lipid transfer from a lipoprotein-like nanoparticle to the HDL fraction. Brazil nut ingestion did not alter HDL, low-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A-I, or apolipoprotein B concentrations. HDL particle diameter and the activity of antioxidative paraoxonase 1, mostly found in the HDL fraction, were also unaffected. Supplementation increased the reception of cholesteryl esters (P < .05) by the HDL yet did not alter the reception of phospholipids, free cholesterol, or triacylglycerols. As expected, plasma selenium was significantly increased. However, the consumption of Brazil nuts for short duration by normolipidemic subjects in comparable amounts to those tested for other nuts did not alter serum lipid profile. The only alteration in HDL function was the increase in cholesteryl ester transfer. This latter finding may be beneficial because it would improve the nonatherogenic reverse cholesterol transport pathway. PMID:19083402

  17. Intake of cooked tomato sauce preserves coronary endothelial function and improves apolipoprotein A-I and apolipoprotein J protein profile in high-density lipoproteins.

    PubMed

    Vilahur, Gemma; Cubedo, Judit; Padró, Teresa; Casaní, Laura; Mendieta, Guiomar; González, Alicia; Badimon, Lina

    2015-07-01

    Intake of tomatoes has been linked with healthy diets (eg, Mediterranean diet). However, it remains unknown whether tomato intake exerts protective effects on the vasculature. The aim of this study was to determine whether medium-term supplementation with cooked tomato sauce (CTS) Mediterranean style (sofrito) attenuates diet-induced coronary endothelial dysfunction in an animal model with clinical impact and explore the mechanisms behind the effects. Pigs (N = 18) were fed a 10-day hypercholesterolemic diet. Half of the animals were given a supplement of 100 g/d of CTS (21.5 mg lycopene per day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calcium ionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide synthase [eNOS] inhibitor) were measured using flow Doppler. In the coronary arteries, we investigated eNOS gene expression and activation, monocyte chemoattractant protein 1 (MCP-1) expression, and oxidative DNA damage. In the circulation, we investigated lipoprotein resistance to oxidation and the differential proteomic protein profile. In dyslipidemic animals, CTS intake prevented diet-induced impairment of receptor-operated and nonreceptor-operated endothelial-dependent coronary vasodilation. These beneficial effects were associated with enhanced eNOS transcription and activation and diminished DNA damage in the coronary arteries. CTS-fed animals showed lower lipid peroxidation, higher high-density lipoprotein (HDL) antioxidant potential and plasma lycopene levels of 0.16 mg/L. Interestingly, improved HDL functionality was associated with protein profile changes in apolipoprotein A-I and apolipoprotein J. Lipids levels and MCP-1 expression were not affected by CTS. We report that CTS intake protects against low-density lipoprotein-induced coronary endothelial dysfunction by reducing oxidative damage, enhancing eNOS expression and activity, and improving HDL functionality. PMID:25514506

  18. Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production

    PubMed Central

    Colin, Sophie; Briand, Olivier; Touche, Véronique; Wouters, Kristiaan; Baron, Morgane; Pattou, François; Hanf, Rémy; Tailleux, Anne; Chinetti, Giulia; Staels, Bart; Lestavel, Sophie

    2013-01-01

    Aims Peroxisome Proliferator-Activated Receptor (PPAR) α is a transcription factor controlling lipid metabolism in liver, heart, muscle and macrophages. PPARα-activation increases plasma HDL-cholesterol and exerts hypotriglyceridemic actions via the liver. However, the intestine expresses PPARα, produces HDL and chylomicrons and is exposed to diet-derived PPARα ligands. Therefore, we examined the effects of PPARα-activation on intestinal lipid and lipoprotein metabolism. Methods and Results The impact of PPARα-activation was evaluated in term of HDL-related gene expression in mice, ex-vivo in human jejunal biopsies and in Caco-2/TC7 cells. ApoAI/HDL secretion, cholesterol esterification and trafficking were also studied in-vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty-acid-oxidation genes, treatment with the dual PPARα/δ-ligand GFT505 resulted in a more pronounced increase of plasma HDL compared to fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL-production genes such as apolipoprotein-AI and ATP-Binding-Cassette-A1 transporter in murine intestines. A similar increase was observed upon PPARα-activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPARα-activation decreased the cholesterol-esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking and reduced apolipoprotein-B secretion. Conclusions PPARα-activation reduces cholesterol esterification, suppresses chylomicron- and increases HDL-secretion by enterocytes. These results identify the intestine as a target organ of PPARα-ligands with entero-hepatic tropism to reduce atherogenic dyslipidemia. PMID:22843443

  19. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins.

    PubMed

    Pownall, H J; Brauchi, D; Kilinç, C; Osmundsen, K; Pao, Q; Payton-Ross, C; Gotto, A M; Ballantyne, C M

    1999-04-01

    Serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations are inversely correlated and mechanistically linked by means of lipid transfer activities. Phospholipid transfer activity (PLTA) moves phospholipids among serum lipoproteins; cholesteryl ester transfer activity (CETA), which exchanges cholesteryl esters (CE) and TG among lipoproteins, is stimulated by nonesterified fatty acids (NEFA). The aims of this study were (a) to develop a quantitative model that correlates the neutral lipid (NL = CE + TG) compositions of HDL and LDL with serum TG concentration; (b) identify the serum lipid determinants of CETA and PLTA, and; (c) identify the effects of serum TG reductions on the neutral lipid compositions of HDL and LDL, serum NEFA concentrations, and on PLTA and CETA. These aims were addressed in 40 hypertriglyceridemic subjects before and after treatment with an 85% concentrate of omega-3 fatty acids (Omacor) and in 16 untreated normolipidemic subjects. In vivo, the NL compositions of LDL and HDL were described by a mathematical model having the form of adsorption isotherms: HDL - (TG/NL) = (0.90 +/- 0.07) serum TG/(7.0 +/- 1.2 mmol/l + serum TG) and LDL - (TG/NL) = (0.65 +/- 0.08) serum TG/(4.9 +/- 1.5 mmol/l + serum TG). Reduction of serum TG was associated with reductions in HDL - (TG/NL), serum NEFA concentration, and serum CETA but not PLTA. These data suggest that both hypertriglyceridemia and the attendant elevated serum CETA but not PLTA are determinants of HDL and LDL composition and structure and that serum TG concentrations are good predictors of the NL compositions of HDL and LDL. PMID:10217357

  20. Enhancement of High-Density Lipoprotein Cholesterol Functions by Encapsulation of Policosanol Exerts Anti-Senescence and Tissue Regeneration Effects Via Improvement of Anti-Glycation, Anti-Apoptosis, and Cholesteryl Ester Transfer Inhibition.

    PubMed

    Lim, So-Mang; Yoo, Jeong-Ah; Lee, Eun-Young; Cho, Kyung-Hyun

    2016-02-01

    Consumption of policosanol (PCO), a refined mixture of sugar cane wax alcohols, can elevate serum levels of high-density lipoprotein cholesterol (HDL-C), although the molecular mechanism is still unknown. To investigate the mechanism of action responsible for the anti-senescence effects of PCO on lipoprotein metabolism and HDL functionality, we synthesized reconstituted HDL (rHDL) containing PCO. Encapsulation of PCO by rHDL (PCO-rHDL) enhanced anti-oxidant activity against cupric ion-mediated low-density lipoprotein (LDL) oxidation. PCO-rHDL (final concentration, 9 μM PCO) showed more potent anti-oxidant activity than vitamin C treatment (final concentration, 100 μM). PCO-rHDL inhibited fructose-mediated glycation, which is a major pathological mechanism of diabetic complications, in a dose-dependent manner. PCO also showed cytoprotective effects in monocytes and macrophages with less triggering of apoptotic processes and reactive oxygen species (ROS) production in the presence of hydrogen peroxide (H2O2). PCO-rHDL strongly inhibited uptake of acetylated LDL into macrophages, which is an initial atherosclerotic process. Surprisingly, PCO-rHDL inhibited human serum cholesteryl ester transfer protein (CETP) activity by up to 47% (final concentration, 10 μM PCO). Subcutaneous injection of PCO-rHDL dose-dependently enhanced tissue regeneration activity by 2.4-fold and 3.6-fold compared to that of the phosphate-buffered saline (PBS) control. In conclusion, PCO in HDL showed potent anti-oxidant, anti-glycation, and CETP inhibitory activities along with tissue regenerative activity, especially upon incorporation into HDL. These results suggest that PCO can enhance functionality of HDL in serum to exert anti-senescence and longevity effects. PMID:26161621

  1. Adverse effect of pregnancy on high density lipoprotein (HDL) cholesterol in young adult women. The CARDIA Study. Coronary Artery Risk Development in Young Adults.

    PubMed

    Lewis, C E; Funkhouser, E; Raczynski, J M; Sidney, S; Bild, D E; Howard, B V

    1996-08-01

    The authors analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study in order to examine associations between parity and lipoproteins. Of 2,787 women recruited in 1985-1986, 2,534 (91%) returned in 1987-1988 and 2,393 (86%) returned in 1990-1991 for repeat evaluations. Two-year change (1987-1988 to 1985-1986) in high density lipoprotein (HDL) cholesterol was significantly different among the parity groups. HDL cholesterol decreased in women who had their first pregnancy of at least 28 weeks duration during follow-up (mean +/- standard error, -3.5 +/- 1.2 mg/dl), and this change was significantly different from the increase in women parous at baseline who had no further pregnancies (2.5 +/- 0.3 mg/dl) and in nullipara (2.4 +/- 0.3 mg/dl). There was a nonsignificant trend for a greater decrease in HDL2 cholesterol fraction in the primipara compared with the other groups. The HDL cholesterol decrease remained significant after controlling for race, age, education, oral contraceptive use, and changes in body mass index, waist-hip ratio, physical activity, smoking status, and alcohol intake. Change in HDL cholesterol was also significantly different among the parity groups in analyses of pregnancies that occurred during the subsequent 3 years of follow-up. There were no differences for change in LDL cholesterol or triglycerides. Potential mechanisms for a detrimental effect of pregnancy on HDL cholesterol include hormonal, body composition, or life-style/behavioral changes. PMID:8686693

  2. Effect of Extended Release Niacin on Serum Lipids and on Endothelial Function in Adults with Sickle Cell Anemia and Low High-Density Lipoprotein Cholesterol Levels

    PubMed Central

    Scoffone, Heather M.; Krajewski, Megan; Zorca, Suzana; Bereal-Williams, Candice; Littel, Patricia; Seamon, Catherine; Mendelsohn, Laurel; Footman, Eleni; Jaoudeh, Nadine Abi; Sachdev, Vandana; Machado, Roberto F.; Cuttica, Michael; Shamburek, Robert; Cannon, Richard O.; Remaley, Alan; Minniti, Caterina P.; Kato, Gregory J.

    2014-01-01

    Through bound apolipoprotein A-I (apoA-I), high density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD)have low apoA-I andendothelial dysfunction,we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C, and improves vascular function in SCD. Twenty-seven SCD patientswith HDL-C <39 mg/dL or apoA-I <99 mg/dL were randomized to 12 weeks of niacin-ER, increased in 500mg increments to a maximum of 1500mg daily, or placebo. The primary outcome was the absolute change in HDL-C after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C compared with placebo treatment at 12 weeks (5.1±7.7 vs. 0.9±3.8 mg/dL, one-tailed p=0.07), associated with significantly greater, improvements in the ratios of low-density lipoprotein to HDL-C (1.24 vs. 1.95, p = 0.003), and apolipoprotein B to apoA-I (0.46 vs. 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in three independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C. PMID:24035168

  3. Apolipoprotein A-I helical structure and stability in discoidal high-density lipoprotein (HDL) particles by hydrogen exchange and mass spectrometry.

    PubMed

    Sevugan Chetty, Palaniappan; Mayne, Leland; Kan, Zhong-Yuan; Lund-Katz, Sissel; Englander, S Walter; Phillips, Michael C

    2012-07-17

    To understand high-density lipoprotein (HDL) structure at the molecular level, the location and stability of α-helical segments in human apolipoprotein (apo) A-I in large (9.6 nm) and small (7.8 nm) discoidal HDL particles were determined by hydrogen-deuterium exchange (HX) and mass spectrometry methods. The measured HX kinetics of some 100 apoA-I peptides specify, at close to amino acid resolution, the structural condition of segments throughout the protein sequence and changes in structure and stability that occur on incorporation into lipoprotein particles. When incorporated into the large HDL particle, the nonhelical regions in lipid-free apoA-I (residues 45-53, 66-69, 116-146, and 179-236) change conformation from random coil to α-helix so that nearly the entire apoA-I molecule adopts helical structure (except for the terminal residues 1-6 and 237-243). The amphipathic α-helices have relatively low stability, in the range 3-5 kcal/mol, indicating high flexibility and dynamic unfolding and refolding in seconds or less. A segment encompassed by residues 125-158 exhibits bimodal HX labeling indicating co-existing helical and disordered loop conformations that interchange on a time scale of minutes. When incorporated around the edge of the smaller HDL particle, the increase in packing density of the two apoA-I molecules forces about 20% more residues out of direct contact with the phospholipid molecules to form disordered loops, and these are the same segments that form loops in the lipid-free state. The region of disc-associated apoA-I that binds the lecithin-cholesterol acyltransferase enzyme is well structured and not a protruding unstructured loop as reported by others. PMID:22745166

  4. Prevalence of High Non-high-density Lipoprotein Cholesterol and Associated Risk Factors in Patients with Diabetes Mellitus in Jilin Province, China: A Cross-sectional Study.

    PubMed

    He, Huan; Zhen, Qing; Li, Yong; Kou, Chang Gui; Tao, Yu Chun; Wang, Chang; Kanu, Joseph Sam; Lu, Yu Ping; Yu, Ming Xi; Zhang, Hui Ping; Yu, Ya Qin; Li, Bo; Liu, Ya Wen

    2016-07-01

    Dyslipidemia is a risk factor for cardiovascular diseases (CVDs) in patients with diabetes, and non-high-density lipoprotein cholesterol (non-HDL-C) is a better predictor of CVDs than low-density lipoprotein cholesterol (LDL-C) in patients with diabetes. Therefore, we aimed to investigate the distribution of non-HDL-C and the prevalence of high non-HDL-C level in Chinese patients with diabetes mellitus and identify the associated risk factors. Non-HDL-C concentration positively correlated with total cholesterol, triglycerides, and LDL-C concentrations. Although both non-HDL-C and LDL-C concentration both related positively with TC concentration, the magnitude of correlation was relatively higher for non-HDL-C. The prevalence of high non-HDL-C (⋝4.14 mmol/L) was higher in two age groups (55-64 years: 46.7%; 65-79 years: 47.3%) than other age groups (18-24 years: 4.2%; 25-34 years: 43.6%; 35-44 years: 38.1%; 45-54 years: 41.0%). It was also higher among overweight (45.1%), generally obese (50.9%), or abdominally obese (47.3%) subjects, compared with normal weight subjects (34.5%). The risk of high non-HDL-C increased with advancing age. Both general obesity [odds ratio (OR)=1.488, 95% confidence interval (CI): 1.003-2.209] and abdominal obesity (OR=1.561, 95% CI: 1.101-2.214) were significantly associated with high non-HDL-C levels. PMID:27554125

  5. Synthetic High-Density Lipoprotein-Like Nanocarrier Improved Cellular Transport of Lysosomal Cholesterol in Human Sterol Carrier Protein-Deficient Fibroblasts.

    PubMed

    Nam, Da-Eun; Kim, Ok-Kyung; Park, Yoo Kyoung; Lee, Jeongmin

    2016-01-01

    Sterol carrier protein-2 (SCP-2), which is not found in tissues of people with Zellweger syndrome, facilitates the movement of cholesterol within cells, resulting in abnormal accumulation of cholesterol in SCP-2-deficient cells. This study investigated whether synthetic high-density lipoprotein-like nanocarrier (sHDL-NC) improves the cellular transport of lysosomal cholesterol to plasma membrane in SCP-2-deficient fibroblasts. Human SCP-2-deficient fibroblasts were incubated with [(3)H-cholesterol]LDL as a source of cholesterol and sHDL-NC. The cells were fractionated by centrifugation permit tracking of [(3)H]-cholesterol from lysosome into plasma membrane. Furthermore, cellular content of cholesteryl ester as a storage form and mRNA expression of low-density lipoprotein (LDL) receptor were measured to support the cholesterol transport to plasma membrane. Incubation with sHDL-NC for 8 h significantly increased uptake of [(3)H]-cholesterol to lysosome by 53% and further enhanced the transport of [(3)H]-cholesterol to plasma membrane by 32%. Treatment with sHDL-NC significantly reduced cellular content of cholesteryl ester and increased mRNA expression of LDL receptor (LDL-R). In conclusion, sHDL-NC enables increased transport of lysosomal cholesterol to plasma membrane. In addition, these data were indirectly supported by decreased cellular content of cholesteryl ester and increased gene expression of LDL-R. Therefore, sHDL-NC may be a useful vehicle for transporting cholesterol, which may help to prevent accumulation of cholesterol in SCP-2-deficient fibroblasts. PMID:26684407

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

    PubMed Central

    Jayaraman, Shobini; Cavigiolio, Giorgio; Gursky, Olga

    2013-01-01

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

  7. Reconstituted high density lipoprotein mediated targeted co-delivery of HZ08 and paclitaxel enhances the efficacy of paclitaxel in multidrug-resistant MCF-7 breast cancer cells.

    PubMed

    Zhang, Fangrong; Wang, Xiaoyi; Xu, Xiangting; Li, Min; Zhou, Jianping; Wang, Wei

    2016-09-20

    In the past decades, reconstituted high density lipoprotein (rHDL) has been successfully developed as a drug carrier since the enhanced HDL-lipids uptake is demonstrated in several human cancers. In this paper, rHDL, for the first time, was utilized to co-encapsulate two hydrophobic drugs: an anticancer drug, paclitaxel (PTX), and a new reversal agent for P-gp (P-glycoprotein)-mediated multidrug resistance (MDR) of cancer, N-cyano-1-[(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide (HZ08). We proposed this drug co-delivery strategy to reverse PTX resistance. The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted PTX-HZ08 delivery for cancer therapy. Using sodium cholate dialysis method, we successfully formulated dual-agent co-delivering rHDL nanoparticles (PTX-HZ08-rHDL NPs) with a typical spherical morphology, well-distributed size (~100nm), high drug encapsulation efficiency (approximately 90%), sustained drug release properties and exceptional stability even after storage for 1month or incubation in 10% fetal bovine serum (FBS) DMEM for up to 2days. Results demonstrated that PTX-HZ08-rHDL NPs significantly enhanced anticancer efficacy in vitro, including higher cytotoxicity and better ability to induce cell apoptosis against both PTX-sensitive and -resistant MCF-7 human breast cancer cell lines (MCF-7 and MCF-7/PTX cells). Mechanism studies demonstrated that these improvements could be correlated with increased cellular uptake of PTX mediated by scavenger receptor class B type I (SR-BI) as well as prolonged intracellular retention of PTX due to the HZ08 mediated drug-efflux inhibition. In addition, in vivo investigation showed that the PTX-HZ08-rHDL NPs were substantially safer, have higher tumor-targeted capacity and have stronger antitumor activity than the corresponding dosage of paclitaxel injection. These findings suggested that rHDL NPs could

  8. Implications of Total to High-Density Lipoprotein Cholesterol Ratio Discordance With Alternative Lipid Parameters for Coronary Atheroma Progression and Cardiovascular Events.

    PubMed

    Elshazly, Mohamed B; Nicholls, Stephen J; Nissen, Steven E; St John, Julie; Martin, Seth S; Jones, Steven R; Quispe, Renato; Stegman, Brian; Kapadia, Samir R; Tuzcu, E Murat; Puri, Rishi

    2016-09-01

    The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio may quantify atherogenic lipoproteins beyond low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apolipoprotein B (apoB). We analyzed pooled data from 9 trials involving 4,957 patients with coronary artery disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and 2-year major adverse cardiovascular event (MACE) rates when TC/HDL-C levels were discordant with LDL-C, non-HDL-C, and apoB. Discordance was investigated when lipid levels were stratified by

  9. Treatment with the herbal medicine, naoxintong improves the protective effect of high-density lipoproteins on endothelial function in patients with type 2 diabetes

    PubMed Central

    LV, PU; TONG, XUNLIANG; PENG, QING; LIU, YUANYUAN; JIN, HAIQIANG; LIU, RAN; SUN, WEI; PAN, BING; ZHENG, LEMIN; HUANG, YINING

    2016-01-01

    The protective effect of high-density lipoprotein (HDL) on endothelial function is impaired in patients with type 2 diabetes mellitus (T2DM), which may result in atherosclerotic complications. Naoxintong (NXT) is a compound preparation that includes Radix Astragali, Angelicae sinensis, Radix Paeoniae Rubra and Ligusticum wallichii. It is widely administered in China to prevent atherosclerotic complications. In the present study, NXT was administered to 69 patients with T2DM. HDLs were isolated from patient blood samples prior to and following the intervention. In vitro endothelial functions of HDL, including proliferation, migration, angiogenesis, and anti-apoptosis were investigated by bromodeoxyuridine, wound healing, Transwell and Matrigel tube formation assays on human umbilical vein endothelial cells (HUVECs). The results from the present study demonstrated that HUVECs treated with HDL isolated from diabetic patients following NXT therapy exhibited increased proliferative effects (10–27%; P<0.05), and improved migration ability (15–35%; P<0.05), anti-apoptotic function (23–34%; P<0.05) and angiogenesis (30–54%; P<0.001). Furthermore, the phosphorylation levels of Akt (26–36%; P<0.01) and extracellular signal-regulated kinase (16–80%; P<0.01) were increased following NXT therapy. The present in vitro study demonstrates that the protective effect of HDL on endothelial function is markedly impaired in diabetic patients who tend to develop atherosclerosis, and the impaired function may be partly abrogated by NXT. PMID:26781332

  10. Synthetic high-density lipoprotein-like nanoparticles potently inhibit cell signaling and production of inflammatory mediators induced by lipopolysaccharide binding Toll-like receptor 4.

    PubMed

    Foit, Linda; Thaxton, C Shad

    2016-09-01

    Toll-like receptor 4 (TLR4) plays a critical role in the innate immune system. Stimulation of TLR4 occurs upon binding lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls. Due to the potency of the induced inflammatory response, there is a growing interest in agents that can most proximally modulate this LPS/TLR4 interaction to prevent downstream cell signaling events and the production of inflammatory mediators. Building on the natural ability of human high-density lipoprotein (HDL) to bind LPS, we synthesized a suite of HDL-like nanoparticles (HDL-like NP). We identified one HDL-like NP that was particularly effective at decreasing TLR4 signaling caused by addition of purified LPS or Gram-negative bacteria to model human cell lines or primary human peripheral blood cells. The HDL-like NP functioned to inhibit TLR4-dependent inflammatory response to LPS derived from multiple bacterial species. Mechanistically, data show that the NP mainly functions by scavenging and neutralizing the LPS toxin. Taken together, HDL-like NPs constitute a powerful endotoxin scavenger with the potential to significantly reduce LPS-mediated inflammation. PMID:27244690

  11. Anti-atherogenic properties of high-density lipoproteins in psychiatric patients before and after two months of atypical anti-psychotic therapy.

    PubMed

    Hussein, Osamah; Izikson, Lidia; Bathish, Yunis; Dabur, Enas; Hanna, Alaa; Zidan, Jamal

    2015-12-01

    Some of the medications used for the management of schizophrenia are associated with clinically significant increases in weight and adverse alterations in serum lipid levels. The aim of the study was to investigate the effect of short-term (two months) treatment with atypical anti-psychotics on coronary heart disease risk factors, including the functional properties of high-density lipoprotein (HDL), in psychiatric patients. Nineteen patients diagnosed with schizophrenia, schizoaffective, and bipolar disorder and ten healthy volunteers were enrolled in the study. In the present study blood was drawn at baseline and after two months of atypical anti-psychotic treatment. Wilcoxon non-parametric-test was used to examine differences in the psychotic group before and two months after treatment.Waist circumference and oxidative stress in psychiatric patients were higher compared with the control group. Serum-mediated cholesterol efflux capacity was lower in psychotic patients compared to controls. Two months of anti-psychotic therapy was associated with increased abdominal obesity, decreased paraoxonase lactonase activity, but with no further change in serum-mediated cholesterol efflux from macrophages. Psychotic patients have low serum-mediated cholesterol efflux from macrophages as a parameter of HDL functionality. Atypical anti-psychotic treatment for two months increased metabolic derangements in these patients but without further decrement in serum-mediated cholesterol efflux. PMID:26253619

  12. Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl).

    PubMed

    Hadfield, Katrina A; Pattison, David I; Brown, Bronwyn E; Hou, Liming; Rye, Kerry-Anne; Davies, Michael J; Hawkins, Clare L

    2013-01-15

    Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA-I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate). PMID:23088652

  13. Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence: correlation with plasma testosterone levels

    SciTech Connect

    Kirkland, R.T.; Keenan, B.S.; Probstfield, J.L.; Patsch, W.; Lin, T.L.; Clayton, G.W.; Insull, W. Jr.

    1987-01-23

    A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate. Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant of plasma HDL-C levels during pubertal development.

  14. A Biomimic Reconstituted High-Density-Lipoprotein-Based Drug and p53 Gene Co-delivery System for Effective Antiangiogenesis Therapy of Bladder Cancer

    NASA Astrophysics Data System (ADS)

    Ouyang, Qiaohong; Duan, Zhongxiang; Jiao, Guangli; Lei, Jixiao

    2015-07-01

    A biomimic reconstituted high-density-lipoprotein-based drug and p53 gene co-delivery system (rHDL/CD-PEI/p53 complexes) was fabricated as a targeted co-delivery nanovector of drug and gene for potential bladder cancer therapy. Here, CD-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL, and to act as an antitumor drug to suppress tumor angiogenesis. The rHDL/CD-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge, and low cytotoxicity in vitro. The results of confocal laser scanning microscopy and flow cytometry confirmed that SR-BI-targeted function induced specific cytoplasmic delivery and high gene transfection efficiency in MBT-2 murine bladder cells. In addition, rHDL/CD-PEI/p53 complexes co-delivering CD and p53 gene achieved synergistic angiogenesis suppression by more effectively downregulating the expression of vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and protein via different pathways in vitro. In vivo investigation on C3H/He mice bearing MBT-2 tumor xenografts revealed that rHDL/CD-PEI/p53 complexes possessed strong antitumor activity. These findings suggested that rHDL/CD-PEI/p53 complexes could be an ideal tumor-targeting system for simultaneous transfer of drug and gene, which might be a new promising strategy for effective bladder cancer therapy.

  15. Using tandem mass spectrometry to quantify site-specific chlorination and nitration of proteins: model system studies with high-density lipoprotein oxidized by myeloperoxidase.

    PubMed

    Shao, Baohai; Heinecke, Jay W

    2008-01-01

    Protein oxidation is implicated in atherogenesis and other inflammatory conditions. Measuring levels of chlorinated and nitrated proteins in biological matrices serves as a quantitative index of oxidative stress in vivo. One potential mechanism for oxidative stress involves myeloperoxidase, a heme protein expressed by neutrophils, monocytes, and some populations of macrophages. The enzyme uses hydrogen peroxide to generate an array of cytotoxic oxidants, including hypochlorous acid (HOCl), a potent chlorinating intermediate, and nitrogen dioxide radical, a reactive nitrogen species (RNS). One important target may be high-density lipoprotein (HDL), which is implicated in atherogenesis. This chapter describes liquid chromatography-tandem mass spectrometric methods for quantifying site-specific modifications of proteins that have been oxidized by HOCl or RNS. Our studies center on apolipoprotein A-I, the major HDL protein, which provides an excellent model system for investigating factors that target specific residues for oxidative damage. Our approach is sensitive and rapid, applicable to a wide array of posttranslational modifications, and does not require peptides to be derivatized or labeled with an isotope. PMID:18423210

  16. Is abnormal non-high-density lipoprotein cholesterol a gender-specific predictor for metabolic syndrome in patients with schizophrenia taking second-generation antipsychotics?

    PubMed

    Lin, Esther Ching-Lan; Shao, Wen-Chuan; Yang, Hsin-Ju; Yen, Miaofen; Lee, Sheng-Yu; Wu, Pei-Chun; Lu, Ru-Band

    2015-02-01

    Evidence supports an association between metabolic syndrome (MetS) and schizophrenia. However, specific risk factors for MetS and gender differences in patients with schizophrenia taking second-generation antipsychotics (SGAs) have not been well explored. A cross-sectional cohort of 329 Han Chinese patients was recruited in a psychiatric hospital in central Taiwan. Using the definitions of the International Diabetes Federation for Chinese, the prevalence of MetS was 23.7% (men: 25.7%; women: 21.2%). Logistic regression analyses showed that patients with a BMI ≥ 24 and an abnormal non-high-density lipoprotein cholesterol (non-HDL-C) were significantly (p < 0.001) more likely to develop MetS. A BMI ≥ 24 was a significant risk factor in men (OR: 6.092, p < 0.001) and women (OR: 5.886, p < 0.001). An abnormal non-HDL-C was a significant specific risk factor for men with MetS (OR: 4.127, p < 0.001), but not for women. This study supports a greater prevalence of MetS in patients with schizophrenia taking SGAs than in the general population. Abnormal BMI and non-HDL-C were significantly associated with developing MetS, and an abnormal non-HDL-C was a specific risk factor for men. Future development of specific interventions and regular monitoring for MetS is imperative for early identification and prevention. PMID:25034455

  17. A novel anti-inflammatory mechanism of high density lipoprotein through up-regulating annexin A1 in vascular endothelial cells.

    PubMed

    Pan, Bing; Kong, Jinge; Jin, Jingru; Kong, Jian; He, Yubin; Dong, Shuying; Ji, Liang; Liu, Donghui; He, Dan; Kong, Liming; Jin, David K; Willard, Belinda; Pennathur, Subramaniam; Zheng, Lemin

    2016-06-01

    High density lipoprotein (HDL) as well as annexin A1 have been reported to be associated with cardiovascular protection. However, the correlation between HDL and annexin A1 was still unknown. In this study, HDL increased endothelial annexin A1 and prevented the decrease of annexin A1 in TNF-α-activated endothelial cells in vitro and in vivo, and above effects were attenuated after knockdown of annexin A1. Annexin A1 modulation affected HDL-mediated inhibition of monocyte adhesion to TNF-α-activated endothelium (45.2±13.7% decrease for annexin A1 RNA interference; 78.7±16.3% decrease for anti-Annexin A1 antibody blocking; 11.2±6.9% increase for Ad-ANXA1 transfection). Additionally, HDL up-regulated annexin A1 through scavenger receptor class B type I, involving ERK, p38MAPK, Akt and PKC signaling pathways, and respective inhibitors of these pathways attenuated HDL-induced annexin A1 expression as well as impaired HDL-mediated inhibition of monocyte-endothelial cell adhesion. Apolipoprotein AI also increased annexin A1 and activated similar signaling pathways. Endothelial annexin A1 from apolipoprotein AI knockout mice was decreased in comparison to that from wild type mice. Finally, HDL-induced annexin A1 inhibited cell surface VCAM-1, ICAM-1 and E-selectin, and secretion of MCP-1, IL-8, VCAM-1 and E-selectin, thereby inhibiting monocyte adhesion. PMID:27012521

  18. Detection and quantification of a very high density lipoprotein in different tissues of Triatoma infestans during the last nymphal and adult stages.

    PubMed

    Rimoldi, O J; Córsico, B; González, M S; Brenner, R R

    1996-07-01

    The presence of a very high density lipoprotein (VHDL), an hexameric protein, was explored in different tissues of Triatoma infestans throughout the last nymphal and adult stages, and in egg extracts by Western blot assays. The VHDL was always detected in both, hemolymph and fat body, during the above mentioned stages and it was also observed in the buffer soluble fraction of testis and egg homogenates. An enzyme-linked immunosorbent assay (ELISA) was used to measure the VHDL titer in these tissues. Hemolymph VHDL reaches a maximum value before the last molt, then it abruptly declines in males and females just after emergence, but during adult life it increases again. Fat body VHDL decreases slowly and continuously during the nymph growth reaching a minimum value prior to molting, and in the first week of adult life the values were even two-fold lower; then, it shows a different cycle of accumulation and depletion in males and females. In adult testis the VHDL undergoes a cycle similar to the one observed in male fat body. This protein increases progressively during embryonic development and, at the time of larval hatching it reaches its maximum value. The hexameric protein presents homologies in its N-terminal sequence with storage hexamerins of Diptera, Lepidoptera and Hymenoptera. PMID:8995792

  19. Crystal Structure of C-terminal Truncated Apolipoprotein A-I Reveals the Assembly of High Density Lipoprotein (HDL) by Dimerization*

    PubMed Central

    Mei, Xiaohu; Atkinson, David

    2011-01-01

    Apolipoprotein A-I (apoA-I) plays important structural and functional roles in plasma high density lipoprotein (HDL) that is responsible for reverse cholesterol transport. However, a molecular understanding of HDL assembly and function remains enigmatic. The 2.2-Å crystal structure of Δ(185–243)apoA-I reported here shows that it forms a half-circle dimer. The backbone of the dimer consists of two elongated antiparallel proline-kinked helices (five AB tandem repeats). The N-terminal domain of each molecule forms a four-helix bundle with the helical C-terminal region of the symmetry-related partner. The central region forms a flexible domain with two antiparallel helices connecting the bundles at each end. The two-domain dimer structure based on helical repeats suggests the role of apoA-I in the formation of discoidal HDL particles. Furthermore, the structure suggests the possible interaction with lecithin-cholesterol acyltransferase and may shed light on the molecular details of the effect of the Milano, Paris, and Fin mutations. PMID:21914797

  20. Effect of High-Density Lipoprotein Metabolic Pathway Gene Variations and Risk Factors on Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in China

    PubMed Central

    Sun, Yaoyao; Bai, Yujing; Wang, Bin; Yu, Wenzhen; Zhao, Mingwei; Li, Xiaoxin

    2015-01-01

    Purpose To investigate the effect of genetic variants in the high-density lipoprotein (HDL) metabolic pathway and risk factors on neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in China. Methods A total of 742 Chinese subjects, including 221 controls, 230 cases with nAMD, and 291 cases with PCV, were included in the present study. Five single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway (HDLMP) including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC) and lipoprotein lipase (LPL) were genotyped in all study subjects with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Risk factors including gender, hypertension, hyperlipidemia, diabetes mellitus, and coronary artery disease were identified. Chi-square tests or Fisher’s exact tests were applied to discover associations between SNPs and risk factors for PCV and nAMD. Gene-gene interactions and gene-environment interactions were evaluated by the multifactor-dimensionality reduction (MDR) method. Results CETP rs3764261 were significantly associated with an increased risk for PCV (odds ratio (OR) = 1.444, P = 0.0247). LIPC rs1532085 conferred an increased risk for PCV (OR = 1.393, P = 0.0094). We found no association between PCV and LPL rs12678919, LIPC rs10468017 or CETP rs173539. No association was found between five SNPs with nAMD. Regarding risk factors, females were found to have significantly decreased risks for both PCV and nAMD (P = 0.006 and 0.001, respectively). Coronary artery disease (CAD) was a risk factor in PCV patients but played a protective role in nAMD patients. Hyperlipidemia was associated with PCV but not with nAMD. Neither hypertension nor diabetes mellitus was associated with PCV or nAMD. The MDR analysis revealed that a three-locus model with rs12678919, rs1532085, and gender was the best model for nAMD, while a five-locus model consisting of rs

  1. Vitamin C may have similar beneficial effects to Gemfibrozil on serum high-density lipoprotein-cholesterol in type 2 diabetic patients

    PubMed Central

    Siavash, Mansour; Amini, Masoud

    2014-01-01

    Objective: Type 2 diabetes mellitus (DM-T2) is commonly associated with increased triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) levels. Fibrates like gemfibrozil are frequently used in diabetic patients to decrease TG and increase HDL-C levels. We compared the efficacy of Vitamin C, an antioxidant vitamin, with gemfibrozil on serum HDL-C in diabetic patients. Methods: Type 2 diabetic patients, referred to our out-patient clinic were randomly divided into three groups. After 1 month of lifestyle and diet modifications, groups A, B, and C were prescribed 1000 mg Vitamin C, 600 mg gemfibrozil and combination of both, respectively. Before the study initiation and after 6th week of drug prescription, the blood samples were taken and analyzed for total cholesterol (Total-C), HDL-C, TG, fasting blood sugar (FBS), and hemoglobin A1c (HbA1c) levels. Findings: Sixty-seven patients entered, and 50 patients (18 male, 32 female) finished the study. Overall, serum HDL-C increased significantly from 39.8 to 45.2 mg/dL in the participants (P = 0.001). HDL-C increased 6.3, 4.4 and 5.0 mg/dL in groups A, B and C, respectively (related significances were 0.017, 0.022 and 0.033, respectively). Significant decrease of serum TG and Total-C occurred in gemfibrozil and combination groups, but not in Vitamin C group. Changes in serum HDL-C between three groups were not significant (P = 0.963). We found a significant decrease in TG and Total-C in the groups B and C (P < 0.05), but no significant changes of TG, Total-C, LDL-C, FBS and HbA1c in group A (P > 0.05). Conclusion: The results demonstrated that Vitamin C may have beneficial effects on HDL-C in diabetic patients without significant effects on plasma glucose or other lipid parameters; however, its role for the treatment of low HDL-C patients should be evaluated in larger studies. PMID:25328896

  2. Proinflammatory high-density lipoprotein results from oxidized lipid mediators in the pathogenesis of both idiopathic and associated types of pulmonary arterial hypertension.

    PubMed

    Ross, David J; Hough, Greg; Hama, Susan; Aboulhosn, Jamil; Belperio, John A; Saggar, Rajan; Van Lenten, Brian J; Ardehali, Abbas; Eghbali, Mansoureh; Reddy, Srinivasa; Fogelman, Alan M; Navab, Mohamad

    2015-12-01

    Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for high-density lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the

  3. Comparison of High-Density Lipoprotein Cholesterol to Apolipoprotein A-I and A-II to Predict Coronary Calcium and the Effect of Insulin Resistance

    PubMed Central

    Martin, Seth S.; Qasim, Atif N.; Wolfe, Megan; Clair, Caitlin; Schwartz, Stanley; Iqbal, Nayyar; Schutta, Mark; Bagheri, Roshanak; Mehta, Nehal N.; Rader, Daniel J.; Reilly, Muredach P.

    2011-01-01

    High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance. PMID:21257004

  4. Comparison of high-density lipoprotein cholesterol to apolipoprotein A-I and A-II to predict coronary calcium and the effect of insulin resistance.

    PubMed

    Martin, Seth S; Qasim, Atif N; Wolfe, Megan; St Clair, Caitlin; Schwartz, Stanley; Iqbal, Nayyar; Schutta, Mark; Bagheri, Roshanak; Mehta, Nehal N; Rader, Daniel J; Reilly, Muredach P

    2011-02-01

    High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance. PMID:21257004

  5. Proinflammatory high-density lipoprotein results from oxidized lipid mediators in the pathogenesis of both idiopathic and associated types of pulmonary arterial hypertension

    PubMed Central

    Hough, Greg; Hama, Susan; Aboulhosn, Jamil; Belperio, John A.; Saggar, Rajan; Van Lenten, Brian J.; Ardehali, Abbas; Eghbali, Mansoureh; Reddy, Srinivasa; Fogelman, Alan M.; Navab, Mohamad

    2015-01-01

    Abstract Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for high-density lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the “inflammatory indices” HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a “dysfunctional HDL phenotype,” that is, proinflammatory HDL effects. In contrast to “normal HDL function,” the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant “salutary effect” of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of

  6. Increased plasma total cholesterol and high density lipoprotein levels produced by the crude extract from the leaves of Viscum album (mistletoe).

    PubMed

    Ben, E E; Eno, A E; Ofem, O E; Aidem, U; Itam, E H

    2006-01-01

    The effect of an aqueous extract prepared from the leaves of Viscum album (Mistletoe) on plasma cholesterol and albumin levels in male Wistar rats was studied. Lethality studies revealed that the extract had an LD50 value of 417.0 mg/kg mice, intraperitoneally. The rats were randomly divided into seven (7) groups of 5 rats per group with one animal per metabolic cage. Group one served as the control (C1), groups two to six were treated with extract (200 mg/kg body weight orally and daily) for a maximum of ten (10) weeks, whereas, group seven (C2) received no extract treatment but was fed on normal rat chow. All the rats had free access to rat food and drinking water. The first group (C1) was sacrificed a fortnight after the commencement of the experiment, while group seven (C2) was sacrificed at the end (10th week) of the experiment. The extract-treated groups were sacrificed respectively in the order two, four, six, eight and ten week of extract administration. Whole blood was collected from these groups for analysis. Results showed significant [P < 0.01] increases in the level of total cholesterol (TC) from 1.92 +/- 0.11 mMol/L to 2.59 +/- 0.02 mMol/L (about 35% increase) and high-density lipoproteins (HDL) from 0.95 +/- 0.02 mMol/L to 1.50 +/- 0.08 mMol/L (about 58.50% increase) at week ten. The LDL levels, the total protein and albumin levels did not show any significant change from the control values. From the results, it is suggested that the crude aqueous extract from mistletoe leaf may be relatively safe for therapeutic use as it neither predisposes to cardiovascular risk nor adversely affects protein metabolism following prolonged period of administration. PMID:17242719

  7. Alterations in plasma total and high density lipoprotein cholesterol levels in hyperlipidemic rats fed diets with varied content of selenium and vitamin E.

    PubMed

    Liu, W; Boylan, L M

    1994-07-01

    The effect of dietary selenium and vitamin E on plasma total (TC) and high density lipoprotein cholesterol (HDLC) was evaluated in 54 Sprague Dawley rats fed cholesterol/cholic acid enriched diets. Diets 1, 2, and 3 had no added selenium (low Se) and 0 (low), 60 (adequate), and 600 (high) mg/kg dL alpha tocopheryl acetate added respectively. Sodium selenite at 0.2 mg/kg (adequate Se) was added to diets 4, 5, and 6 and at 4.0 mg/kg (toxic Se) to diet 7, 8, and 9 with the same pattern of vitamin E added to the diet as described above. TC and HDLC were measured using the Kodak Ectachem system. Rats in the low and adequate Se groups fed high vitamin E had lower TC values than rats fed lower vitamin E levels but differences were not significant. In the toxic Se groups, rats fed high vitamin E had significantly (p < 0.05) higher plasma TC values than did lower Vitamin E groups. Rats on the high vitamin E diets with low or adequate Se had significantly (p < 0.05) higher mean plasma HDLC values when compared to rats fed low or adequate vitamin E diets. HDLC values for animals on Se toxic diets were significantly (p < 0.05) lower in rats fed a low vitamin E diet. In rats fed Se deficient and adequate diets, a high vitamin E intake resulted in a decrease in TC and an increase in HDLC.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7986664

  8. Impaired Cholesterol Efflux Capacity of High-Density Lipoprotein Isolated From Interstitial Fluid in Type 2 Diabetes Mellitus—Brief Report

    PubMed Central

    Tietge, Uwe J.F.; Dikkers, Arne; Parini, Paolo; Angelin, Bo; Rudling, Mats

    2016-01-01

    Objective— Patients with type 2 diabetes mellitus (T2D) have an increased risk of cardiovascular disease, the mechanism of which is incompletely understood. Their high-density lipoprotein (HDL) particles in plasma have been reported to have impaired cholesterol efflux capacity. However, the efflux capacity of HDL from interstitial fluid (IF), the starting point for reverse cholesterol transport, has not been studied. We here investigated the cholesterol efflux capacity of HDL from IF and plasma from T2D patients and healthy controls. Approach and Results— HDL was isolated from IF and peripheral plasma from 35 T2D patients and 35 age- and sex-matched healthy controls. Cholesterol efflux to HDL was determined in vitro, normalized for HDL cholesterol, using cholesterol-loaded macrophages. Efflux capacity of plasma HDL was 10% lower in T2D patients than in healthy controls, in line with previous observations. This difference was much more pronounced for HDL from IF, where efflux capacity was reduced by 28% in T2D. Somewhat surprisingly, the efflux capacity of HDL from IF was lower than that of plasma HDL, by 15% and 32% in controls and T2D patients, respectively. Conclusion— These data demonstrate that (1) HDL from IF has a lower cholesterol efflux capacity than plasma HDL and (2) the efflux capacity of HDL from IF is severely impaired in T2D when compared with controls. Because IF comprises the compartment where reverse cholesterol transport is initiated, the marked reduction in cholesterol efflux capacity of IF-HDL from T2D patients may play an important role for their increased risk to develop atherosclerosis. PMID:27034474

  9. Different impact of high-density lipoprotein-related genetic variants on polypoidal choroidal vasculopathy and neovascular age-related macular degeneration in a Chinese Han population.

    PubMed

    Zhang, Xiongze; Li, Meng; Wen, Feng; Zuo, Chengguo; Chen, Hui; Wu, Kunfang; Zeng, Renpan

    2013-03-01

    Neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) are both major serosanguinous maculopathies among the Asian elderly. They are similar in phenotype. Genetic variants in high-density lipoprotein (HDL) pathway were discovered to be associated with AMD in two genome-wide association studies. In this study with a Chinese Han cohort, we investigated the impacts of these genetic variants on nAMD and PCV separately. The missense coding variants and previously identified variants at LIPC, ABCA1, CETP, LPL and FADS1 loci were genotyped in 157 nAMD patients, 250 PCV patients and 204 controls without any macular abnormality. The known variants in CFH, ARMS2 and near HTRA1 were also genotyped. Fasting serum cholesterol levels were determined. The variants in CFH, ARMS2 and near HTRA1 were strongly associated with both PCV (P < 10(-6), 10(-7) and 10(-7) respectively) and nAMD (P < 10(-6), 10(-16) and 10(-17) respectively). None of the studied HDL-related variants were significantly associated with nAMD. A missense variant in CETP, rs5882, was significantly associated with PCV (P = 2.73 × 10(-4)). The rs5882 GG genotype had a 3.53-fold (95% CI: 1.93-6.45) increased risk for PCV, and conferred a significantly lower serum HDL-cholesterol level for PCV patients than the AA genotype (P = 0.048). These results suggest the need to separate PCV from nAMD in association studies especially with Asian cohorts, and that the HDL pathway may involve in the pathogenesis of PCV and nAMD differently. PMID:23274582

  10. Differential Benefit of Statin in Secondary Prevention of Acute Myocardial Infarction according to the Level of Triglyceride and High Density Lipoprotein Cholesterol

    PubMed Central

    Kim, Kyung Hwan; Kim, Cheol Hwan; Ahn, Youngkeun; Kim, Young Jo; Cho, Myeong Chan; Kim, Wan; Kim, Jong Jin

    2016-01-01

    Background and Objectives The differential benefit of statin according to the state of dyslipidemia has been sparsely investigated. We sought to address the efficacy of statin in secondary prevention of myocardial infarction (MI) according to the level of triglyceride and high density lipoprotein cholesterol (HDL-C) on admission. Subjects and Methods Acute MI patients (24653) were enrolled and the total patients were divided according to level of triglyceride and HDL-C on admission: group A (HDL-C≥40 mg/dL and triglyceride<150 mg/dL; n=11819), group B (HDL-C≥40 mg/dL and triglyceride≥150 mg/dL; n=3329), group C (HDL-C<40 mg/dL and triglyceride<150 mg/dL; n=6062), and group D (HDL-C<40 mg/dL & triglyceride≥150 mg/dL; n=3443). We evaluated the differential efficacy of statin according to the presence or absence of component of dyslipidemia. The primary end points were major adverse cardiac events (MACE) for 2 years. Results Statin therapy significantly reduced the risk of MACE in group A (hazard ratio=0.676; 95% confidence interval: 0.582-0.785; p<0.001). However, the efficacy of statin was not prominent in groups B, C, or D. In a propensity-matched population, the result was similar. In particular, the benefit of statin in group A was different compared with group D (interaction p=0.042) Conclusion The benefit of statin in patients with MI was different according to the presence or absence of dyslipidemia. In particular, because of the insufficient benefit of statin in patients with MI and dyslipidemia, a different lipid-lowering strategy is necessary in these patients. PMID:27275169

  11. Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels

    PubMed Central

    Bandarian, Fatemeh; Daneshpour, Maryam Sadat; Hedayati, Mehdi; Naseri, Mohsen; Azizi, Fereidoun

    2016-01-01

    Background: Apolipoprotein A2 (APOA2) is the second major apolipoprotein of the high-density lipoprotein cholesterol (HDL-C). The study aim was to identify APOA2 gene variation in individuals within two extreme tails of HDL-C levels and its relationship with HDL-C level. Methods: This cross-sectional survey was conducted on participants from Tehran Glucose and Lipid Study (TLGS) at Research Institute for Endocrine Sciences, Tehran, Iran from April 2012 to February 2013. In total, 79 individuals with extreme low HDL-C levels (≤5th percentile for age and gender) and 63 individuals with extreme high HDL-C levels (≥95th percentile for age and gender) were selected. Variants were identified using DNA amplification and direct sequencing. Results: Screen of all exons and the core promoter region of APOA2 gene identified nine single nucleotide substitutions and one microsatellite; five of which were known and four were new variants. Of these nine variants, two were common tag single nucleotide polymorphisms (SNPs) and seven were rare SNPs. Both exonic substitutions were missense mutations and caused an amino acid change. There was a significant association between the new missense mutation (variant Chr.1:16119226, Ala98Pro) and HDL-C level. Conclusion: None of two common tag SNPs of rs6413453 and rs5082 contributes to the HDL-C trait in Iranian population, but a new missense mutation in APOA2 in our population has a significant association with HDL-C. PMID:26590203

  12. Contributions of a disulfide bond and a reduced cysteine side chain to the intrinsic activity of the high-density lipoprotein receptor SR-BI.

    PubMed

    Yu, Miao; Lau, Thomas Y; Carr, Steven A; Krieger, Monty

    2012-12-18

    The high-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI), binds HDL and mediates selective cholesteryl ester uptake. SR-BI's structure and mechanism are poorly understood. We used mass spectrometry to assign the two disulfide bonds in SR-BI that connect cysteines within the conserved Cys(321)-Pro(322)-Cys(323) (CPC) motif and connect Cys(280) to Cys(334). We used site-specific mutagenesis to evaluate the contributions of the CPC motif and the side chain of extracellular Cys(384) to HDL binding and lipid uptake. The effects of CPC mutations on activity were context-dependent. Full wild-type (WT) activity required Pro(322) and Cys(323) only when Cys(321) was present. Reduced intrinsic activities were observed for CXC and CPX, but not XXC, XPX, or XXX mutants (X ≠ WT residue). Apparently, a free thiol side chain at position 321 that cannot form an intra-CPC disulfide bond with Cys(323) is deleterious, perhaps because of aberrant disulfide bond formation. Pro(322) may stabilize an otherwise strained CPC disulfide bond, thus supporting WT activity, but this disulfide bond is not absolutely required for normal activity. C(384)X (X = S, T, L, Y, G, or A) mutants exhibited altered activities that varied with the side chain's size: larger side chains phenocopied WT SR-BI treated with its thiosemicarbazone inhibitor BLT-1 (enhanced binding, weakened uptake); smaller side chains produced almost inverse effects (increased uptake:binding ratio). C(384)X mutants were BLT-1-resistant, supporting the proposal that Cys(384)'s thiol interacts with BLT-1. We discuss the implications of our findings on the functions of the extracellular loop cysteines in SR-BI and compare our results to those presented by other laboratories. PMID:23205738

  13. Apolipoprotein AI tertiary structures determine stability and phospholipid-binding activity of discoidal high-density lipoprotein particles of different sizes

    SciTech Connect

    Chen, Bin; Ren, Xuefeng; Neville, Tracey; Jerome, W. Gray; Hoyt, David W.; Sparks, Daniel L.; Ren, Gang; Wang, Jianjun

    2009-05-18

    Human high-density lipoprotein (HDL) plays a key role in the reverse cholesterol transport pathway that delivers excess cholesterol back to the liver for clearance. In vivo, HDL particles vary in size, shape and biological function. The discoidal HDL is a 140-240 kDa, disk-shaped intermediate of mature HDL. During mature spherical HDL formation, discoidal HDLs play a key role in loading cholesterol ester onto the HDL particles by activating the enzyme, lecithin:cholesterol acyltransferase (LCAT). One of the major problems for high-resolution structural studies of discoidal HDL is the difficulty in obtaining pure and, foremost, homogenous sample. We demonstrate here that the commonly used cholate dialysis method for discoidal HDL preparation usually contains 5-10% lipid-poor apoAI that significantly interferes with the high-resolution structural analysis of discoidal HDL using biophysical methods. Using an ultracentrifugation method, we quickly removed lipid-poor apoAI. We also purified discoidal reconstituted HDL (rHDL) into two pure discoidal HDL species of different sizes that are amendable for high-resolution structural studies. A small rHDL has a diameter of 7.6 nm, and a large rHDL has a diameter of 9.8 nm. We show that these two different sizes of discoidal HDL particles display different stability and phospholipid-binding activity. Interestingly, these property/functional differences are independent from the apoAI -helical secondary structure, but are determined by the tertiary structural difference of apoAI on different discoidal rHDL particles, as evidenced by two-dimensional NMR and negative stain electron microscopy data. Our result further provides the first high-resolution NMR data, demonstrating a promise of structural determination of discoidal HDL at atomic resolution using a combination of NMR and other biophysical techniques.

  14. Combined Analysis of Genome Scans of Dutch and Finnish Families Reveals a Susceptibility Locus for High-Density Lipoprotein Cholesterol on Chromosome 16q

    PubMed Central

    Pajukanta, Päivi; Allayee, Hooman; Krass, Kelly L.; Kuraishy, Ali; Soro, Aino; Lilja, Heidi E.; Mar, Rebecca; Taskinen, Marja-Riitta; Nuotio, Ilpo; Laakso, Markku; Rotter, Jerome I.; de Bruin, Tjerk W. A.; Cantor, Rita M.; Lusis, Aldons J.; Peltonen, Leena

    2003-01-01

    Several genomewide screens have been performed to identify novel loci predisposing to unfavorable serum lipid levels and coronary heart disease (CHD). We hypothesized that the accumulating data of these screens in different study populations could be combined to verify which of the identified loci truly harbor susceptibility genes. The power of this strategy has recently been demonstrated with other complex diseases, such as inflammatory bowel disease and asthma. We assessed the largely unknown genetic background of CHD by investigating the most common dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL), affecting 1%–2% of Western populations and 10%–20% of families with premature CHD. To be able to perform a combined data analysis, we unified the diagnostic criteria for FCHL and its component traits and combined the data from two genomewide scans performed in two populations, the Finns and the Dutch. As a result of our pooled data analysis, we identified three chromosomal regions, on chromosomes 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a LOD score >2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein cholesterol (HDL-C) trait. In addition, the previously recognized 1q21 region also obtained additional support in the other study sample, when the triglyceride trait was used. Analysis of the 16q24.1 region resulted in a statistically significant LOD score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families. PMID:12638083

  15. Effects of red grape juice consumption on high density lipoprotein-cholesterol, apolipoprotein AI, apolipoprotein B and homocysteine in healthy human volunteers.

    PubMed

    Khadem-Ansari, Mohammad H; Rasmi, Yousef; Ramezani, Fatemeh

    2010-01-01

    It has suggested that grape juice consumption has lipid- lowering effect and it is associated with a decreased risk of heart disease. We aimed to evaluate the effects of red grape juice (RGj) consumption on high density lipoprotein-cholesterol (HDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB) and homocysteine (Hcy) levels in healthy human volunteers. Twenty six healthy and nonsmoking males, aged between 25-60 years, who were under no medication asked to consume 150 ml of RGj twice per day for one month. Serum HDL-C, apoAI, apoB and plasma Hcy levels were measured before and after one month RGj consumption. HDL-C levels after RGj consumption were significantly higher than the corresponding levels before the RGj consumption (41.44 ± 4.50 and 44.37 ± 4.30 mg/dl; P<0.0001). Also, apoB was significantly increased after RGj consumption (149.0 ± 22.35 and 157.19 ± 18.60 mg/dl; P<0.002). But apoAI levels were not changed significantly before and after of RGj consumption (154.27 ± 21.55 and 155.35 ± 21.07 mg/dl; P>0.05). Hcy levels were decreased after RGj consumption (7.70 ± 2.80 and 6.20 ± 2.30 µmol/l; P<0.001). The present study demonstrates that RGj consumption can significantly increase serum HDL-C levels and decrease Hcy levels. These findings may have important implications for the prevention of atherosclerosis in healthy individuals. PMID:21633724

  16. Very high-density lipoprotein and vitellin as carriers of novel biliverdins IXα with a farnesyl side-chain presumably derived from heme A in Spodoptera littoralis.

    PubMed

    Kayser, Hartmut; Nimtz, Manfred; Ringler, Philippe; Müller, Shirley A

    2016-01-01

    Bilins in complex with specific proteins play key roles in many forms of life. Biliproteins have also been isolated from insects; however, structural details are rare and possible functions largely unknown. Recently, we identified a high-molecular weight biliprotein from a moth, Cerura vinula, as an arylphorin-type hexameric storage protein linked to a novel farnesyl biliverdin IXα; its unusual structure suggests formation by cleavage of mitochondrial heme A. In the present study of another moth, Spodoptera littoralis, we isolated two different biliproteins. These proteins were identified as a very high-density lipoprotein (VHDL) and as vitellin, respectively, by mass spectrometric sequencing. Both proteins are associated with three different farnesyl biliverdins IXα: the one bilin isolated from C. vinula and two new structurally closely related bilins, supposed to be intermediates of heme A degradation. The different bilin composition of the two biliproteins suggests that the presumed oxidations at the farnesyl side-chain take place mainly during egg development. The egg bilins are supposedly transferred from hemolymph VHDL to vitellin in the female. Both biliproteins show strong induced circular dichroism activity compatible with a predominance of the M-conformation of the bilins. This conformation is opposite to that of the arylphorin-type biliprotein from C. vinula. Electron microscopy of the VHDL-type biliprotein from S. littoralis provided a preliminary view of its structure as a homodimer and confirmed the biochemically determined molecular mass of ∼350 kDa. Further, images of S. littoralis hexamerins revealed a 2 × 3 construction identical to that known from the hexamerin from C. vinula. PMID:26546815

  17. Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residues of apolipoproteins AI and AII.

    PubMed

    Garner, B; Waldeck, A R; Witting, P K; Rye, K A; Stocker, R

    1998-03-13

    Human high density lipoproteins (HDL) can reduce cholesteryl ester hydroperoxides to the corresponding hydroxides (Sattler W., Christison J. K., and Stocker, R. (1995) Free Radical Biol. & Med. 18, 421-429). Here we demonstrate that this reducing activity extended to hydroperoxides of phosphatidylcholine, was similar in HDL2 and HDL3, was independent of arylesterase and lecithin:cholesteryl acyltransferase activity, was unaffected by sulfhydryl reagents, and was expressed by reconstituted particles containing apoAI or apoAII only, as well as isolated human apoAI. Concomitant with the reduction of lipid hydroperoxides specific oxidized forms of apoAI and apoAII formed in blood-derived and reconstituted HDL. Similarly, specific oxidized forms of apoAI accumulated upon treatment of isolated apoAI with authentic cholesteryl linoleate hydroperoxide. These specific oxidized forms of apoAI and apoAII have been shown previously to contain Met sulfoxide (Met(O)) at Met residues and are also formed when HDL is exposed to Cu2+ or soybean lipoxygenase. Lipid hydroperoxide reduction and the associated formation of specific oxidized forms of apoAI and apoAII were inhibited by solubilizing HDL with SDS or by pretreatment of HDL with chloramine T. The inhibitory effect of chloramine T was dose-dependent and accompanied by the conversion of specific Met residues of apoAI and apoAII into Met(O). Canine HDL, which contains apoAI as the predominant apolipoprotein and which lacks the oxidation-sensitive Met residues Met112 and Met148, showed much weaker lipid hydroperoxide reducing activity and lower extents of formation of oxidized forms of apoAI than human HDL. We conclude that the oxidation of specific Met residues of apoAI and apoAII to Met(O) plays a significant role in the 2-electron reduction of hydroperoxides of cholesteryl esters and phosphatidylcholine associated with human HDL. PMID:9497326

  18. Hypo-high-density Lipoprotein Cholesterolemia Caused by Evacuation after the Fukushima Daiichi Nuclear Power Plant Accident: Results from the Fukushima Health Management Survey.

    PubMed

    Satoh, Hiroaki; Ohira, Tetsuya; Nagai, Masato; Hosoya, Mitsuaki; Sakai, Akira; Watanabe, Tsuyoshi; Ohtsuru, Akira; Kawasaki, Yukihiko; Suzuki, Hitoshi; Takahashi, Atsushi; Kobashi, Gen; Ozasa, Kotaro; Yasumura, Seiji; Yamashita, Shunichi; Kamiya, Kenji; Abe, Masafumi

    2016-01-01

    Objective The Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster forced the evacuation of residents and led to many changes in the lifestyle of the evacuees. A comprehensive health check was implemented to support the prevention of lifestyle-related disease, and we analyzed changes in lipid metabolism before and after these disasters. Methods Subjects included Japanese men and women living near the Fukushima Daiichi nuclear power plant in Fukushima Prefecture. Annual health checkups, focusing on metabolic syndromes, were conducted for persons ≥40 years of age by the Heath Care Insures. Results A total of 27,486 subjects underwent a follow-up examination after the disaster, with a mean follow-up of 1.6 years. Following the disaster, the prevalence of hypo-high-density lipoprotein (HDL) cholesterolemia increased significantly from 6.0% to 7.2%. In the hypo-HDL cholesterolemia group, the body mass index (BMI), blood pressure, and LDL-C level increased significantly in men after the disaster. On the other hand, in the normal HDL-C level group, the BMI, blood pressure, glucose and lipid metabolism, and liver function were adversely affected. The decrease in HDL-C was significantly greater in evacuees than non-evacuees in the normal HDL-C level group. Furthermore, a multivariate logistic regression analysis showed that the evacuation was significantly associated with the incidence of hypo-HDL cholesterolemia. Conclusion This is the first study to evaluate how the evacuation affected the incidence of hypo-HDL cholesterolemia and led to an increase in cardiovascular disease. This information may be important in the follow-up and lifestyle change recommendations for evacuees. PMID:27477401

  19. Kinetic and thermodynamic analyses of spontaneous exchange between high-density lipoprotein-bound and lipid-free apolipoprotein A-I.

    PubMed

    Handa, Daisuke; Kimura, Hitoshi; Oka, Tatsuya; Takechi, Yuki; Okuhira, Keiichiro; Phillips, Michael C; Saito, Hiroyuki

    2015-02-01

    It is thought that apolipoprotein A-I (apoA-I) spontaneously exchanges between high-density lipoprotein (HDL)-bound and lipid-free states, which is relevant to the occurrence of preβ-HDL particles in plasma. To improve our understanding of the mechanistic basis for this phenomenon, we performed kinetic and thermodynamic analyses for apoA-I exchange between discoidal HDL-bound and lipid-free forms using fluorescence-labeled apoA-I variants. Gel filtration experiments demonstrated that addition of excess lipid-free apoA-I to discoidal HDL particles promotes exchange of apoA-I between HDL-associated and lipid-free pools without alteration of the steady-state HDL particle size. Kinetic analysis of time-dependent changes in NBD fluorescence upon the transition of NBD-labeled apoA-I from HDL-bound to lipid-free state indicates that the exchange kinetics are independent of the collision frequency between HDL-bound and lipid-free apoA-I, in which the lipid binding ability of apoA-I affects the rate of association of lipid-free apoA-I with the HDL particles and not the rate of dissociation of HDL-bound apoA-I. Thus, C-terminal truncations or mutations that reduce the lipid binding affinity of apoA-I strongly impair the transition of lipid-free apoA-I to the HDL-bound state. Thermodynamic analysis of the exchange kinetics demonstrated that the apoA-I exchange process is enthalpically unfavorable but entropically favorable. These results explain the thermodynamic basis of the spontaneous exchange reaction of apoA-I associated with HDL particles. The altered exchangeability of dysfunctional apoA-I would affect HDL particle rearrangement, leading to perturbed HDL metabolism. PMID:25564321

  20. 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

  1. Discordance of Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol Particle Versus Cholesterol Concentration for the Prediction of Cardiovascular Disease in Patients With Metabolic Syndrome and Diabetes Mellitus (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

    PubMed

    Tehrani, David M; Zhao, Yanglu; Blaha, Michael J; Mora, Samia; Mackey, Rachel H; Michos, Erin D; Budoff, Matthew J; Cromwell, William; Otvos, James D; Rosenblit, Paul D; Wong, Nathan D

    2016-06-15

    A stronger association for low-density lipoprotein particle (LDL-P) and high-density lipoprotein particle (HDL-P) versus cholesterol concentrations (LDL-C and HDL-C) in predicting coronary heart disease (CHD) has been noted. We evaluate the role of these factors and extent of particle-cholesterol discordance in those with diabetes mellitus (DM) and metabolic syndrome (MetS) for event prediction. In the Multi-Ethnic Study of Atherosclerosis, we examined discordance of LDL and HDL (defined as a subject's difference between baseline particle and cholesterol percentiles), LDL-C, LDL-P, HDL-C, and HDL-P in relation to incident CHD and cardiovascular disease (CVD) events in subjects with DM, MetS (without DM), or neither condition using Cox regression. Of the 6,417 subjects with 10-year follow-up, those with MetS (n = 1,596) and DM (n = 838) had significantly greater LDL and HDL discordance compared with those without these conditions. In discordance models, only LDL discordance (per SD) within the MetS group was positively associated with CHD events (adjusted hazard ratio [HR] = 1.22, 95% confidence interval [CI] 1.01 to 1.48, p <0.05). In models with individual particle/cholesterol variables (per SD), within the DM group, HDL-P was inversely (HR 0.71, 95% CI 0.52 to 0.96, p <0.05) and LDL-C positively (HR 1.47, 95% CI 1.07 to 2.03, p <0.05) associated with CHD. In those with MetS, only LDL-P was positively associated with CHD (HR 1.34, 95% CI 1.00 to 1.78, p <0.05). Similar findings were also seen for CVD. LDL discordance and higher LDL-P in MetS, and higher LDL-C and lower HDL-P in DM, predict CHD and CVD, supporting a potential role for examining lipoprotein particles and discordances in those with MetS and DM. PMID:27156827

  2. [Lipoproteins].

    PubMed

    Manso, C

    1991-02-01

    The problem of plasma lipid transport between several organs is reviewed. The constitution of plasma lipoproteins is described as well as the importance of enzymes related to them. The problem of lipid transfer proteins is discussed. The origin of atherosclerosis is analyzed in relation to abnormalities of cholesterol metabolism, of its transport and of free radicals generation. PMID:2059473

  3. 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.

  4. A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein.

    PubMed

    Gu, Xiaodong; Wu, Zhiping; Huang, Ying; Wagner, Matthew A; Baleanu-Gogonea, Camelia; Mehl, Ryan A; Buffa, Jennifer A; DiDonato, Anthony J; Hazen, Leah B; Fox, Paul L; Gogonea, Valentin; Parks, John S; DiDonato, Joseph A; Hazen, Stanley L

    2016-03-18

    The interaction of lecithin-cholesterol acyltransferase (LCAT) with apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) maturation. We previously identified a highly solvent-exposed apoA-I loop domain (Leu(159)-Leu(170)) in nascent HDL, the so-called "solar flare" (SF) region, and proposed that it serves as an LCAT docking site (Wu, Z., Wagner, M. A., Zheng, L., Parks, J. S., Shy, J. M., 3rd, Smith, J. D., Gogonea, V., and Hazen, S. L. (2007) Nat. Struct. Mol. Biol. 14, 861-868). The stability and role of the SF domain of apoA-I in supporting HDL binding and activation of LCAT are debated. Here we show by site-directed mutagenesis that multiple residues within the SF region (Pro(165), Tyr(166), Ser(167), and Asp(168)) of apoA-I are critical for both LCAT binding to HDL and LCAT catalytic efficiency. The critical role for possible hydrogen bond interaction at apoA-I Tyr(166) was further supported using reconstituted HDL generated from apoA-I mutants (Tyr(166) → Glu or Asn), which showed preservation in both LCAT binding affinity and catalytic efficiency. Moreover, the in vivo functional significance of NO2-Tyr(166)-apoA-I, a specific post-translational modification on apoA-I that is abundant within human atherosclerotic plaque, was further investigated by using the recombinant protein generated from E. coli containing a mutated orthogonal tRNA synthetase/tRNACUA pair enabling site-specific insertion of the unnatural amino acid into apoA-I. NO2-Tyr(166)-apoA-I, after subcutaneous injection into hLCAT(Tg/Tg), apoA-I(-/-) mice, showed impaired LCAT activation in vivo, with significant reduction in HDL cholesteryl ester formation. The present results thus identify multiple structural features within the solvent-exposed SF region of apoA-I of nascent HDL essential for optimal LCAT binding and catalytic efficiency. PMID:26797122

  5. High-density lipoprotein-mediated anti-atherosclerotic and endothelial-protective effects: a potential novel therapeutic target in cardiovascular disease.

    PubMed

    Besler, Christian; Heinrich, Kathrin; Riwanto, Meliana; Lüscher, Thomas F; Landmesser, Ulf

    2010-05-01

    Reduced levels of high-density lipoprotein cholesterol (HDL) are associated with a substantially increased risk of coronary disease and cardiovascular events. Furthermore, numerous studies have suggested that HDL may exert several potentially important antiatherosclerotic and endothelial-protective effects. In particular, the promotion of reverse cholesterol transport, i.e. cholesterol efflux from lipid-loaded macrophages in atherosclerotic lesions and the subsequent cholesterol transport back to the liver, has been proposed as an anti-atherogenic effect of HDL that may promote regression of atherosclerotic lesions. Moreover, endothelial dysfunction is thought to play a critical role in development and progression of atherosclerosis and several recent studies have suggested that HDL exerts direct endothelial-protective effects, such as stimulation of endothelial production of the anti-atherogenic molecule nitric oxide, anti-oxidant, anti-inflammatory and anti-thrombotic effects. Furthermore, it has been observed that HDL may stimulate endothelial repair processes, involving mobilisation and promotion of endothelial repair capacity of endothelial progenitor cells. The relative significance of these different potential anti-atherosclerotic effects of HDL remains still unclear at present. Importantly, at the same time it has been recognized that the vascular effects of HDL may be variable, i.e. the capacity of HDL to stimulate macrophage cholesterol efflux and endothelial-protective effects may be altered in patients with inflammatory or cardiovascular disease. The further characterisation of underlying mechanisms and the identification of the clinical relevance of this "HDL dysfunction" are currently an active field of research. HDL-targeted treatment strategies are at present intensely evaluated and may lead to increased HDL plasma levels and/or HDL-stimulated anti-atherosclerotic effects. The cardiovascular protection provided by such approaches may likely depend

  6. High-Density Lipoprotein-Associated miR-223 Is Altered after Diet-Induced Weight Loss in Overweight and Obese Males

    PubMed Central

    Tabet, Fatiha; Cuesta Torres, Luisa F.; Ong, Kwok Leung; Shrestha, Sudichhya; Choteau, Sébastien A.; Barter, Philip J.; Clifton, Peter; Rye, Kerry-Anne

    2016-01-01

    Background and Aims microRNAs (miRNAs) are small, endogenous non-coding RNAs that regulate metabolic processes, including obesity. The levels of circulating miRNAs are affected by metabolic changes in obesity, as well as in diet-induced weight loss. Circulating miRNAs are transported by high-density lipoproteins (HDL) but the regulation of HDL-associated miRNAs after diet-induced weight loss has not been studied. We aim to determine if HDL-associated miR-16, miR-17, miR-126, miR-222 and miR-223 levels are altered by diet-induced weight loss in overweight and obese males. Methods HDL were isolated from 47 subjects following 12 weeks weight loss comparing a high protein diet (HP, 30% of energy) with a normal protein diet (NP, 20% of energy). HDL-associated miRNAs (miR-16, miR-17, miR-126, miR-222 and miR-223) at baseline and after 12 weeks of weight loss were quantified by TaqMan miRNA assays. HDL particle sizes were determined by non-denaturing polyacrylamide gradient gel electrophoresis. Serum concentrations of human HDL constituents were measured immunoturbidometrically or enzymatically. Results miR-16, miR-17, miR-126, miR-222 and miR-223 were present on HDL from overweight and obese subjects at baseline and after 12 weeks of the HP and NP weight loss diets. The HP diet induced a significant decrease in HDL-associated miR-223 levels (p = 0.015), which positively correlated with changes in body weight (r = 0.488, p = 0.032). Changes in miR-223 levels were not associated to changes in HDL composition or size. Conclusion HDL-associated miR-223 levels are significantly decreased after HP diet-induced weight loss in overweight and obese males. This is the first study reporting changes in HDL-associated miRNA levels with diet-induced weight loss. PMID:26962854

  7. High-density lipoprotein-cholesterol levels and risk of cancer in HIV-infected subjects: Data from the ICONA Foundation Cohort.

    PubMed

    Squillace, Nicola; Galli, Laura; Bandera, Alessandra; Castagna, Antonella; Madeddu, Giordano; Caramello, Pietro; Antinori, Andrea; Cattelan, Annamaria; Maggiolo, Franco; Cingolani, Antonella; Gori, Andrea; Monforte, Antonella d'Arminio

    2016-09-01

    Investigation of the relationship between high-density lipoprotein-cholesterol (HDL-c) and the risk of developing cancer in a prospective cohort of human immunodeficiency virus (HIV)-infected patients.The Italian Cohort of Antiretroviral-naïve Patients Foundation Cohort is an Italian multicenter observational study recruiting HIV-positive patients while still antiretroviral treatment-naïve, regardless of the reason since 1997.Patients with at least 1 HDL-c value per year since enrollment and one such value before antiretroviral treatment initiation were included. HDL-c values were categorized as either low (<39 mg/dL in males or <49 mg/dL in females) or normal. Cancer diagnoses were classified as AIDS-defining malignancies (ADMs) or non-AIDS-defining malignancies (NADMs). Kaplan-Meier curves and Cox proportional-hazards regression models were used.Among 4897 patients (13,440 person-years of follow-up [PYFU]), 104 diagnoses of cancer were observed (56 ADMs, 48 NADMs) for an overall incidence rate of 7.7 (95% confidence interval [CI] 6.3-9.2) per 1000 PYFU.Low HDL-c values at enrollment were associated with higher risk both of cancer (crude hazard ratio [HR] 1.72, 95% CI 1.16-2.56, P = 0.007) and of NADM (crude HR 2.50, 95% CI 1.35-4.76, P = 0.003). Multivariate analysis showed that the risk of cancer diagnosis was higher in patients with low HDL-c values (adjusted HR [AHR] 1.87, 95% CI 1.18-2.95, P = 0.007) in older patients, those patients more recently enrolled, and in those with low current cluster of differentiation 4+ levels, and/or high current HIV-ribonucleic acid.The multivariate model confirmed an association between HDL-c (AHR 2.61, 95% CI 1.40-4.89, P = 0.003) and risk of NADM.Low HDL-c is an independent predictor of cancer in HIV-1-infected subjects. PMID:27603338

  8. Frequency of Attainment of Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol Goals in Cardiovascular Clinical Practice (from the National Cardiovascular Data Registry PINNACLE Registry).

    PubMed

    Spinler, Sarah A; Cziraky, Mark J; Willey, Vincent J; Tang, Fengming; Maddox, Thomas M; Thomas, Tyan; Dueñas, Gladys G; Virani, Salim S

    2015-08-15

    Studies have found that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior marker for coronary heart disease compared to low-density lipoprotein cholesterol (LDL-C). Little is known about achievement of non-HDL-C goals outside clinical trials. Within a population of 146,064 patients with dyslipidemia in the PINNACLE Registry and a subgroup of 36,188 patients with diabetes mellitus (DM), we examined the proportion of patients and patient characteristics associated with having LDL-C, non-HDL-C, and both LDL-C and non-HDL-C levels at National Cholesterol Education Program goals. LDL-C, non-HDL-C, and both LDL-C and non-HDL-C goals in the overall cohort were achieved by 73%, 73.4%, and 68.9% patients, respectively. Significant predictors of meeting all 3 goals were age, male gender, statin, nonstatin, and combined statin plus nonstatin use. Patients with co-morbidities of hypertension, previous stroke or transient ischemic attack, peripheral arterial disease, myocardial infarction, and smoking were less likely to have LDL-C, non-HDL-C, and both LDL-C and non-HDL-C levels at National Cholesterol Education Program goal. In the overall cohort, patients with DM were less likely to meet non-HDL-C and both LDL-C and non-HDL-C goals. In the subgroup of patients with DM, predictors of meeting lipid goals were similar to the overall cohort. In conclusion, these data suggest contemporary treatment patterns by cardiologists successfully achieve lipid goals in most patients. Younger, female patients and those with atherosclerotic cardiovascular disease and risk factors, such as hypertension and DM, are less likely to achieve goals and may require more careful follow-up after statin initiation. Both LDL-C and non-HDL-C goals are achieved in <70% of patients, suggesting room for improvement if a goal-targeted individualized strategy is adopted. PMID:26089010

  9. A Unique Case of Aortic Thrombosis With Elevated Lipoprotein(a).

    PubMed

    Ostertag-Hill, Claire A; Titus, Jessica M; Skeik, Nedaa

    2016-05-01

    Aortic thrombosis is a rare condition that can be caused by atherosclerosis, aneurysms, thrombophilia, vasculitis, trauma, and malignancy. Symptoms vary based on thrombus size and site of embolization. It can lead to devastating complications including acute limb ischemia, myocardial infarction, stroke, and other target organ ischemia. Diagnosis is based on clinical presentation, imaging findings, and relevant laboratory work-up. Although not well defined, management for aortic thrombosis includes surgical intervention, such as thromboembolectomy, and conservative measures, such as anticoagulation. Here, we present a unique case of aortic thrombosis causing acute lower limb ischemia with elevated lipoprotein(a) and other comorbidities. Based on our literature review, our article is the first to establish the connection between elevated lipoprotein(a) and aortic thrombosis in the nonaneurysmal aorta. PMID:27075991

  10. Cholesterol efflux to high-density lipoproteins and apolipoprotein A-I phosphatidylcholine complexes is inhibited by ethanol: role of apolipoprotein structure and cooperative interaction of phosphatidylcholine and cholesterol.

    PubMed

    Avdulov, N A; Chochina, S V; Igbavboa, U; Wood, W G

    2000-08-29

    There is a substantial body of evidence showing that moderate alcohol consumption is associated with a reduced risk of cardiovascular morbidity and mortality. One of the factors thought to contribute to this reduction in risk is an increase in the level of high-density lipoproteins (HDL) correlated with alcohol consumption. However, HDL levels are elevated in heavy drinkers, but their risk of vascular disease is greater compared with that of moderate drinkers. Ethanol at concentrations observed in heavy drinkers and alcoholics may directly act on HDL and apolipoproteins and in turn modify cholesterol efflux. In this paper, we show that ethanol significantly inhibited cholesterol efflux from fibroblasts to HDL and to apolipoprotein A-I (apoA-I) complexed with phosphatidylcholine (PC). Ethanol significantly inhibited binding of PC to apoA-I, inhibited incorporation of cholesterol only when apoA-I contained PC, and did not alter incorporation of cholesterol into HDL. ApoA-I structure was altered by ethanol as monitored by steady-state fluorescence polarization of tryptophan residues. The absence of ethanol effects on incorporation of cholesterol into HDL versus inhibition of cholesterol incorporation into the apoA-I-PC complex suggests that the effects of ethanol on cholesterol efflux mediated by HDL involve interaction with the cell surface and that efflux mediated by the apoA-I-PC complex is a combination of aqueous diffusion and contact with the cell surface. In addition, effects of ethanol on apoA-I suggest that pre-beta-HDL or lipid-free apoA-I may be more perturbed by ethanol than mature HDL, and such effects may be pathophysiological with respect to the process of reverse cholesterol transport in heavy drinkers and alcoholics. PMID:10956052

  11. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

    PubMed Central

    Tardif, Jean-Claude; Ballantyne, Christie M.; Barter, Philip; Dasseux, Jean-Louis; Fayad, Zahi A.; Guertin, Marie-Claude; Kastelein, John J. P.; Keyserling, Constance; Klepp, Heather; Koenig, Wolfgang; L'Allier, Philippe L.; Lespérance, Jacques; Lüscher, Thomas F.; Paolini, John F.; Tawakol, Ahmed; Waters, David D.; Pfeffer, M.; Brown, V.; Rouleau, J.; Watkins, P.; Wei, L.J.; Gosselin, G.; Chayer, C.; Lanthier, S.; Pelletier, G.B.; Racine, N.; Agarwal, H.; Brilakis, E.; Cannon, L.; Carrié, D.; Corbelli, J.; Coste, P.; de Winter, R.; Diaz, A.; Eisenberg, S.; Ennis, B.; Fajadet, J.; Fam, N.; Fortuin, D.; Gessler, C.; Grines, C.; Guerra, D.; Gum, H.; Haldis, T.; Heestermans, T.; Herrman, J.P.; Huynh, T.; Kedhi, E.; Koren, M.; Kouz, S.; Krolick, M.; Kumkumian, G.; Lavi, S.; Li, R.J.; Masud, ARZ; McAlhany, C.; McGrew, F.A.; O'Shaughnessy, C.; Oude Ophuis, A.J.M.; Parr, K.; Penny, W.; Pesant, Y.; Post, H.; Robinson, S.; Rodes-Cabau, J.; Roy, A.; Schulman, S.; Spence, F.; Stouffer, G.; Stys, T.; Sussex, B.; Tahirkheli, N.; Tardif, J-C.; Grégoire, J.; ten Berg, J.; van Boven, A.J.; von Birgelen, C.; Weinstein, D.

    2014-01-01

    Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2–5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary

  12. Monocyte subset distribution in patients with stable atherosclerosis and elevated levels of lipoprotein(a)

    PubMed Central

    Krychtiuk, Konstantin A.; Kastl, Stefan P.; Hofbauer, Sebastian L.; Wonnerth, Anna; Goliasch, Georg; Ozsvar-Kozma, Maria; Katsaros, Katharina M.; Maurer, Gerald; Huber, Kurt; Dostal, Elisabeth; Binder, Christoph J.; Pfaffenberger, Stefan; Oravec, Stanislav; Wojta, Johann; Speidl, Walter S.

    2015-01-01

    Background Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. Objective The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100–containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. Methods We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16−), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. Results In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. Conclusions In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease. PMID:26228671

  13. High-density lipoprotein cholesterol esterification and transfer rates to lighter density lipoproteins mediated by cholesteryl ester transfer protein in the fasting and postprandial periods are not altered in type 1 diabetes mellitus.

    PubMed

    Medina; Nunes; Carrilho; Shimabukuru; Lottenberg; Lottenberg; McPherson; Krauss; Quintão

    2000-10-01

    Background: Diabetes mellitus is associated with atherosclerosis that has, in part, been ascribed to abnormalities in the reverse cholesterol transport system. Methods: We determined, in the fasting and post-alimentary periods, rates of HDL cholesterol esterification and transfer to apoB-containing lipoproteins, cholesteryl ester transfer protein (CETP) concentration, and apoB lipoprotein size in 10 type 1 diabetics and 10 well-matched controls. Autologous HDL was labeled with [14C]cholesterol and incubated at 37 degrees C during a period of 30 min for measurement of the cholesterol esterification rate (CER), as well as for 24 h for measurement of the endogenous HDL [14C]cholesteryl ester ([14C]CE) transfer rate to apoB-containing lipoproteins after 2- and 4-h incubations with the subject's own plasma. Exogenous cholesteryl ester transfer activity (CETA) was estimated by incubation of the participant's plasma (CETP source) with [14C]CE-HDL and VLDL from a pool of plasma donors. ApoB lipoprotein size was determined using non-denaturing polyacrylamide gradient gel electrophoresis of whole plasma. Results: Contrary to previous studies, we showed that even not well-controlled type 1 diabetics did not differ from lipid-matched, non-diabetic subjects in HDL-[14C]cholesterol esterification rate, transfer rates, or CETP concentration. CETP concentration correlates with the exogenous method of [14C]CE transfer and with the endogenous method only when the latter is corrected for plasma triacylglycerol (TG) concentration. In addition, during the postprandial phase, diabetic patients' VLDL are smaller and IDL size increases less than in controls. Conclusion: In type 1 diabetes mellitus, CETA is not altered when the plasma levels of donor and/or acceptor lipoproteins are within the normal range. PMID:11025251

  14. Body Fatness and Risk for Elevated Blood Pressure, Total Cholesterol, and Serum Lipoprotein Ratios in Children and Adolescents.

    ERIC Educational Resources Information Center

    Williams, Daniel P.; And Others

    1992-01-01

    Examines the relationship between body fat percent and risk for elevated blood pressure, serum total cholesterol, and serum lipoprotein ratios in 1,230 African-American and 2,090 white 5-18 year olds (1,667 males and 1,653 females). Results support body fatness standards in children and adolescents as cardiovascular risk factors. (SLD)

  15. The V227A polymorphism at the PPARA locus is associated with serum lipid concentrations and modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentrations in Chinese women.

    PubMed

    Chan, Edmund; Tan, Chuen Seng; Deurenberg-Yap, Mabel; Chia, Kee Seng; Chew, Suok Kai; Tai, E Shyong

    2006-08-01

    Peroxisome proliferators activated receptor alpha (PPARalpha) regulates the transcription of several proteins involved in human lipoprotein metabolism. We screened the PPARA locus for polymorphisms in 20 unrelated subjects from each of three ethnic groups (Chinese, Malays and Asian Indians). Only the V227A polymorphism was observed. We genotyped 4248 subjects (2899 Chinese, 761 Malay and 588 Asian Indians) and found allele frequencies for the A227 allele of 0.04 in Chinese, 0.006 in Malays and 0.003 in Asian Indians. We examined the associations between this polymorphism and serum lipid concentrations in Chinese. In women, but not in men, the presence of the A227 allele was associated with lower serum concentrations of total cholesterol [5.38mmol/l (95%CI: 5.22-5.54) versus 5.21mmol/l (95%CI: 4.99-5.43), p=0.047] and triglycerides [1.19mmol/l (95%CI: 1.10-1.28) versus 1.09mmol/l (95%CI: 0.98-1.21), p=0.048]. We also found that the V227A polymorphism modulates the association between dietary polyunsaturated fatty acid intake and serum high density lipoprotein concentration (p-value for interaction=0.049). Our findings implicate PPARalpha in the lipid lowering associated with diets high in PUFA and suggests that genetic variation at the PPARA locus may determine the lipid response to changes in PUFA intake. PMID:16288935

  16. Influence of cholesteryl ester transfer protein, peroxisome proliferator-activated receptor alpha, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study.

    PubMed

    Do, Hong Quang; Nazih, Hassan; Luc, Gérald; Arveiler, Dominique; Ferrières, Jean; Evans, Alun; Amouyel, Philippe; Cambien, François; Ducimetière, Pierre; Bard, Jean-Marie

    2009-03-01

    The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (< or = 28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (> or = 73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the epsilon2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively. PMID:19217440

  17. Relationships between high-density lipoprotein cholesterol and depressive symptoms: Findings of the Korean National Health and Nutrition Examination Survey (KNHANES).

    PubMed

    Shin, Hee-Young; Kang, Gaeun; Kang, Hee-Ju; Kim, Sung-Wan; Shin, Il-Seon; Yoon, Jin-Sang; Kim, Jae-Min

    2016-07-30

    Although serum cholesterol has been associated with late-life depression, few studies on the associations between lipids and depression among middle-aged adults have been performed. This study examined associations between serum lipid levels and depressive symptoms in Korean middle-aged adults. We used data from 8207 participants aged 40-64 years who completed a questionnaire about their experience of depressive symptoms over the last year as part of the 2010-2012 Korean National Health and Nutrition Examination Survey. Higher HDL-C levels were significantly associated with an elevated risk of depressive symptoms (OR=1.32; 95% CI=1.09-1.60) after adjusting for other covariates. PMID:27179182

  18. Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial

    PubMed Central

    Tricoci, Pierluigi; D’Andrea, Denise M; Gurbel, Paul A; Yao, Zhenling; Cuchel, Marina; Winston, Brion; Schott, Robert; Weiss, Robert; Blazing, Michael A; Cannon, Louis; Bailey, Alison; Angiolillo, Dominick J; Gille, Andreas; Shear, Charles L; Wright, Samuel D; Alexander, John H

    2015-01-01

    Background CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease. Methods and Results Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (Tmax≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001). Conclusions CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation. Clinical Trial Registration URL: http

  19. High Density Lipoprotein Structural Changes and Drug Response in Lipidomic Profiles following the Long-Term Fenofibrate Therapy in the FIELD Substudy

    PubMed Central

    Yetukuri, Laxman; Maranghi, Marianna; Hiukka, Anne; Nygren, Heli; Kaski, Samuel; Taskinen, Marja-Riitta; Vattulainen, Ilpo; Jauhiainen, Matti; Orešič, Matej

    2011-01-01

    In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment. PMID:21887280

  20. Phospholipid transfer protein is expressed in cerebrovascular endothelial cells and involved in high density lipoprotein biogenesis and remodeling at the blood-brain barrier.

    PubMed

    Chirackal Manavalan, Anil Paul; Kober, Alexandra; Metso, Jari; Lang, Ingrid; Becker, Tatjana; Hasslitzer, Karin; Zandl, Martina; Fanaee-Danesh, Elham; Pippal, Jyotsna Brijesh; Sachdev, Vinay; Kratky, Dagmar; Stefulj, Jasminka; Jauhiainen, Matti; Panzenboeck, Ute

    2014-02-21

    Phospholipid transfer protein (PLTP) is a key protein involved in biogenesis and remodeling of plasma HDL. Several neuroprotective properties have been ascribed to HDL. We reported earlier that liver X receptor (LXR) activation promotes cellular cholesterol efflux and formation of HDL-like particles in an established in vitro model of the blood-brain barrier (BBB) consisting of primary porcine brain capillary endothelial cells (pBCEC). Here, we report PLTP synthesis, regulation, and its key role in HDL metabolism at the BBB. We demonstrate that PLTP is highly expressed and secreted by pBCEC. In a polarized in vitro model mimicking the BBB, pBCEC secreted phospholipid-transfer active PLTP preferentially to the basolateral ("brain parenchymal") compartment. PLTP expression levels and phospholipid transfer activity were enhanced (up to 2.5-fold) by LXR activation using 24(S)-hydroxycholesterol (a cerebral cholesterol metabolite) or TO901317 (a synthetic LXR agonist). TO901317 administration elevated PLTP activity in BCEC from C57/BL6 mice. Preincubation of HDL3 with human plasma-derived active PLTP resulted in the formation of smaller and larger HDL particles and enhanced the capacity of the generated HDL particles to remove cholesterol from pBCEC by up to 3-fold. Pre-β-HDL, detected by two-dimensional crossed immunoelectrophoresis, was generated from HDL3 in pBCEC-derived supernatants, and their generation was markedly enhanced (1.9-fold) upon LXR activation. Furthermore, RNA interference-mediated PLTP silencing (up to 75%) reduced both apoA-I-dependent (67%) and HDL3-dependent (30%) cholesterol efflux from pBCEC. Based on these findings, we propose that PLTP is actively involved in lipid transfer, cholesterol efflux, HDL genesis, and remodeling at the BBB. PMID:24369175

  1. Triglyceride High-Density Lipoprotein Ratios Predict Glycemia-Lowering in Response to Insulin Sensitizing Drugs in Type 2 Diabetes: A Post Hoc Analysis of the BARI 2D

    PubMed Central

    Zonszein, Joel; Lombardero, Manuel; Ismail-Beigi, Faramarz; Palumbo, Pasquale; Foucher, Suzy; Groenewoud, Yolanda; Cushing, Gary; Wajchenberg, Bernardo; Genuth, Saul; BARI 2D Study Group

    2015-01-01

    Glycemic management is central in prevention of small vessel and cardiovascular complications in type 2 diabetes. With the plethora of newer medications and recommendations for a patient centered approach, more information is necessary to match the proper drug to each patient. We showed that BARI 2D, a five-year trial designed to compare two different glycemic treatment strategies, was suitable for assessing different responses according to different phenotypic characteristics. Treatment with insulin sensitizing medications such as thiazolidinediones and metformin was more effective in improving glycemic control, particularly in the more insulin resistant patient, when compared to the insulin provision strategy using insulin and or sulfonylureas. Triglyceride and high density lipoprotein ratio (TG/HDL-cholesterol ratio) was found to be a readily available and practical biomarker that helps to identify the insulin resistant patient. These results support the concept that not all medications for glycemic control work the same in all patients. Thus, tailored therapy can be done using phenotypic characteristics rather than a “one-size-fits-all approach.” PMID:26106623

  2. ATP-Binding Cassette Transporter G1 and High-Density Lipoprotein Promote Endothelial NO Synthesis Through a Decrease in the Interaction of Caveolin-1 and Endothelial NO Synthase

    PubMed Central

    Terasaka, Naoki; Westerterp, Marit; Koetsveld, Joris; Fernández-Hernando, Carlos; Yvan-Charvet, Laurent; Wang, Nan; Sessa, William C.; Tall, Alan R.

    2016-01-01

    Objective To investigate whether cholesterol efflux to high-density lipoprotein (HDL) via ATP-binding cassette transporter G1 (ABCG1) modulates the interaction of caveolin (Cav) 1 and endothelial NO synthase (eNOS). Methods and Results ABCG1 promotes cholesterol and 7-oxysterol efflux from endothelial cells (ECs) to HDL. It was previously reported that ABCG1 protects against dietary cholesterol-induced endothelial dysfunction by promoting the efflux of 7-oxysterols to HDL. Increased cholesterol loading in ECs is known to cause an inhibitory interaction between Cav-1 and eNOS and impaired NO release. In human aortic ECs, free cholesterol loading promoted the interaction of Cav-1 with eNOS, reducing eNOS activity. These effects of cholesterol loading were reversed by HDL in an ABCG1-dependent manner. HDL also reversed the inhibition of eNOS by cholesterol loading in murine lung ECs, but this effect of HDL was abolished in Cav-1–deficient murine lung ECs. Increased interaction of Cav-1 with eNOS was also detected in aortic homogenates of high-cholesterol diet–fed Abcg1−/− mice, paralleling a decrease in eNOS activity and impaired endothelial function. Conclusion The promotion of cholesterol efflux via ABCG1 results in a reduced inhibitory interaction of eNOS with Cav-1. PMID:20798376

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

    PubMed

    Jin, Ya; Bu, Shujie; Zhang, Jun; Yuan, Qi; Manabe, Takashi; Tan, Wen

    2014-07-01

    A human plasma sample was subjected to nondenaturing micro 2DE and a gel area (5 mm × 18 mm) that includes high-density lipoprotein (HDL) was cut into 1 mm × 1 mm squares, then the proteins in the 90 gel pieces were analyzed by quantitative LC-MS/MS. Grid-cutting of the gel was employed to; (i) ensure the total analysis of the proteins in the area, (ii) standardize the conditions of analysis by LC-MS/MS, (iii) reconstruct the protein distribution patterns from the quantity data. Totally 154 proteins were assigned in the 90 gel pieces and the quantity distribution of each was reconstructed as a color density pattern (a native protein map). The map of apolipoprotein (Apo) A-I showed a wide apparent mass distribution characteristic to HDL and was compared with the maps of the other 153 proteins. Eleven proteins showed maps of wide distribution that overlapped with the map of Apo A-I, and all have been reported to be the components of HDL. Further, seven minor proteins associated with HDL were detected at the gel positions of high Apo A-I quantity. These results for the first time visualized the localization of HDL apolipoproteins on a nondenaturing 2DE gel and strongly suggested their interactions. PMID:24668886

  4. Effect of lithocholic acid feeding on plasma lipoproteins and binding of radioiodinated human lipoproteins to hepatic membranes in rats.

    PubMed

    Loo, G; Kessie, G; Berlin, E; Nair, P P

    1992-06-01

    1. Male Sprague-Dawley rats fed diets containing 0.25% lithocholic acid for 6 weeks exhibited elevated serum cholesterol. 2. The rats were fed diets containing 5 or 20% fat with and without the lithocholate and/or oxytetracycline-HCl. 3. The cholesterol elevation was associated with high density lipoprotein (HDL) and not very low density lipoprotein (VLDL) or low density lipoprotein (LDL). 4. Specific binding of human [125I]HDL to hepatic membranes was lowered in lithocholate-fed rats, but binding of human [125I]LDL to these membranes was not affected. PMID:1354585

  5. Expression of recombinant human serum amyloid A in mammalian cells and demonstration of the region necessary for high-density lipoprotein binding and amyloid fibril formation by site-directed mutagenesis.

    PubMed Central

    Patel, H; Bramall, J; Waters, H; De Beer, M C; Woo, P

    1996-01-01

    Site-directed mutagenesis of the acute-phase human serum amyloid A (SAA1 alpha) protein was used to evaluate the importance of the N-terminal amino acid residues, namely RSFFSFLGEAF The full-length cDNA clone of SAA1 alpha (pA1.mod.) was used to create two mutations, namely Gly-8 to Asp-8 and an 11 amino acid truncation between Arg-1 and Phe-11 respectively. Wild-type and mutant cDNAs were expressed in Chinese hamster ovary (CHO) cells under the control of the human cytomegalovirus promoter, which resulted in the secretion of the processed proteins into the culture media. Wild-type recombinant human SAA (rSAA) protein was shown to have pI values of 6.0 and 6.4, similar to the human SAA isoform SAA1 alpha and SAA1 alpha desArg found in acute-phase plasma. N-terminal sequencing of 56 residues confirmed its identity with human SAA1 alpha. The total yield of wild-type rSAA measured by ELISA was between 3.5 and 30 mg/l. The two mutations resulted in reduced expression levels of the mutant SAA proteins (3-10 mg/l). Further measurements of rSAA concentration in lipid fractions of culture medium collected at a density of 1.21 g/ml (high-density liporotein; HDL) and 1.063-1.18 g/ml (very-low-density lipoprotein/low-density lipoprotein; VLDL/LDL) showed that 76% of the wild-type protein was found in the HDL fraction and the remaining 24% in the infranatant non-lipid fraction. In contrast the relative concentration of mutant rSAA in HDL and infranatant fractions was reversed. This is consistent with the previously proposed involvement of the 11 amino acid peptide in anchoring. SAA protein on to HDL3 [Turnell, Sarra, Glover, Baum, Caspi, Baltz and Pepys (1986) Mol. Biol. Med. 3, 387-407]. Wild-type rSAA protein was shown to from amyloid fibrils in vitro under acidic conditions as shown by electron microscopy, and stained positive with Congo Red and exhibited apple-green birefringence when viewed under polarized light. Under the same conditions mutSAA(G8D) and mutSAA delta 1

  6. A Cross-Sectional Study Demonstrating Increased Serum Amyloid A Related Inflammation in High-Density Lipoproteins from Subjects with Type 1 Diabetes Mellitus and How This Association Was Augmented by Poor Glycaemic Control

    PubMed Central

    McEneny, Jane; Daniels, Jane-Ann; McGowan, Anne; Gunness, Anjuli; Moore, Kevin; Stevenson, Michael; Young, Ian S.; Gibney, James

    2015-01-01

    Inflammatory atherosclerosis is increased in subjects with type 1 diabetes mellitus (T1DM). Normally high-density lipoproteins (HDL) protect against atherosclerosis; however, in the presence of serum amyloid-A- (SAA-) related inflammation this property may be reduced. Fasting blood was obtained from fifty subjects with T1DM, together with fifty age, gender and BMI matched control subjects. HDL was subfractionated into HDL2 and HDL3 by rapid ultracentrifugation. Serum-hsCRP and serum-, HDL2-, and HDL3-SAA were measured by ELISAs. Compared to control subjects, SAA was increased in T1DM subjects, nonsignificantly in serum (P = 0.088), and significantly in HDL2(P = 0.003) and HDL3(P = 0.005). When the T1DM group were separated according to mean HbA1c (8.34%), serum-SAA and HDL3-SAA levels were higher in the T1DM subjects with HbA1c ≥ 8.34%, compared to when HbA1c was <8.34% (P < 0.05). Furthermore, regression analysis illustrated, that for every 1%-unit increase in HbA1c, SAA increased by 20% and 23% in HDL2 and HDL3, respectively, independent of BMI. HsCRP did not differ between groups (P > 0.05). This cross-sectional study demonstrated increased SAA-related inflammation in subjects with T1DM that was augmented by poor glycaemic control. We suggest that SAA is a useful inflammatory biomarker in T1DM, which may contribute to their increased atherosclerosis risk. PMID:26557720

  7. Involvement of the Ca(2+)-dependent phosphorylation of a 20 kDa protein in the proliferative effect of high-density lipoproteins (subclass 3) on the adenocarcinoma cell line A549.

    PubMed Central

    Tazi, K A; Bonnafous, M; Favre, G; Soula, G; Le Gaillard, F

    1995-01-01

    Previous studies from our laboratory demonstrated that high-density lipoproteins (subclass 3; HDL3) bind to sites specific for apolipoprotein AI on the human adenocarcinoma cell line A549 and that HDL3 binding promotes a mitogenic effect [Favre, Tazi, Le Gaillard, Bennis, Hachem and Soula (1993) J. Lipid Res. 34, 1093-1106]. In the present study, we have examined the cell proteins that showed modified phosphorylation after binding of HDL3 to specific sites, and the roles of Ca2+ and protein kinase C. Native HDL3 (but not tetranitromethane-modified HDL3) and Ca2+ ionophore A23187 strongly enhanced the phosphorylation of a 20 kDa protein (x 3.6) and, to a lower extent, the phosphorylation of 24 and 28 kDa proteins (x 2.2 and 2.6 respectively). The two effectors were equally able to stimulate cell growth. Down-regulation of protein kinase C by a 24 h incubation of cells with phorbol myristate acetate prevented the effects of HDL3 on the phosphorylation of 24 and 28 kDa proteins. However, the extent of phosphorylation of the 20 kDa protein was not affected. In contrast, activation of protein kinase C by a short incubation with phorbol myristate acetate resulted in inhibition of proliferation and an increase in 24 and 28 kDa (but not 20 kDa) protein phosphorylation. These results suggest that HDL3 putative receptors exert their proliferative effect on A549 cells through activation of a Ca(2+)-dependent protein kinase. This kinase activity is not modulated by phorbol ester and thus may be a calmodulin kinase or an isoenzyme of protein kinase C that is independent of phorbol ester. It allows a subsequent 20 kDa protein to be phosphorylated. Images Figure 1 Figure 2 Figure 3 PMID:7733897

  8. Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial

    PubMed Central

    Eppinga, Ruben N.; Hartman, Minke H. T.; van Veldhuisen, Dirk J.; Lexis, Chris P. H.; Connelly, Margery A.; Lipsic, Erik; van der Horst, Iwan C. C.; van der Harst, Pim; Dullaart, Robin P. F.

    2016-01-01

    Objective Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI. Methods 371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging. Results Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001). Conclusion LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size. PMID:26808474

  9. High-density lipoprotein of patients with breast cancer complicated with type 2 diabetes mellitus promotes cancer cells adhesion to vascular endothelium via ICAM-1 and VCAM-1 upregulation.

    PubMed

    Huang, Xiaoqin; He, Dan; Ming, Jia; He, Yubin; Zhou, Champion; Ren, Hui; He, Xin; Wang, Chenguang; Jin, Jingru; Ji, Liang; Willard, Belinda; Pan, Bing; Zheng, Lemin

    2016-02-01

    Adhesion of disseminating tumor cells to vascular endothelium is a pivotal starting point in the metastasis cascade. We have shown previously that diabetic high-density lipoprotein (HDL) has the capability of promoting breast cancer metastasis, and this report summarizes our more recent work studying the role of abnormal HDL in facilitating the adhesion of the circulating tumor cells to the endothelium. This is an initiating step in breast cancer metastasis, and this work assesses the role of ICAM-1 and VCAM-1 in this process. MDA-MB-231, MCF 7, and human umbilical vein endothelial cells (HUVECs) were treated with normal HDL from healthy controls (N-HDL), HDL from breast cancer patients (B-HDL), or HDL from breast cancer patients complicated with type 2 diabetes mellitus (BD-HDL), and the cell adhesion abilities were determined. ICAM-1 and VCAM-1 expression as well as the protein kinase C (PKC) activity were evaluated. The effect of PKC inhibitor and PKC siRNA on adhesion was also studied. The immunohistochemical staining of ICAM-1, VCAM-1, and E-selectin from breast cancer patients and breast cancer patients complicated with type 2 diabetes mellitus (T2DM) were examined. Our results indicate that BD-HDL promoted an increase in breast cancer cell adhesion to HUVECs and stimulated higher ICAM-1 and VCAM-1 expression on the cells surface of both breast cancer and HUVEC cells, along with the activation of PKC. Increased tumor cell (TC)-HUVEC adhesion, as well as ICAM-1 and VCAM-1 expression induced by BD-HDL, could be inhibited by staurosporine and PKC siRNA. In addition, a Db/db type 2 diabetes mouse model has more TC-Vascular Endothelium adhesion compared to a normal model. However, BD patients have a lower expression of ICAM-1, VCAM-1, and E-selectin in their tumor tissues. BD-HDL facilitates the adhesion of tumor cells to vascular endothelium by upregulating the expression of ICAM-1 and VCAM-1, thereby promoting the initial progression of breast cancer metastasis

  10. Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded—end point (probe) trial

    PubMed Central

    Bevilacqua, Maurizio; Guazzini, Barbara; Righini, Velella; Barrella, Massimo; Toscano, Rosanna; Chebat, Enrica

    2004-01-01

    Background Diabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM). Objective The aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C. Methods This 4-month, prospective, open-label, randomized, blinded—end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels <50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study. Results One hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean

  11. Arachnid lipoproteins: comparative aspects.

    PubMed

    Cunningham, Mónica; Garcia, Fernando; Pollero, Ricardo J

    2007-01-01

    Findings on hemolymph lipoproteins in the class Arachnida are reviewed in relation to their lipid and protein compositions, hydrated densities, the capacity of apoproteins to bind lipids, and the influence of xenobiotics on their structures and functionality. The occurrence of hemolymphatic lipoproteins in arachnids has been reported in species belonging to the orders Araneida, Scorpionida, Solpugida and Acarina. However, lipoproteins were properly characterized in only three species, Eurypelma californicum, Polybetes pythagoricus and Latrodectus mirabilis. Like insect and crustaceans the arachnids examined contain high density lipoproteins (HDLs) as predominant circulating lipoproteins. Although in most arachnids these particles resemble those of insect HDLs called "lipophorins", in two arachnid species they differ from lipophorins in their apoproteins, total mass and lipid composition. The hemolymph of P. pythagoricus and L. mirabilis contains another HDL of higher density, while P. pythagoricus and E. californicum hemolymph contain a third lipoprotein of very high density (VHDL). Composition of arachnid lipoproteins regarding apoprotein classes as well as lipid classes differ among species. Hemocyanin, in addition to the classical role of this protein as respiratory pigment, is presented here performing the function of apolipoprotein in some arachnid species. Reports on experiments demonstrating the capacity of hemocyanin to bind neutral and polar lipid classes, including ecdysteroids, are commented. Recent works about the changes evoked by a phosphorous pesticide on the structures and functionality of spider lipoproteins are also reviewed. PMID:16887396

  12. Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus

    PubMed Central

    Al Gadban, Mohammed M.; German, Jashalynn; Truman, Jean-Philip; Soodavar, Farzan; Riemer, Ellen C; Twal, Waleed O; Smith, Kent J; Heller, Demarcus; Hofbauer, Ann F; Oates, Jim C.; Hammad, Samar M.

    2012-01-01

    Systemic lupus erythematosus (SLE) patients display impaired endothelial nitric oxide synthase (eNOS) function required for normal vasodilatation. SLE patients express increased compensatory activity of inducible nitric oxide synthase (iNOS) generating excess nitric oxide that may result in inflammation. We examined the effects of genetic deletion of NOS2 and NOS3, encoding iNOS and eNOS respectively, on accelerated vascular disease in MRL/lpr lupus mouse model. NOS2 and NOS3 knockout (KO) MRL/lpr mice had higher plasma levels of triglycerides (23% and 35%, respectively), ceramide (45% and 21%, respectively), and sphingosine 1-phosphate (S1P) (21%) compared to counterpart MRL/lpr controls. Plasma levels of the anti-inflammatory cytokine interleukin 10 (IL-10) in NOS2 and NOS3 KO MRL/lpr mice were lower (53% and 80%, respectively) than counterpart controls. Nodule-like lesions in the adventitia were detected in aortas from both NOS2 and NOS3 KO MRL/lpr mice. Immunohistochemical evaluation of the lesions revealed activated endothelial cells and lipid-laden macrophages (foam cells), elevated sphingosine kinase 1 expression, and oxidized low-density lipoprotein immune complexes (oxLDL-IC). The findings suggest that advanced vascular disease in NOS2 and NOS3 KO MRL/lpr mice maybe mediated by increased plasma triglycerides, ceramide and S1P; decreased plasma IL-10; and accumulation of oxLDL-IC in the vessel wall. The results expose possible new targets to mitigate lupus-associated complications. PMID:22560558

  13. Feeding the nitric oxide synthase inhibitor L-N(omega)nitroarginine elevates serum very low density lipoprotein and hepatic triglyceride synthesis in rats.

    PubMed

    Goto, T; Ohnomi, S; Khedara, A; Kato, N; Ogawa, H; Yanagita, T

    1999-05-01

    This study was conducted to study the influence of dietary L-N(omega)nitroarginine (L-NNA), a nitric oxide (NO) synthase inhibitor, on serum lipids and lipoproteins and on the activities of enzymes related to lipid metabolism in rats. Feeding rats a diet containing 0.2 g/kg L-NNA for 5 weeks elevated serum concentrations of triglyceride, cholesterol, phospholipid, and free fatty acid and reduced serum nitrate (an oxidation product of NO). The elevation in serum triglyceride was mainly due to the elevation in very low density lipoprotein (VLDL) triglyceride. Contents of cholesterol and phospholipid in the VLDL fraction also were elevated by L-NNA. L-NNA treatment caused significantly higher activity of hepatic microsomal phosphatidate phosphohydrolase (the rate-limiting enzyme in triglyceride synthesis) and lower activity of hepatic carnitine palmitoyltransferase (the rate-limiting enzyme in fatty acid oxidation). Activities of hepatic enzymes responsible for fatty acid synthesis such as glucose-6-phosphate dehydrogenase, malic enzyme, and fatty acid synthase were unaffected by L-NNA. The activity of hepatic microsomal phosphocholine cytidyltransferase (the rate-limiting enzyme in phosphatidylcholine synthesis) was reduced significantly by L-NNA. Our results suggest that lower NO production caused the elevations in hepatic triglyceride synthesis by higher esterification of fatty acid and lower fatty acid oxidation, leading to an enrichment of VLDL triglyceride. PMID:15539300

  14. Premature and severe cardiovascular disease in a Mexican male with markedly low high-density-lipoprotein-cholesterol levels and a mutation in the lecithin:cholesterol acyltransferase gene: a family study.

    PubMed

    Posadas-Sánchez, Rosalinda; Posadas-Romero, Carlos; Ocampo-Arcos, Wendy Angélica; Villarreal-Molina, María Teresa; Vargas-Alarcón, Gilberto; Antúnez-Argüelles, Erika; Mendoza-Pérez, Enrique; Cardoso-Saldaña, Guillermo; Martínez-Alvarado, Rocío; Medina-Urrutia, Aída; Jorge-Galarza, Esteban

    2014-06-01

    Epidemiological and clinical studies have shown that a low plasma high‑density lipoprotein cholesterol (HDL-C) level is a strong predictor of cardiovascular disease (CVD). Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the formation, maturation and function of HDL. Therefore impaired LCAT function may enhance atherosclerosis because of defective cholesterol transport. In this study, we examined a 34-year old LCAT‑deficient patient and eight first-degree family members. There was a strong family history for CVD and type 2 diabetes mellitus (DM2). The proband was found homozygous for a previously reported LCAT gene mutation (Thr37Met). A sister and two sons of the proband were heterozygous for the same mutation. The proband had DM2 and showed severe multivessel coronary artery disease, corneal opacification and extremely low HDL-C levels. Large HDL particles were absent while small HDL particles were increased. The HDL of the patient had a reduced ability to promote cell cholesterol efflux, and the low‑density lipoproteins (LDL) were more susceptible to oxidation. Among his family members, two heterozygotes and one non-carrier had early carotid or coronary atherosclerosis. In conclusion, as the increased LDL oxidability and structural and functional abnormalities of HDL particles have been reported in patients with obesity and diabetes, the results suggested that the adverse coronary risk profile, and not being LCAT deficient, may be responsible for the CVD found in our proband, and for the early atherosclerosis observed in the two heterozygotes and in the wild‑type family members. PMID:24715031

  15. Serum lipid & lipoprotein profiles of obese Chinese children.

    PubMed

    Ho, T F; Paramsothy, S; Aw, T C; Yip, W C

    1996-03-01

    The serum lipid and lipoprotein levels of 59 obese Chinese children with a mean age of 13.0 years and mean relative weight of 164.2% were analysed. Between 40% to 54% of these children had elevated lipid and lipoprotein levels and about 78% had reduced high density lipoprotein (HDL) level when compared to healthy American and Japanese children. The obese children also had higher mean levels of total cholesterol (TC) and lower HDL compared to male adults in the local population. Those with elevated TC had higher mean relative weight (170% vs 159%, p < 0.05). In view of the close association between hyperlipidaemia and atherosclerosis, obese children should be carefully screened and managed to prevent long term morbidity and mortality of coronary artery disease. PMID:10967982

  16. Multimerization of Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1) and Familial Chylomicronemia from a Serine-to-Cysteine Substitution in GPIHBP1 Ly6 Domain*

    PubMed Central

    Plengpanich, Wanee; Young, Stephen G.; Khovidhunkit, Weerapan; Bensadoun, André; Karnman, Hirankorn; Ploug, Michael; Gårdsvoll, Henrik; Leung, Calvin S.; Adeyo, Oludotun; Larsson, Mikael; Muanpetch, Suwanna; Charoen, Supannika; Fong, Loren G.; Niramitmahapanya, Sathit; Beigneux, Anne P.

    2014-01-01

    GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. The ability of GPIHBP1 to bind LPL depends on the Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in the GPIHBP1 Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the preheparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, whereas wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in the GPIHBP1 Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia. PMID:24847059

  17. Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain.

    PubMed

    Plengpanich, Wanee; Young, Stephen G; Khovidhunkit, Weerapan; Bensadoun, André; Karnman, Hirankorn; Ploug, Michael; Gårdsvoll, Henrik; Leung, Calvin S; Adeyo, Oludotun; Larsson, Mikael; Muanpetch, Suwanna; Charoen, Supannika; Fong, Loren G; Niramitmahapanya, Sathit; Beigneux, Anne P

    2014-07-11

    GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. The ability of GPIHBP1 to bind LPL depends on the Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in the GPIHBP1 Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the preheparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, whereas wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in the GPIHBP1 Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia. PMID:24847059

  18. Lipoprotein (a), lipids, and lipoproteins in patients with rheumatoid arthritis.

    PubMed Central

    Rantapää-Dahlqvist, S; Wållberg-Jonsson, S; Dahlén, G

    1991-01-01

    Lipoprotein (a), (Lp(a)), an independent atherogenic factor, was significantly increased in 93 patients with classical, seropositive rheumatoid arthritis of median disease activity. In the patients with Lp(a) concentrations above the upper reference value of 480 mg/l there was a significant correlation between Lp(a) and the concentration of orosomucoid, erythrocyte sedimentation rate, and the platelet count. The plasma concentrations of cholesterol and high density lipoprotein-cholesterol in both male and female patients were significantly lower than in controls. Apolipoprotein B and apolipoprotein AI in the patients correlated significantly with total cholesterol and high density lipoprotein-cholesterol respectively. PMID:1829348

  19. Procollagen C-endopeptidase Enhancer Protein 2 (PCPE2) Reduces Atherosclerosis in Mice by Enhancing Scavenger Receptor Class B1 (SR-BI)-mediated High-density Lipoprotein (HDL)-Cholesteryl Ester Uptake.

    PubMed

    Pollard, Ricquita D; Blesso, Christopher N; Zabalawi, Manal; Fulp, Brian; Gerelus, Mark; Zhu, Xuewei; Lyons, Erica W; Nuradin, Nebil; Francone, Omar L; Li, Xiang-An; Sahoo, Daisy; Thomas, Michael J; Sorci-Thomas, Mary G

    2015-06-19

    Studies in human populations have shown a significant correlation between procollagen C-endopeptidase enhancer protein 2 (PCPE2) single nucleotide polymorphisms and plasma HDL cholesterol concentrations. PCPE2, a 52-kDa glycoprotein located in the extracellular matrix, enhances the cleavage of C-terminal procollagen by bone morphogenetic protein 1 (BMP1). Our studies here focused on investigating the basis for the elevated concentration of enlarged plasma HDL in PCPE2-deficient mice to determine whether they protected against diet-induced atherosclerosis. PCPE2-deficient mice were crossed with LDL receptor-deficient mice to obtain LDLr(-/-), PCPE2(-/-) mice, which had elevated HDL levels compared with LDLr(-/-) mice with similar LDL concentrations. We found that LDLr(-/-), PCPE2(-/-) mice had significantly more neutral lipid and CD68+ infiltration in the aortic root than LDLr(-/-) mice. Surprisingly, in light of their elevated HDL levels, the extent of aortic lipid deposition in LDLr(-/-), PCPE2(-/-) mice was similar to that reported for LDLr(-/-), apoA-I(-/-) mice, which lack any apoA-I/HDL. Furthermore, LDLr(-/-), PCPE2(-/-) mice had reduced HDL apoA-I fractional clearance and macrophage to fecal reverse cholesterol transport rates compared with LDLr(-/-) mice, despite a 2-fold increase in liver SR-BI expression. PCPE2 was shown to enhance SR-BI function by increasing the rate of HDL-associated cholesteryl ester uptake, possibly by optimizing SR-BI localization and/or conformation. We conclude that PCPE2 is atheroprotective and an important component of the reverse cholesterol transport HDL system. PMID:25947382

  20. Lipoproteins and lipoprotein metabolism in periodontal disease

    PubMed Central

    Griffiths, Rachel; Barbour, Suzanne

    2010-01-01

    A growing body of evidence indicates that the incidence of atherosclerosis is increased in subjects with periodontitis – a chronic infection of the oral cavity. This article summarizes the evidence that suggests periodontitis shifts the lipoprotein profile to be more proatherogenic. LDL-C is elevated in periodontitis and most studies indicate that triglyceride levels are also increased. By contrast, antiatherogenic HDL tends to be low in periodontitis. Periodontal therapy tends to shift lipoprotein levels to a healthier profile and also reduces subclinical indices of atherosclerosis. In summary, periodontal disease alters lipoprotein metabolism in ways that could promote atherosclerosis and cardiovascular disease. PMID:20835400

  1. Understanding Lipoproteins as Transporters of Cholesterol and Other Lipids

    ERIC Educational Resources Information Center

    Biggerstaff, Kyle D.; Wooten, Joshua S.

    2004-01-01

    A clear picture of lipoprotein metabolism is essential for understanding the pathophysiology of atherosclerosis. Many students are taught that low-density lipoprotein-cholesterol is "bad" and high-density lipoprotein-cholesterol is "good." This misconception leads to students thinking that lipoproteins are types of cholesterol rather than…

  2. Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function

    PubMed Central

    Mak, Angel C. Y.; Pullinger, Clive R.; Tang, Ling Fung; Wong, Jinny S.; Deo, Rahul C.; Schwarz, Jean-Marc; Gugliucci, Alejandro; Movsesyan, Irina; Ishida, Brian Y.; Chu, Catherine; Poon, Annie; Kim, Phillip; Stock, Eveline O.; Schaefer, Ernst J.; Asztalos, Bela F.; Castellano, Joseph M.; Wyss-Coray, Tony; Duncan, Jacque L.; Miller, Bruce L.; Kane, John P.; Kwok, Pui-Yan; Malloy, Mary J.

    2016-01-01

    IMPORTANCE The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE). OBJECTIVES To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on the patient’s DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband’s mother, wife, 2 daughters, and normolipidemic control participants. MAIN OUTCOME MEASURES Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTS The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apo

  3. High-density lipoprotein particles, coronary heart disease, and niacin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In clinical trials, the use of statins in patients with high risk for cardiovascular disease (CVD) has resulted in a 25% to 40% decrease in major clinical events. However, despite a marked reduction (up to 60%) in LDL-C, approximately 50% (or more) of patients continue to have CVD events. This high ...

  4. Low High-Density Lipoprotein and Risk of Myocardial Infarction.

    PubMed

    Ramirez, A; Hu, P P

    2015-01-01

    Low HDL is an independent risk factor for myocardial infarction. This paper reviews our current understanding of HDL, HDL structure and function, HDL subclasses, the relationship of low HDL with myocardial infarction, HDL targeted therapy, and clinical trials and studies. Furthermore potential new agents, such as alirocumab (praluent) and evolocumab (repatha) are discussed. PMID:26692765

  5. Low High-Density Lipoprotein and Risk of Myocardial Infarction

    PubMed Central

    Ramirez, A.; Hu, P. P.

    2015-01-01

    Low HDL is an independent risk factor for myocardial infarction. This paper reviews our current understanding of HDL, HDL structure and function, HDL subclasses, the relationship of low HDL with myocardial infarction, HDL targeted therapy, and clinical trials and studies. Furthermore potential new agents, such as alirocumab (praluent) and evolocumab (repatha) are discussed. PMID:26692765

  6. Altered properties of high density lipoprotein subfractions in obese subjects.

    PubMed

    Sasahara, T; Yamashita, T; Sviridov, D; Fidge, N; Nestel, P

    1997-03-01

    Human HDL are heterogeneous in their metabolism and comprise small, nascent pre-beta-HDL and more mature alpha-HDL. Evidence exists that pre-beta 1-HDL is the initial acceptor of cellular free cholesterol, which then transfers sequentially to other pre-beta species and then, after esterification, into alpha-HDL. As HDL particles are themselves transformed during this process, we postulated that in disorders in which HDL-cholesterol is low, such as obesity, the distribution of HDL particles may be disturbed. In this study, we analyzed the HDL profile in 23 obese and 18 lean subjects, and further investigated the effects of dietary change in 15 obese subjects. HDL were separated by two-dimensional nondenaturing electrophoresis and the apoA-I content in each fraction was quantified. alpha 1-HDL in obese subjects was significantly lower (P < 0.001) and alpha 2-, alpha 3-, and pre-beta 1-HDL were significantly higher (P < 0.05 for alpha 2-HDL, P < 0.001 for alpha 3- and pre-beta 1-HDL) than in lean subjects. On stepwise regression analysis, body mass index accounted for 52% (negatively) of the variance in alpha 1-HDL and for 16% and 33% (positively) for the variances in alpha 3- and pre-beta 1-HDL, respectively. alpha 1- and pre-beta 3-HDL increased significantly after low-fat, oleic acid-rich, or alpha-linolenic acid-rich diets. The profile of alpha-HDL particles and also of pre-beta-HDL particles therefore shifted to smaller species in obese subjects, and this was influenced by dietary fat. Increased pre-beta 1-HDL-apoA-I in obese subjects is likely to derive from increased HDL catabolism but may also reflect diminished transformation of pre-beta 1- to pre-beta 2-HDL which might reduce capacity for reverse cholesterol transport and partly explain lower HDL-cholesterol levels. PMID:9101441

  7. Metabolism of lipoproteins by human fetal hepatocytes

    SciTech Connect

    Carr, B.R.

    1987-12-01

    The rate of clearance of lipoproteins from plasma appears to play a role in the development of atherogenesis. The liver may account for as much as two thirds of the removal of low-density lipoprotein and one third of the clearance of high-density lipoprotein in certain animal species and humans, mainly by receptor-mediated pathways. The purpose of the present investigation was to determine if human fetal hepatocytes maintained in vitro take up and degrade lipoproteins. We first determined that the maximal binding capacity of iodine 125-iodo-LDL was approximately 300 ng of low-density lipoprotein protein/mg of membrane protein and an apparent dissociation constant of approximately 60 micrograms low-density lipoprotein protein/ml in membranes prepared from human fetal liver. We found that the maximal uptake of (/sup 125/I)iodo-LDL and (/sup 125/I)iodo-HDL by fetal hepatocytes occurred after 12 hours of incubation. Low-density lipoprotein uptake preceded the appearance of degradation products by 4 hours, and thereafter the degradation of low-density lipoprotein increased linearly for at least 24 hours. In contrast, high-density lipoprotein was not degraded to any extent by fetal hepatocytes. (/sup 125/I)Iodo-LDL uptake and degradation were inhibited more than 75% by preincubation with low-density lipoprotein but not significantly by high-density lipoprotein, whereas (/sup 125/I)iodo-HDL uptake was inhibited 70% by preincubation with high-density lipoprotein but not by low-density lipoprotein. In summary, human fetal hepatocytes take up and degrade low-density lipoprotein by a receptor-mediated process similar to that described for human extrahepatic tissues.

  8. 21 CFR 866.5580 - Alpha-1-lipoprotein immuno-logical test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Alpha-1-lipoprotein immuno-logical test system....5580 Alpha-1-lipoprotein immuno-logical test system. (a) Identification. An alpha-1-lipoprotein... the alpha-1-lipoprotein (high-density lipoprotein) in serum and plasma. Measurement of...

  9. 21 CFR 866.5580 - Alpha-1-lipoprotein immuno-logical test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Alpha-1-lipoprotein immuno-logical test system....5580 Alpha-1-lipoprotein immuno-logical test system. (a) Identification. An alpha-1-lipoprotein... the alpha-1-lipoprotein (high-density lipoprotein) in serum and plasma. Measurement of...

  10. 21 CFR 866.5580 - Alpha-1-lipoprotein immuno-logical test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Alpha-1-lipoprotein immuno-logical test system....5580 Alpha-1-lipoprotein immuno-logical test system. (a) Identification. An alpha-1-lipoprotein... the alpha-1-lipoprotein (high-density lipoprotein) in serum and plasma. Measurement of...

  11. High density modular avionics packaging

    NASA Astrophysics Data System (ADS)

    Poradish, F.

    Requirements and design configurations for high density modular avionics packaging are examined, with particular attention given to new hardware trends, the design of high-density standard modules (HDSM's), and HDSM requirements. The discussion of the HDSM's covers thermal management, system testability, power supply, and performance specifications. The general design of an integrated HDSM demonstration system currently under construction is briefly described, and some test data are presented.

  12. Effects of Bulbus allii macrostemi on clinical outcomes and oxidized low-density lipoprotein and plasminogen in unstable angina/non-ST-segment elevation myocardial infarction patients.

    PubMed

    Liu, Yan; Zhang, Lei; Liu, Yun-Fang; Yan, Fang-Fang; Zhao, Yu-Xia

    2008-11-01

    Unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) is associated with an increased risk of cardiac death and an efficacious drug with few side effects is necessary. The study aimed to evaluate the effects of Bulbus allii macrostemi (B. macrostemi) on UA/NSTEMI patients as well as to elucidate possible mechanisms. 79 patients were randomly divided into two groups: the trial group received B. macrostemi plus baseline therapy, the control group was given placebo plus baseline therapy. The trial lasted 8 weeks. The evaluation involved main clinical symptoms, changes of electrocardiogram and biochemical examination. After treatment, the trial group showed more significant improvement on clinical manifestation. The plasma oxidized low-density lipoprotein (ox-LDL) level decreased significantly in the trial group (p < 0.01); the plasminogen activator inhibitor-1 (PAI-1) level decreased in both groups and it decreased more significantly in the trial group (p < 0.01). In contrast, the activity of plasminogen (PLG) increased in both groups and the change was more marked in the trial group (p < 0.01). The results suggested that B. macrostemi combined with baseline therapy could improve clinical symptoms of UA/NSTEMI patients by decreasing the ox-LDL and PAI-1 levels and enhancing the activity of PLG. PMID:18688814

  13. Association of Elevated Serum Lipoprotein(a), Inflammation, Oxidative Stress and Chronic Kidney Disease with Hypertension in Non-diabetes Hypertensive Patients.

    PubMed

    Tangvarasittichai, Surapon; Pingmuanglaew, Patcharin; Tangvarasittichai, Orathai

    2016-10-01

    Hypertension is the most common cardiovascular risk factor. Lipoprotein(a) [Lp(a)], inflammation, oxidative stress and chronic kidney disease (CKD) exacerbate the response to tissue injury and acts as markers of the vascular disease, especially in glomerulosclerosis. We compared the clinical characteristics of 138 non-diabetes hypertensive women (ndHT) patients with 417 non-diabetes normotensive subjects and tested the association of hypertension with Lp(a), inflammation, CKD and oxidative stress by using multiple logistic regression. BP, BMI, waist circumference, creatinine, Lp(a), inflammation and malondialdehyde levels were significantly higher and CKD state in the ndHT patients (p < 0.05). Multiple logistic regression showed hypertension associated with increased Lp(a), inflammation, ORs and 95 % CIs were 2.52 (1.33, 4.80), 2.75 (1.44, 5.27) after adjusting for their covariates. Elevated serum Lp(a) and inflammation levels concomitants with increased oxidative stress and CKD were the major risk factors associated with hypertension and implications for the increased risk of HT and vascular disease. PMID:27605742

  14. Lipoprotein-induced phenoloxidase-activity in tarantula hemocyanin.

    PubMed

    Schenk, Sven; Schmidt, Juliane; Hoeger, Ulrich; Decker, Heinz

    2015-08-01

    Phenoloxidases play vital roles in invertebrate innate immune reactions, wound closure and sclerotization processes in arthropods. In chelicerates, where phenoloxidases are lacking, phenoloxidase-activity can be induced in the oxygen carrier hemocyanin in vitro by proteolytic cleavage, incubation with the artificial inducer SDS, or lipids. The role of protein-protein interaction has up to now received little attention. This is remarkable, as lipoproteins - complexes of proteins and lipids - are present at high concentrations in arthropod hemolymph. We characterized the three lipoproteins present in tarantula hemolymph, two high-density lipoproteins and one very high-density lipoprotein, and show that the two high-density lipoproteins have distinct structures: the more abundant high-density lipoprotein is an ellipsoid particle with axes of ~22.5 nm and ~16.8 nm, respectively. The second high-density lipoprotein, present only in trace amount, is a large discoidal lipoprotein with a diameter of ~38.4 nm and an on-edge thickness of ~7.1 nm. We further demonstrate that the interaction between lipoproteins and hemocyanin induces phenoloxidase activity in hemocyanin, and propose that this activation is due to protein-protein interaction rather than protein-lipid interaction, as neither lipid micelles nor lipid monomers were found to be activating. Activation was strongest in the presence of high-density lipoproteins; very high-density lipoproteins were found to be non-activating. This is the first time that the ability of lipoproteins to induce phenoloxidase activity of hemocyanin has been demonstrated, thus adding novel aspects to the function of lipoproteins apart from their known role in nutrient supply. PMID:25817204

  15. Phytosterols, Phytostanols, and Lipoprotein Metabolism

    PubMed Central

    Gylling, Helena; Simonen, Piia

    2015-01-01

    The efficacy of phytosterols and phytostanols added to foods and food supplements to obtain significant non-pharmacologic serum and low density lipoprotein (LDL) cholesterol reduction is well documented. Irrespective of age, gender, ethnic background, body weight, background diet, or the cause of hypercholesterolemia and, even added to statin treatment, phytosterols and phytostanols at 2 g/day significantly lower LDL cholesterol concentration by 8%–10%. They do not affect the concentrations of high density lipoprotein cholesterol, lipoprotein (a) or serum proprotein convertase subtilisin/kexin type 9. In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in subjects with slightly increased baseline concentrations. Phytosterols and phytostanols lower LDL cholesterol by displacing cholesterol from mixed micelles in the small intestine so that cholesterol absorption is partially inhibited. Cholesterol absorption and synthesis have been carefully evaluated during phytosterol and phytostanol supplementation. However, only a few lipoprotein kinetic studies have been performed, and they revealed that LDL apoprotein B-100 transport rate was reduced. LDL particle size was unchanged, but small dense LDL cholesterol concentration was reduced. In subjects with metabolic syndrome and moderate hypertriglyceridemia, phytostanols reduced not only non- high density lipoprotein (HDL) cholesterol concentration but also serum triglycerides by 27%, and reduced the large and medium size very low density lipoprotein particle concentrations. In the few postprandial studies, the postprandial lipoproteins were reduced, but detailed studies with apoprotein B-48 are lacking. In conclusion, more kinetic studies are required to obtain a more complete understanding of the fasting and postprandial lipoprotein metabolism caused by phytosterols and phytostanols. It seems obvious, however, that the most atherogenic lipoprotein particles will be

  16. Seasonal variation in plasma lipids, lipoproteins, apolipoprotein A-I and vitellogenin in the freshwater turtle, Chrysemys picta.

    PubMed

    Duggan, A; Paolucci, M; Tercyak, A; Gigliotti, M; Small, D; Callard, I

    2001-09-01

    An analysis of plasma lipids and lipoprotein fractions was performed over the course of the annual ovarian cycle of the female turtle, Chrysemys picta. Determinations of total plasma triglycerides, cholesterol, vitellogenin and apolipoprotein A-I (apoA-I) were made. The lipid and protein composition of the lipoprotein fractions [very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) and very high density lipoprotein (VHDL)] were also observed over the same period. Plasma triglyceride and vitellogenin levels were significantly increased in the spring preovulatory period and fall recrudescent phase. Total plasma cholesterol levels were significantly elevated only at the onset of the fall recrudescent phase and apoA-I levels were highest during the postoviposition/ovarian arrest phase. The triglyceride content of VLDL was highest in preovulatory animals and there were apparent seasonal changes in the expression of apoA-I and apoE of HDL/VHDL. We conclude that the coordinate regulation of lipids and protein contributes to seasonal ovarian growth and clearance of lipids from plasma, both of which are most likely under hormonal control. PMID:11544071

  17. Raising highly desirable lipoprotein versus lowering deleterious lipoprotein.

    PubMed

    Cheung, Bernard My; Kumana, Cyrus R

    2010-03-01

    Evaluation of: Taylor AJ, Villines TC, Stanek EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N. Engl. J. Med. 361(22), 2113-2122 (2009). Epidemiological evidence suggests that elevated low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) are both factors causing coronary heart disease. These authors compared extended-release niacin, which raises HDL-C, with ezetimibe, which lowers LDL-C, in a study named Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER 6-HALTS). The study was terminated early and only 208 patients were included in the analysis. Ezetimibe decreased LDL-C by 19.2%, to 66 mg/dl (1.7 mmol/l), whereas niacin increased HDL-C by 18.4%. Ezetimibe did not reduce carotid intima-media thickness, whereas niacin decreased it significantly. Moreover, major adverse cardiovascular events occurred in 5% of the ezetimibe group but only 1% of the niacin group (p = 0.04). The study suggests that niacin may be more effective than ezetimibe as an adjunct to statin in regressing atherosclerosis and in preventing cardiovascular events. This small study of short duration reported a very large treatment effect, so the findings need to be confirmed in a larger longer trial. Nevertheless, it provides the evidence that we now have an additional class of drugs besides statins that can reduce atherosclerosis and cardiovascular events. PMID:22111565

  18. Photoionization and High Density Gas

    NASA Technical Reports Server (NTRS)

    Kallman, T.; Bautista, M.; White, Nicholas E. (Technical Monitor)

    2002-01-01

    We present results of calculations using the XSTAR version 2 computer code. This code is loosely based on the XSTAR v.1 code which has been available for public use for some time. However it represents an improvement and update in several major respects, including atomic data, code structure, user interface, and improved physical description of ionization/excitation. In particular, it now is applicable to high density situations in which significant excited atomic level populations are likely to occur. We describe the computational techniques and assumptions, and present sample runs with particular emphasis on high density situations.

  19. Low-density lipoprotein apheresis: an overview.

    PubMed

    Bambauer, Rolf; Schiel, Ralf; Latza, Reinhard

    2003-08-01

    Atherosclerosis with myocardial infarction, stroke, and peripheral cellular disease still maintains its position at the top of morbidity and mortality statistics in industrialized nations. Established risk factors widely accepted are smoking, arterial hypertension, diabetes mellitus, and central obesity. Furthermore, there is a strong correlation between hyperlipidemia and atherosclerosis. The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lpa) levels, and coronary heart disease (CHD) refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are four different LDL apheresis systems available: immunoadsorption, heparin-induced extracorporeal LDL/fibrinogen precipitation, dextran sulfate LDL adsorption and LDL hemoperfusion. Regarding the different LDL apheresis systems used, there is no significant difference with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein (HDL), or triglyceride concentrations. With respect to elevated Lpa levels, however, the immunoadsorption method seems to be the most effective. In 45 patients (25 women, 20 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 95.6 +/- 44.7 months. Four different systems (Liposorber, 32 of 45, Kaneka, Osaka, Japan; Therasorb, 6 of 45, Baxter, Munich, Germany; Lipopak, 2 of 45, Pocard, Moscow, Russia; and Dali, 5 of 45, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 57% for total cholesterol, 55.9% for LDL, 75.8% for lipoprotein a (Lpa), and 45.9% for triglycerides, and an average increase of 14.3% for HDL were reached. Severe side-effects such as shock or allergic reactions were very rare (0.3%) in all methods. In the course of treatment, an improvement

  20. Effects of hormones on lipids and lipoproteins

    SciTech Connect

    Krauss, R.M.

    1991-12-01

    Levels of plasma lipids and lipoproteins are strong predictors for the development of atherosclerotic cardiovascular disease in postmenopausal women. In women, as in men, numerous factors contribute to variations in plasma lipoproteins that may affect cardiovascular disease risk. These include age, dietary components, adiposity, genetic traits, and hormonal changes. Each of these factors may operate to varying degrees in determining changes in plasma lipoprotein profiles accompanying menopause- Cross-sectional and longitudinal studies have suggested increases in levels of cholesterol, low density lipoproteins (LDL) and triglyceride-rich lipoproteins associated with menopause. High density lipoproteins (HDL), which are higher in women than men and are thought to contribute to relative protection of premenopausal women from cardiovascular disease, remain relatively constant in the years following menopause, although small, and perhaps transient reductions in the HDL{sub 2} subfraction have been reported in relation to reduced estradiol level following menopause. Despite these associations, it has been difficult to determine the role of endogenous hormones in influencing the plasma lipoproteins of postmenopausal women. In principle, the effects of hormone replacement should act to reverse any alterations in lipoprotein metabolism that are due to postmenopausal hormone changes. While there may be beneficial effects on lipoproteins, hormone treatment does not restore a premenopausal lipoprotein profile. Furthermore, it is not dear to what extent exogenous hormone-induced lipoprotein changes contribute to the reduced incidence of cardiovascular disease with hormone replacement therapy.

  1. Effect of serum lipoproteins on the adenylate cyclase activity of rat liver plasma membranes.

    PubMed Central

    Ghiselli, G; Sirtori, C R; Nicosia, S

    1981-01-01

    Four rat lipoprotein classes [lymph chylomicrons, VLD (very-low-density), LD (low-density) and HD (high-density) lipoproteins] were tested for their ability to affect basal adenylate cyclase (EC 4.6.1.1) activity of rat liver plasma membranes. All the lipoproteins, with the exception of lymph chylomicrons, effectively increase the enzyme activity. VLD lipoproteins are the most active class (67% maximal increase), followed by HD lipoproteins (33%) and LD lipoproteins (23%). The effect of VLD lipoproteins is additive to that elicited by GTP or GTP plus glucagon (at least within a certain concentration range). VLD lipoproteins affect only the Vmax. of the enzyme, not the Km. PMID:7317023

  2. High-density digital recording

    NASA Technical Reports Server (NTRS)

    Kalil, F. (Editor); Buschman, A. (Editor)

    1985-01-01

    The problems associated with high-density digital recording (HDDR) are discussed. Five independent users of HDDR systems and their problems, solutions, and insights are provided as guidance for other users of HDDR systems. Various pulse code modulation coding techniques are reviewed. An introduction to error detection and correction head optimization theory and perpendicular recording are provided. Competitive tape recorder manufacturers apply all of the above theories and techniques and present their offerings. The methodology used by the HDDR Users Subcommittee of THIC to evaluate parallel HDDR systems is presented.

  3. Admission Lipoprotein-Associated Phospholipase A2 Activity Is Not Associated with Long-Term Clinical Outcomes after ST-Segment Elevation Myocardial Infarction

    PubMed Central

    Woudstra, Pier; Damman, Peter; Kuijt, Wichert J.; Kikkert, Wouter J.; Grundeken, Maik J.; van Brussel, Peter M.; Stroobants, An K.; van Straalen, Jan P.; Fischer, Johan C.; Koch, Karel T.; Henriques, José P. S.; Piek, Jan J.; Tijssen, Jan G. P.; de Winter, Robbert J.

    2014-01-01

    Background Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is a biomarker predicting cardiovascular diseases in a real-world. However, the prognostic value in patients undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) on long-term clinical outcomes is unknown. Methods Lp-PLA2 activity was measured in samples obtained prior to pPCI from consecutive STEMI patients in a high-volume intervention center from 2005 until 2007. Five years all-cause mortality was estimated with the Kaplan-Meier method and compared among tertiles of Lp-PLA2 activity during complete follow-up and with a landmark at 30 days. In a subpopulation clinical endpoints were assessed at three years. The prognostic value of Lp-PLA2, in addition to the Thrombolysis In Myocardial Infarction or multimarker risk score, was assessed in multivariable Cox regression. Results The cohort (n = 987) was divided into tertiles (low <144, intermediate 144–179, and high >179 nmol/min/mL). Among the tertiles differences in baseline characteristics associated with long-term mortality were observed. However, no significant differences in five years mortality in association with Lp-PLA2 activity levels were found; intermediate versus low Lp-PLA2 (HR 0.97; CI 95% 0.68–1.40; p = 0.88) or high versus low Lp-PLA2 (HR 0.75; CI 95% 0.51–1.11; p = 0.15). Both in a landmark analysis and after adjustments for the established risk scores and selection of cases with biomarkers obtained, non-significant differences among the tertiles were observed. In the subpopulation no significant differences in clinical endpoints were observed among the tertiles. Conclusion Lp-PLA2 activity levels at admission prior to pPCI in STEMI patients are not associated with the incidence of short and/or long-term clinical endpoints. Lp-PLA2 as an independent and clinically useful biomarker in the risk stratification of STEMI patients still remains to be proven

  4. Central Nervous System Lipoproteins

    PubMed Central

    Mahley, Robert W.

    2016-01-01

    ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease. PMID:27174096

  5. Spatially revolved high density electroencephalography

    NASA Astrophysics Data System (ADS)

    Wu, Jerry; Szu, Harold; Chen, Yuechen; Guo, Ran; Gu, Xixi

    2015-05-01

    Electroencephalography (EEG) measures voltage fluctuations resulting from ionic current flows within the neurons of the brain. In practice, EEG refers to the recording of the brain's spontaneous electrical activity over a short period of time, several tens of minutes, as recorded from multiple electrodes placed on the scalp. In order to improve the resolution and the distortion cause by the hair and scalp, large array magnetoencephalography (MEG) systems are introduced. The major challenge is to systematically compare the accuracy of epileptic source localization with high electrode density to that obtained with sparser electrode setups. In this report, we demonstrate a two dimension (2D) image Fast Fourier Transform (FFT) analysis along with utilization of Peano (space-filling) curve to further reduce the hardware requirement for high density EEG and improve the accuracy and performance of the high density EEG analysis. The brain-computer interfaces (BCIs) in this work is enhanced by A field-programmable gate array (FPGA) board with optimized two dimension (2D) image Fast Fourier Transform (FFT) analysis.

  6. Cholesterol in serum lipoprotein fractions after spaceflight

    NASA Technical Reports Server (NTRS)

    Leach, Carolyn S.; Johnson, Philip C., Jr.; Krauhs, Jane M.; Cintron, Nitza M.

    1988-01-01

    Results are reported from blood-lipid measurements obtained from 125 Space Shuttle crew members before and after space flight. The data are presented in tables and discussed in detail. The main differences noted between preflight and postflight values are a 12.8-percent decrease in high-density lipoproteins on postflight day 1 and significant decreases in total cholesterol and both high- and low-density lipoproteins later in the 23-day postflight period.

  7. Binding of temoporfin to the lipoprotein fractions of human serum.

    PubMed Central

    Michael-Titus, A T; Whelpton, R; Yaqub, Z

    1995-01-01

    The binding of a new photosensitizer, temoporfin, to human serum lipoproteins was investigated. [14C]-Temoporfin (0.1-10 micrograms ml-1) was incubated with human serum for 30 min at room temperature or for 20 h at 4 degrees C, prior to stepwise density flotation to separate the lipoprotein fractions. The distribution of the drug was independent of the initial concentration or time and temperature of the incubation. The proportion of temoporfin in each fraction was: very low density lipoprotein 6%, low density lipoprotein 22%, lipoprotein(a) 17%, high density lipoprotein 39% and lipoprotein deficient serum 16%. Autoradiography of agarose gels showed that the drug was associated with the lipoprotein in the fractions. Fractionation of plasma samples collected from a patient after an intravenous infusion of temoporfin revealed a binding profile similar to that obtained in the in vitro study. Images Figure 1 PMID:8703668

  8. The effects of extended release niacin on lipoprotein sub-particle concentrations in HIV-infected patients.

    PubMed

    Lin, Chunrong; Grandinetti, Andrew; Shikuma, Cecilia; Souza, Scott; Parikh, Nisha; Nakamoto, Beau; Kallianpur, Kalpana J; Chow, Dominic

    2013-04-01

    With the advent of highly active antiretroviral therapy (HAART), Cardiovascular Disease (CVD) has emerged as the leading cause of death in Human Immunodeficiency Virus (HIV) infected patients. An atherogenic lipoprotein phenotype has been described in HIV- infected patients with a predominance of small, low density lipoprotein (SLDL) particles with accompanying elevated triglycerides and reduced high density lipoprotein cholesterol. This randomized controlled pilot study was conducted to evaluate the efficacy of Extended Release Niacin (ERN) in improving the lipid profile in HIV patients. A total of 17 HIV positive subjects on HAART therapy with High Density Lipoprotein Cholesterol (HDL) levels below 40mg/dl and Low Density Lipoprotein Cholesterol (LDL) below 130mg/dl were enrolled. Nine were randomized to be treated with ERN titrated from a starting level of 500mg/night and titrated to a level of 1500mg/night. Eight patients were assigned to the control arm. No placebo was used. Lipoprotein profiles of the subjects were analyzed at baseline and at the end of 12 weeks using Nuclear Magnetic Resonance (NMR) spectroscopy. At the end of 12 weeks, NMR spectroscopic analysis revealed a significant increase in overall LDL size (1.2% in ERN treated subjects vs 2.0% decrease in control patients, P=.04) and a decrease in small LDL particle concentration (17.0% in ERN treated subjects vs 21.4% increase in control patients, P=.03) in subjects receiving ERN as compared to those in the control group. Only 1 subject receiving ERN developed serious flushing which was attributed to an accidental overdose of the drug. This pilot study demonstrates that ERN therapy in HIV-infected patients with low HDL is safe and effective in improving the lipoprotein profile in these patients. PMID:23795312

  9. Laboratory approaches for predicting and managing the risk of cardiovascular disease: postanalytical opportunities of lipid and lipoprotein testing.

    PubMed

    Langlois, Michel R

    2012-07-01

    Abstract Lipoprotein-related risk of cardiovascular disease (CVD) can be adequately predicted in subjects with elevated total cholesterol and low-density lipoprotein (LDL-)cholesterol using the available guidelines. However, individuals with dyslipidemia can have normal total- and LDL-cholesterol concentrations. Many statin-treated patients remain at high residual risk of CVD despite achieving LDL goals. The small dense LDL phenotype, frequently presenting with hypertriglyceridemia and low high-density lipoprotein (HDL-)cholesterol (lipid triad), may contribute to failure to identify and treat high-risk individuals. Therefore, calculated non-HDL-cholesterol is recommended as secondary therapeutic target to LDL-cholesterol in patients with hypertriglyceridemia and mixed dyslipidemia. On-treatment apolipoprotein B adds prognostic information to LDL- and non-HDL-cholesterol by indicating the total number of atherogenic lipoproteins, regardless of their cholesterol content. Risk may be higher than indicated in the risk estimation systems in additional subjects with elevated lipoprotein(a) and homocysteine concentrations. To improve the (post-)post-analytical phase of lipid tests, aiming for maximal health outcome effectiveness of test interpretation and utilization, laboratory professionals should deliver clinical added value services by providing readily interpreted and guideline-adjusted test reports, interpretative commenting, proactive reflex testing or recommending additional tests, and joining multidisciplinary cooperations in guideline development and cost/benefit studies. PMID:22850050

  10. A clustering analysis of lipoprotein diameters in the metabolic syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The presence of smaller low-density lipoproteins (LDL) has been associated with atherosclerosis risk, and the insulin resistance (IR) underlying the metabolic syndrome (MetS). In addition, some research has supported the association of very low-, low- and high-density lipoprotein (VLDL HDL) particle...

  11. Hypertriglyceridemia and unusual lipoprotein subclass distributions associated with late pregnancy

    SciTech Connect

    Forte, T.M.; Kretchmer, N.; Silliman, K. )

    1991-03-15

    In the human adult population elevated plasma triglyceride (TG) levels are associated with decreased high density lipoprotein-cholesterol (HDL-C) levels and decreased HDL and LDL particle sizes. Late pregnancy is a hypertriglyceridemic state where little is known about LDL and HDL subpopulation distribution. Plasma lipids, apolipoproteins (apo) and lipoprotein subpopulations were examined in 36 pregnant women at 36 wk pregnancy and 6 wk postpartum and correlated with HDL and LDL size. There was a significant decrease in LDL diameter at 36 wk pre, 25 {plus minus} 0.7 nm compared, with 6 wk post, 26.4 {plus minus} 0.8 nm. A total of 97% of the 36 wk pre subjects had small dense LDL which paralleled increases in apoB concentration. Unlike LDL HDL at 36 wks pre showed a significant increase in larger sized particles where HDL{sub 2b} predominated. There was a positive correlation between HDL{sub 2b} mass and apoAl and HDL-C concentrations. Late pregnancy is a metabolic state where the predominance of large, HDL{sub 2b} particles is discordant with the predominance of small LDL and elevated TG. This annual metabolic pattern may in part be due to hormonal changes occurring in late pregnancy.

  12. Lipids and lipoproteins in Friedreich's ataxia.

    PubMed Central

    Walker, J L; Chamberlain, S; Robinson, N

    1980-01-01

    Friedreich's ataxia is an autosomal recessively inherited disease affecting the nervous system with a high incidence of heart involvement. Abnormalities of lipid metabolism are known to be associated with several progressive ataxic conditions. In this study of 46 Friedreich's ataxia patients, serum lipids, fatty acids and lipoproteins were assayed and compared with some earlier findings on Friedreich's ataxia and related disorders. Abnormalities of low and high density lipoproteins suggestive of a major defect have been reported; in the present study the level and chemical composition of high density lipoprotein has been assessed in 20 Friedreich's ataxia patients but previous abnormalities could not be substantiated. Lipid compositional analysis of Friedreich's ataxia central nervous tissue and heart, which has not been previously reported, did not markedly differ from control tissue. PMID:7359148

  13. Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance.

    PubMed

    Hyötyläinen, Tuulia; Mattila, Ismo; Wiedmer, Susanne K; Koivuniemi, Artturi; Taskinen, Marja-Riitta; Yki-Järvinen, Hannele; Orešič, Matej

    2012-10-01

    While the molecular lipid composition of lipoproteins has been investigated in detail, little is known about associations of small polar metabolites with specific lipoproteins. The aim of the present study was to investigate the profiles of polar metabolites in different lipoprotein fractions, i.e., very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and two sub-fractions of the high-density lipoprotein (HDL). The VLDL, IDL, LDL, HDL(2), and HDL(3) fractions were isolated from serum of sixteen individuals having a broad range of insulin sensitivity and characterized using comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOFMS). The lipoprotein fractions had clearly different metabolite profiles, which correlated with the particle size and surface charge. Lipoprotein-specific associations of individual metabolites with insulin resistance were identified, particularly in VLDL and IDL fractions, even in the absence of such associations in serum. The results indicate that the polar molecules are strongly attached to the surface of the lipoproteins. Furthermore, strong lipoprotein-specific associations of metabolites with insulin resistance, as compared to their serum profiles, indicate that lipoproteins may be a rich source of tissue-specific metabolic biomarkers. PMID:22722885

  14. Recent advances in physiological lipoprotein metabolism.

    PubMed

    Ramasamy, Indra

    2014-12-01

    Research into lipoprotein metabolism has developed because understanding lipoprotein metabolism has important clinical indications. Lipoproteins are risk factors for cardiovascular disease. Recent advances include the identification of factors in the synthesis and secretion of triglyceride rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL). These included the identification of microsomal transfer protein, the cotranslational targeting of apoproteinB (apoB) for degradation regulated by the availability of lipids, and the characterization of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation factor 1, glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 and an angiopoietin-like protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right amount of fatty acid is delivered to the right tissue at the right time. Expression of the low density lipoprotein (LDL) receptor is regulated at both transcriptional and post-transcriptional level. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a pivotal role in the degradation of LDL receptor. Plasma remnant lipoproteins bind to specific receptors in the liver, the LDL receptor, VLDL receptor and LDL receptor-like proteins prior to removal from the plasma. Reverse cholesterol transport occurs when lipid free apoAI recruits cholesterol and phospholipid to assemble high density lipoprotein (HDL) particles. The discovery of ABC transporters (ABCA1 and ABCG1) and scavenger receptor class B type I (SR-BI) provided further information on the biogenesis of HDL. In humans HDL-cholesterol can be returned to the liver either by direct uptake by SR-BI or through cholesteryl ester transfer protein exchange of cholesteryl ester for triglycerides in apoB lipoproteins, followed by hepatic uptake of apoB containing particles. Cholesterol content in cells is regulated by several

  15. [Lipoprotein lipase and diabetic cardiomyopathy].

    PubMed

    Liu, Xiang-Yu; Yin, Wei-Dong; Tang, Chao-Ke

    2014-02-01

    Lipoprotein lipase (LPL) hydrolyzes plasma triglyceride-rich lipoproteins into free fatty acids (FFA) to provide energy for cardiac tissue. During diabetes, cardiac energy supply is insufficient due to defected utilization of glucose. As a compensation of cardiac energy supply, FFAs are released through the hydrolysis of very low density lipoprotein (VLDL) and chylomicrons (CM) due to activation of LPL activity. In diabetic patients, activated LPL activity and elevated FFAs result in the intracellular accumulation of reactive oxygen species and lipids in myocardium and potentially induce the diabetic cardiomyopathy (DCM). The present review summarizes the regulatory mechanisms of myocardial LPL and the pathogenesis of DCM induced by LPL and provides novel therapeutic targets and pathways for DCM. PMID:24873138

  16. Computational studies of plasma lipoprotein lipids.

    PubMed

    Pan, Lurong; Segrest, Jere P

    2016-10-01

    Plasma lipoproteins are macromolecular assemblies of proteins and lipids found in the blood. The lipid components of lipoproteins are amphipathic lipids such as phospholipids (PLs), and unesterified cholesterols (UCs) and hydrophobic lipids such as cholesteryl esters (CEs) and triglycerides (TGs). Since lipoproteins are soft matter supramolecular assemblies easily deformable by thermal fluctuations and they also exist in varying densities and protein/lipid components, a detailed understanding of their structure/function is experimentally difficult. Molecular dynamics (MD) simulation has emerged as a particularly promising way to explore the structure and dynamics of lipoproteins. The purpose of this review is to survey the current status of computational studies of the lipid components of the lipoproteins. Computational studies aim to explore three levels of complexity for the 3-dimensional structural dynamics of lipoproteins at various metabolic stages: (i) lipoprotein particles consist of protein with minimal lipid; (ii) lipoprotein particles consist of PL-rich discoidal bilayer-like lipid particles; (iii) mature circulating lipoprotein particles consist of CE-rich or TG-rich spheroidal lipid-droplet-like particles. Due to energy barriers involved in conversion between these species, other biomolecules also participate in lipoprotein biological assembly. For example: (i) lipid-poor apolipoprotein A-I (apoA-I) interacts with ATP-binding cassette transporter A1 (ABCA1) to produce nascent discoidal high density lipoprotein (dHDL) particles; (ii) lecithin-cholesterol acyltransferase (LCAT) mediates the conversion of UC to CE in dHDL, driving spheroidal HDL (sHDL) formation; (iii) transfer proteins, cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP), transfer both CE and TG and PL, respectively, between lipoprotein particles. Computational studies have the potential to explore different lipoprotein particles at each metabolic stage in

  17. Lipoprotein abnormalities in South Asians and its association with cardiovascular disease: Current state and future directions

    PubMed Central

    Bilen, Ozlem; Kamal, Ayeesha; Virani, Salim S

    2016-01-01

    South Asians have a high prevalence of coronary heart disease (CHD) and suffer from early-onset CHD compared to other ethnic groups. Conventional risk factors may not fully explain this increased CHD risk in this population. Indeed, South Asians have a unique lipid profile which may predispose them to premature CHD. Dyslipidemia in this patient population seems to be an important contributor to the high incidence of coronary atherosclerosis. The dyslipidemia in South Asians is characterized by elevated levels of triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, elevated lipoprotein(a) levels, and a higher atherogenic particle burden despite comparable low-density lipoprotein cholesterol levels compared with other ethnic subgroups. HDL particles also appear to be smaller, dysfunctional, and proatherogenic in South Asians. Despite the rapid expansion of the current literature with better understanding of the specific lipid abnormalities in this patient population, studies with adequate sample sizes are needed to assess the significance and contribution of a given lipid parameter on overall cardiovascular risk in this population. Specific management goals and treatment thresholds do not exist for South Asians because of paucity of data. Current treatment recommendations are mostly extrapolated from Western guidelines. Lastly, large, prospective studies with outcomes data are needed to assess cardiovascular benefit associated with various lipid-lowering therapies (including combination therapy) in this patient population. PMID:27022456

  18. High density harp for SSCL linac

    SciTech Connect

    Fritsche, C.T.; Krogh, M.L.; Crist, C.E.

    1993-05-01

    AlliedSignal Inc., Kansas City Division, and the Superconducting Super Collider Laboratory (SSCL) are collaboratively developing a high density harp for the SSCL linac. This harp is designed using hybrid microcircuit (HMC) technology to obtain a higher wire density than previously available. The developed harp contains one hundred twenty-eight 33-micron-diameter carbon wires on 0.38-mm centers. The harp features an onboard broken wire detection circuit. Carbon wire preparation and attachment processes were developed. High density surface mount connectors were located. The status of high density harp development will be presented along with planned future activities.

  19. Characterization of the serum lipoproteins and their apoproteins in hypercholesterolaemic guinea pigs.

    PubMed Central

    Chapman, M J; Mills, G L

    1977-01-01

    1. Hypercholesterolaemia was induced in male guinea pigs after 6 days on a chow diet supplemented with 1.6% (w/w) cholesterol and 15% (w/w) corn oil. Both the VLD (very-low-density) and LD (low-density) lipoproteins were increased in cholesterol-fed animals, although the low concentrations of HD (high-density) lipoproteins remained essentially unchanged. LD lipoproteins of d 1.019-1.100 were the major class, accounting for 74% of the total substances of d less than 1.100. 2. Both VLD and LD lipoproteins exhibited alterations in their chemical composition, physical properties and apolipoprotein content. The VLD lipoproteins in cholesterolaemic animals were rich in cholesterol (25.9%), deficient in protein (4.9%) and exhibited electrophoretic mobility greater than that of beta-globulin; their average particle size (64.5 nm) was larger than that in controls (46.3 nm). The LD lipoproteins in animals fed on the experimental diet were also richer in cholesterol (53.1%) and of larger diameter (24.3 nm) than in the control group (41.1% and 21.4 nm respectively). 3. The apolipoprotein-B content of both VLD and LD lipoproteins was elevated in cholesterolaemic animals, particularly in the VLD class, where it represented 74.8% of the total protein moiety. 4. Apo-VLD lipoprotein exhibited an increase from 6 to 19% in its complement of tetramethylurea-soluble apolipoproteins with low electrophoretic mobility (relative mobility less than 0.29); this was primarily accounted for by apolipoproteins characterized by high arginine (7.2 and 6.4% respectively) and glutamic acid (20.1 and 20.0% respectively) contents. 5. By contrast, there was little change in the soluble apolipoproteins of LD lipoproteins in hypercholesterolaemic animals.6. These studies show the response of the guinea pig to dietary fat and cholesterol to be distinct from that elicited by similar stimuli in the rabbit, rat, pig and dog. Images PLATE 1 PLATE 2 PLATE 3 PLATE 4 PMID:588269

  20. [Biochemistry of the developmental cycle of Triatoma infestans (Vinchuca). VI. Identification and lipid composition of hemolymph lipoproteins of adult males].

    PubMed

    Fichera, L E; Brenner, R R

    1982-01-01

    Three lipoproteins were separated from the haemolymph of adult males of Triatoma infestans fed on hen blood. The densities were similar to the high density lipoprotein (HDL) and to two very high density lipoproteins (VHDL) isolated from a pool of adult male and female insects fasted during twelve days. The relative distribution and composition of the three lipoproteins were studied. The fatty acids were mainly carried by the 1.3 and 1.2 diacylglycerols of high density lipoprotein. Triacylglycerols were minor components. Similarly to fasted insects, the main fatty acids were oleic and palmitic. Linoleic was also present. Very high density lipoproteins (VHDL-II) (d 1.25-1.26) were found in the haemolymph of male insects. The relative distribution of HDL and VHDL on fed and fasted insects was different. PMID:6760669

  1. High Density Fuel Development for Research Reactors

    SciTech Connect

    Daniel Wachs; Dennis Keiser; Mitchell Meyer; Douglas Burkes; Curtis Clark; Glenn Moore; Jan-Fong Jue; Totju Totev; Gerard Hofman; Tom Wiencek; Yeon So Kim; Jim Snelgrove

    2007-09-01

    An international effort to develop, qualify, and license high and very high density fuels has been underway for several years within the framework of multi-national RERTR programs. The current development status is the result of significant contributions from many laboratories, specifically CNEA in Argentina, AECL in Canada, CEA in France, TUM in Germany, KAERI in Korea, VNIIM, RDIPE, IPPE, NCCP and RIARR in Russia, INL, ANL and Y-12 in USA. These programs are mainly engaged with UMo dispersion fuels with densities from 6 to 8 gU/cm3 (high density fuel) and UMo monolithic fuel with density as high as 16 gU/cm3 (very high density fuel). This paper, mainly focused on the French & US programs, gives the status of high density UMo fuel development and perspectives on their qualification.

  2. High density load bearing insulation peg

    DOEpatents

    Nowobilski, J.J.; Owens, W.J.

    1985-01-29

    A high density peg is disclosed which can support a large load and exhibits excellent thermal resistance produced by a method wherein the peg is made in compliance with specified conditions of time, temperature and pressure. 4 figs.

  3. High density load bearing insulation peg

    DOEpatents

    Nowobilski, Jeffert J.; Owens, William J.

    1985-01-01

    A high density peg which can support a large load and exhibits excellent thermal resistance produced by a method wherein the peg is made in compliance with specified conditions of time, temperature and pressure.

  4. Genome-wide association study indicates variants associated with insulin signaling and inflammation mediate lipoprotein responses to fenofibrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A shift towards overall larger very low-density lipoprotein (VLDL), and smaller low-density lipoprotein and high-density lipoprotein (HDL) diameters occurs in insulin resistance (IR), which reflects shifts in the distribution of the subfraction concentrations. Fenofibrate, indicated for hypertriglyc...

  5. Identification of the major lipoproteins in crayfish hemolymph as proteins involved in immune recognition and clotting.

    PubMed

    Hall, M; van Heusden, M C; Söderhäll, K

    1995-11-22

    Lipid-containing hemolymph proteins from males of the crayfish Pacifastacus leniusculus were isolated by density gradient ultracentrifugation. Two major lipoproteins, one high density lipoprotein (HDL) and one very high density lipoprotein (VHDL), were characterized. The HDL and the VHDL were found to be identical to two proteins previously studied for their roles in immune recognition and hemolymph clotting, namely the beta-1,3-glucan binding protein and the clotting protein. These results imply that crayfish lipoproteins have dual functions, and that they are involved in immunity, hemolymph clotting, and lipid transport in these animals. Also, the oxygen-transporting protein hemocyanin was found to have a small lipid content. PMID:7488215

  6. Apolipoprotein C-II deficiency syndrome. Clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients.

    PubMed Central

    Baggio, G; Manzato, E; Gabelli, C; Fellin, R; Martini, S; Enzi, G B; Verlato, F; Baiocchi, M R; Sprecher, D L; Kashyap, M L

    1986-01-01

    Two patients (brother and sister, 41 and 39 yr of age, respectively) have been shown to have marked elevation of plasma triglycerides and chylomicrons, decreased low density lipoproteins (LDL) and high density lipoproteins (HDL), a type I lipoprotein phenotype, and a deficiency of plasma apolipoprotein C-II (apo C-II). The male patient had a history of recurrent bouts of abdominal pain often accompanied by eruptive xanthomas. The female subject, identified by family screening, was asymptomatic. Hepatosplenomegaly was present in both subjects. Analytical and zonal ultracentrifugation revealed a marked increase in triglyceride-rich lipoproteins including chylomicrons and very low density lipoproteins, a reduction in LDL, and the presence of virtually only the HDL3 subfraction. LDL were heterogeneous with the major subfraction of a higher hydrated density than that observed in plasma lipoproteins of normal subjects. Apo C-II levels, quantitated by radioimmunoassay, were 0.13 mg/dl and 0.12 mg/dl, in the male and female proband, respectively. A variant of apo C-II (apo C-IIPadova) with lower apparent molecular weight and more acidic isoelectric point was identified in both probands by two-dimensional gel electrophoresis. The marked hypertriglyceridemia and elevation of triglyceride-rich lipoproteins were corrected by the infusion of normal plasma or the injection of a biologically active synthesized 44-79 amino acid residue peptide fragment of apo C-II. The reduction in plasma triglycerides after the injection of the synthetic apo C-II peptide persisted for 13-20 d. These results definitively established that the dyslipoproteinemia in this syndrome is due to a deficiency of normal apo C-II. A possible therapeutic role for replacement therapy of apo C-II by synthetic or recombinant apo C-II in those patients with severe hypertriglyceridemia and recurrent pancreatitis may be possible in the future. Images PMID:3944267

  7. High Density Digital Data Storage System

    NASA Technical Reports Server (NTRS)

    Wright, Kenneth D., II; Gray, David L.; Rowland, Wayne D.

    1991-01-01

    The High Density Digital Data Storage System was designed to provide a cost effective means for storing real-time data from the field-deployable digital acoustic measurement system. However, the high density data storage system is a standalone system that could provide a storage solution for many other real time data acquisition applications. The storage system has inputs for up to 20 channels of 16-bit digital data. The high density tape recorders presently being used in the storage system are capable of storing over 5 gigabytes of data at overall transfer rates of 500 kilobytes per second. However, through the use of data compression techniques the system storage capacity and transfer rate can be doubled. Two tape recorders have been incorporated into the storage system to produce a backup tape of data in real-time. An analog output is provided for each data channel as a means of monitoring the data as it is being recorded.

  8. Aerodynamic Focusing Of High-Density Aerosols

    SciTech Connect

    Ruiz, D. E.; Fisch, Nathaniel

    2014-02-24

    High-density micron-sized particle aerosols might form the basis for a number of applications in which a material target with a particular shape might be quickly ionized to form a cylindrical or sheet shaped plasma. A simple experimental device was built in order to study the properties of high-density aerosol focusing for 1 m silica spheres. Preliminary results recover previous findings on aerodynamic focusing at low densities. At higher densities, it is demonstrated that the focusing properties change in a way which is consistent with a density dependent Stokes number.

  9. Increased production of apolipoprotein B and its lipoproteins by oleic acid in Caco-2 cells.

    PubMed

    Dashti, N; Smith, E A; Alaupovic, P

    1990-01-01

    The production of lipids, apolipoproteins (apo), and lipoproteins induced by oleic acid has been examined in Caco-2 cells. The rates of accumulation in the control medium of 15-day-old Caco-2 cells of triglycerides, unesterified cholesterol, and cholesteryl esters were 102 +/- 8, 73 +/- 5, and 11 +/- 1 ng/mg cell protein/h, respectively; the accumulation rates for apolipoproteins A-I, B, C-III, and E were 111 +/- 9, 53 +/- 4, 13 +/- 1, and 63 +/- 4 ng/mg cell protein/h, respectively. Whereas apolipoproteins A-IV and C-II were detected by immunoblotting, apoA-II was absent in most culture media. In contrast to an early production of apolipoproteins A-I and E occurring 2 days after plating, the apoB expression appeared to be differentiation-dependent and was not measurable in the medium until the sixth day post-confluency. In the control medium, very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL), and lipid-poor very high density lipoproteins (VHDL) accounted for 12%, 46%, 18%, and 24% of the total lipid and apolipoprotein contents, respectively. The triglyceride-rich VLDL contained mainly apoE (75%) and apoB (23%), while the protein moiety of LDL was composed of apoB (59%), apoE (20%), apoA-I (15%), and apoC-III (6%). The cholesterol-rich HDL contained mainly apoA-I (69%) and apoE (27%). In the control medium, major portions of apolipoproteins B and C-III (93-97%) were present in LDL, whereas the main parts of apoA-I (92%) and apoE (76%) were associated with HDL and VHDL. Oleate increased the production of triglycerides 10-fold, cholesteryl esters 7-fold, and apoB 2- to 4-fold. There was also a moderate increase (39%) in the production of apoC-III but no significant changes in those of apolipoproteins A-I and E. These increases were reflected mainly in a 55-fold elevation in the concentration of VLDL, and a 2-fold increase in the level of LDL; there were no significant changes in HDL and VHDL. VLDL contained the

  10. High density carbon dispersion fuels program

    NASA Technical Reports Server (NTRS)

    Salvesen, R. H.; Lavid, M.

    1980-01-01

    High density carbon dispersion fuels were studied. Promising results were obtained which indicate stable carbon loaded fuels with a minimum of 180,000 Btu per gallon can be made and successfully burned in prototype turbine combustors components. Tests were completed which provide insights to obtaining a better understanding of what types of carbon can be successfully formulated and combusted.

  11. Supernovae and high density nuclear matter

    SciTech Connect

    Kahana, S.

    1986-01-01

    The role of the nuclear equation of state (EOS) in producing prompt supernova explosions is examined. Results of calculations of Baron, Cooperstein, and Kahana incorporating general relativity and a new high density EOS are presented, and the relevance of these calculations to laboratory experiments with heavy ions considered. 31 refs., 6 figs., 2 tabs.

  12. High density laser-driven target

    DOEpatents

    Lindl, John D.

    1981-01-01

    A high density target for implosion by laser energy composed of a central quantity of fuel surrounded by a high-Z pusher shell with a low-Z ablator-pusher shell spaced therefrom forming a region filled with low-density material.

  13. High Density Diffusion-Free Nanowell Arrays

    PubMed Central

    Takulapalli, Bharath R; Qiu, Ji; Magee, D. Mitchell; Kahn, Peter; Brunner, Al; Barker, Kristi; Means, Steven; Miersch, Shane; Bian, Xiaofang; Mendoza, Alex; Festa, Fernanda; Syal, Karan; Park, Jin; LaBaer, Joshua; Wiktor, Peter

    2012-01-01

    Proteomics aspires to elucidate the functions of all proteins. Protein microarrays provide an important step by enabling high-throughput studies of displayed proteins. However, many functional assays of proteins include untethered intermediates or products, which could frustrate the use of planar arrays at very high densities because of diffusion to neighboring features. The nucleic acid programmable protein array (NAPPA), is a robust, in situ synthesis method for producing functional proteins just-in-time, which includes steps with diffusible intermediates. We determined that diffusion of expressed proteins led to cross-binding at neighboring spots at very high densities with reduced inter-spot spacing. To address this limitation, we have developed an innovative platform using photolithographically-etched discrete silicon nanowells and used NAPPA as a test case. This arrested protein diffusion and cross-binding. We present confined high density protein expression and display, as well as functional protein-protein interactions, in 8,000 nanowell arrays. This is the highest density of individual proteins in nano-vessels demonstrated on a single slide. We further present proof of principle results on ultra-high density protein arrays capable of up to 24,000 nanowells on a single slide. PMID:22742968

  14. Lipoprotein(a) metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein. The metabolism of this lipoprotein is still not well understood. It has long been known that the plasma concentration of Lp(a) is highly heritable, with its genetic determinants located in the apo(a) locus and regulating the rate of hepatic apo(a...

  15. Effects of zinc and cholesterol/choleate on serum lipoproteins and the liver in rats

    SciTech Connect

    Cho, C.H.; Chen, S.M.; Ogle, C.W.; Young, T.K.

    1989-01-01

    The effects of short-term treatment with orally-administered zinc sulfate and/or a mixture of cholesterol/choleate on serum lipoprotein and hepatic enzyme levels were studied. Administration of graded doses of zinc sulfate for 5 days, dose-dependently increased serum and hepatic zinc levels but depressed the serum high-density lipoprotein-cholesterol (HDL-C) concentration and liver cytochrome P-450 activity. However, it did not affect hepatic concentrations of malondialdehyde and free {beta}-glucuronidase. Cholesterol/choleate treatment for 5 days markedly damaged the liver, as reflected by elevations of hepatic concentrations of malondialdehyde (both in the mitochondrial and microsomal fractions) and of free {beta}-glucuronidase; total cholesterol and low-density lipoprotein-cholesterol in the blood were increased, whereas HDL-C was decreased significantly. Concomitant administration of zinc sulfate with cholesterol/choleate further lowered HDL-C levels, but reversed the high hepatic concentrations of both malondialdehyde and free {beta}-glucuronidase. The present study indicates that both zinc ions and cholesterol can decrease circulatory HDL-C levels and that zinc protects against cholesterol-induced hepatic damage by reducing lysosomal enzyme release and preventing lipid peroxidation in the liver.

  16. Lipoprotein ratios: Physiological significance and clinical usefulness in cardiovascular prevention

    PubMed Central

    Millán, Jesús; Pintó, Xavier; Muñoz, Anna; Zúñiga, Manuel; Rubiés-Prat, Joan; Pallardo, Luis Felipe; Masana, Luis; Mangas, Alipio; Hernández-Mijares, Antonio; González-Santos, Pedro; Ascaso, Juan F; Pedro-Botet, Juan

    2009-01-01

    Low-density lipoprotein (LDL) cholesterol concentration has been the prime index of cardiovascular disease risk and the main target for therapy. However, several lipoprotein ratios or “atherogenic indices” have been defined in an attempt to optimize the predictive capacity of the lipid profile. In this review, we summarize their pathophysiological aspects, and highlight the rationale for using these lipoprotein ratios as cardiovascular risk factors in clinical practice, specifying their cut-off risk levels and a target for lipid-lowering therapy. Total/high-density lipoprotein (HDL) cholesterol and LDL/HDL cholesterol ratios are risk indicators with greater predictive value than isolated parameters used independently, particularly LDL. Future recommendations regarding the diagnosis and treatment of dyslipidemia, including instruments for calculating cardiovascular risk or action guidelines, should include the lipoprotein ratios with greater predictive power which, in view of the evidence-based results, are none other than those which include HDL cholesterol. PMID:19774217

  17. Apolipoprotein A-V Deficiency Results in MarkedHypertriglyceridemia Attributable to Decreased Lipolysis ofTriglyceride-Rich Lipoproteins and Removal of Their Remnants

    SciTech Connect

    Grosskopf, Itamar; Baroukh, Nadine; Lee, Sung-Joon; Kamari,Yehuda; Harats, Dror; Rubin, Edward M.; Pennacchio, Len A.; Cooper, AllenD.

    2005-09-01

    Objective--ApoAV, a newly discovered apoprotein, affectsplasma triglyceride level. To determine how this occurs, we studiedtriglyceride-rich lipoprotein (TRL) metabolism in mice deficient inapoAV. Methods and Results No significant difference in triglycerideproduction rate was found between apoa5_/_ mice and controls. Thepresence or absence of apoAV affected TRL catabolism. After the injectionof 14C-palmitate and 3H-cholesterol labeled chylomicrons and 125I-labeledchylomicron remnants, the disappearance of 14C, 3H, and 125I wassignificantly slower in apoa5_/_ mice relative to controls. This wasbecause of diminished lipolysis of TRL and the reduced rate of uptake oftheir remnants in apoa5_/_ mice. Observed elevated cholesterol level wascaused by increased high-density lipoprotein (HDL) cholesterol inapoa5_/_ mice. VLDL from apoa5_/_ mice were poor substrate forlipoprotein lipase, and did not bind to the low-density lipoprotein (LDL)receptor as well as normal very-low-density lipoprotein (VLDL). LDLreceptor levels were slightly elevated in apoa5_/_ mice consistent withlower remnant uptake rates. These alterations may be the result of thelower apoE-to-apoC ratio found in VLDL isolated from apoa5_/_mice.Conclusions These results support the hypothesis that the absence ofapoAV slows lipolysis of TRL and the removal of their remnants byregulating their apoproteins content after secretion.

  18. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.

    PubMed Central

    Watson, A D; Berliner, J A; Hama, S Y; La Du, B N; Faull, K F; Fogelman, A M; Navab, M

    1995-01-01

    Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM-LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi-oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL. Images PMID:8675659

  19. Lipoproteins, nutrition, and heart disease.

    PubMed

    Schaefer, Ernst J

    2002-02-01

    This article reviews the current status of our knowledge of lipoproteins, nutrition, and coronary heart disease (CHD). Special emphasis is placed on CHD risk assessment, dietary intervention studies, diet-gene interactions, and current dietary guidelines and the contributions of my laboratory to these areas. CHD remains a major cause of death and disability, and risk factors include age, sex, hypertension, smoking, diabetes, elevated serum LDL cholesterol, and low HDL cholesterol. Emerging independent risk factors include elevated serum concentrations of lipoprotein(a), remnant lipoproteins, and homocysteine. The cornerstone of CHD prevention is lifestyle modification. Dietary intervention studies support the concepts that restricting saturated fat and cholesterol and increasing the intake of essential fatty acids, especially n - 3 fatty acids, reduces CHD risk. The variability in LDL-cholesterol response to diet is large, related in part to APOE and APOA4 genotype. The use of antioxidants in intervention studies has not been shown to reduce CHD risk. Compliance with dietary recommendations remains a major problem, and directly altering the food supply may be the most effective way to ensure compliance. The available data indicate that the recommendation to use fats, oils, and sugars sparingly for CHD prevention should be modified to a recommendation to use animal, dairy, and hydrogenated fats; tropical oils; egg yolks; and sugars sparingly and to increase the use of vegetables, fruit, and whole grains. PMID:11815309

  20. Lipoprotein sorting in bacteria.

    PubMed

    Okuda, Suguru; Tokuda, Hajime

    2011-01-01

    Bacterial lipoproteins are synthesized as precursors in the cytoplasm and processed into mature forms on the cytoplasmic membrane. A lipid moiety attached to the N terminus anchors these proteins to the membrane surface. Many bacteria are predicted to express more than 100 lipoproteins, which play diverse functions on the cell surface. The Lol system, composed of five proteins, catalyzes the localization of Escherichia coli lipoproteins to the outer membrane. Some lipoproteins play vital roles in the sorting of other lipoproteins, lipopolysaccharides, and β-barrel proteins to the outer membrane. On the basis of results from biochemical, genetic, and structural studies, we discuss the biogenesis of lipoproteins in bacteria, their importance in cellular functions, and the molecular mechanisms underlying efficient sorting of hydrophobic lipoproteins to the outer membrane through the hydrophilic periplasm. PMID:21663440

  1. Prothrombotic lipoprotein patterns in stroke.

    PubMed

    Podrez, Eugene A; Byzova, Tatiana V

    2016-03-10

    The importance of research focused on the final events of atherothrombosis cannot be overestimated. Platelet hyperreactivity leading to thrombosis is the main reason for mortality and morbidity in patients with cardiovascular disease and stroke, which together remain a leading cause of death in developed countries. In this issue of Blood, Shen et al1 establish another functional link between proatherogenic lipoproteins and platelet-mediated thrombus formation with a specific focus on stroke. In their model, the initiating component is L5, the electronegative subfraction of low-density lipoproteins (LDLs), which was shown to be substantially elevated in patients with ischemic stroke. L5 was shown to activate platelets via its receptor, lectin-like oxidized LDL receptor-1 (LOX-1), and αβ amyloid peptide, which together contribute to platelet hyperreactivity and stroke complications. PMID:26965920

  2. The high density Z-pinch

    NASA Astrophysics Data System (ADS)

    McCall, G. H.

    During the past few years techniques have been developed for producing pinches in solid deuterium. The conditions which exist in these plasmas are different from those produced earlier. The pinch is formed from a fiber of solid deuterium rather than from a low density gas, and the current is driven by a low impedance, high voltage pulse generator. Because of the high initial density, it is not necessary to compress the pinch to reach thermonuclear conditions, and the confinement time required for energy production is much shorter than for a gas. Results, which have been verified by experiments performed at higher current were quite surprising and encouraging. The pinch appeared to be stable for a time much longer than the Alfven radial transit time. It is argued that the pinch is not strictly stable, but it does not appear to disassemble in a catastrophic fashion. It appears that there may be a distinction between stability and confinement in the high density pinch. In the discussion below the status of the high density Z-pinch experiments at laboratories around the world is presented, and some of the calculational and experimental results described. Remarks are confined to recent work on the high density pinch.

  3. High density diffusion-free nanowell arrays.

    PubMed

    Takulapalli, Bharath R; Qiu, Ji; Magee, D Mitchell; Kahn, Peter; Brunner, Al; Barker, Kristi; Means, Steven; Miersch, Shane; Bian, Xiaofang; Mendoza, Alex; Festa, Fernanda; Syal, Karan; Park, Jin G; LaBaer, Joshua; Wiktor, Peter

    2012-08-01

    Proteomics aspires to elucidate the functions of all proteins. Protein microarrays provide an important step by enabling high-throughput studies of displayed proteins. However, many functional assays of proteins include untethered intermediates or products, which could frustrate the use of planar arrays at very high densities because of diffusion to neighboring features. The nucleic acid programmable protein array (NAPPA) is a robust in situ synthesis method for producing functional proteins just-in-time, which includes steps with diffusible intermediates. We determined that diffusion of expressed proteins led to cross-binding at neighboring spots at very high densities with reduced interspot spacing. To address this limitation, we have developed an innovative platform using photolithographically etched discrete silicon nanowells and used NAPPA as a test case. This arrested protein diffusion and cross-binding. We present confined high density protein expression and display, as well as functional protein-protein interactions, in 8000 nanowell arrays. This is the highest density of individual proteins in nanovessels demonstrated on a single slide. We further present proof of principle results on ultrahigh density protein arrays capable of up to 24000 nanowells on a single slide. PMID:22742968

  4. Lipolytic degradation of human very low density lipoproteins by human milk lipoprotein lipase: the identification of lipoprotein B as the main lipoprotein degradation product.

    PubMed

    Alaupovic, P; Wang, C S; McConathy, W J; Weiser, D; Downs, D

    1986-01-01

    Although the direct conversion of very low density lipoproteins (VLDL) into low density (LDL) and high density (HDL) lipoproteins only requires lipoprotein lipase (LPL) as a catalyst and albumin as the fatty acid acceptor, the in vitro-formed LDL and HDL differ chemically from their native counterparts. To investigate the reason(s) for these differences, VLDL were treated with human milk LPL in the presence of albumin, and the LPL-generated LDL1-, LDL2-, and HDL-like particles were characterized by lipid and apolipoprotein composition. Results showed that the removal of apolipoproteins B, C, and E from VLDL was proportional to the degree of triglyceride hydrolysis with LDL2 particles as the major and LDL1 and HDL + VHDL particles as the minor products of a complete in vitro lipolysis of VLDL. In comparison with native counterparts, the in vitro-formed LDL2 and HDL + VHDL were characterized by lower levels of triglyceride and cholesterol ester and higher levels of free cholesterol and lipid phosphorus. The characterization of lipoprotein particles present in the in vitro-produced LDL2 showed that, as in plasma LDL2, lipoprotein B (LP-B) was the major apolipoprotein B-containing lipoprotein accounting for over 90% of the total apolipoprotein B. Other, minor species of apolipoprotein B-containing lipoproteins included LP-B:C-I:E and LP-B:C-I:C-II:C-III. The lipid composition of in vitro-formed LP-B closely resembled that of plasma LP-B. The major parts of apolipoproteins C and E present in VLDL were released to HDL + VHDL as simple, cholesterol/phospholipid-rich lipoproteins including LP-C-I, LP-C-II, LP-C-III, and LP-E. However, some of these same simple lipoprotein particles were present after ultracentrifugation in the LDL2 density segment because of their hydrated density and/or because they formed, in the absence of naturally occurring acceptors (LP-A-I:A-II), weak associations with LP-B. Thus, the presence of varying amounts of these cholesterol

  5. 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.

  6. Phospholipid transfer from vesicles to high density lipoproteins, catalyzed by human plasma phospholipid transfer protein

    SciTech Connect

    Sweeny, S.A.

    1985-01-01

    Human plasma phospholipid transfer protein (PLTP) catalyzes the mass transfer of phosphatidylcholine (PC). Partial purification of PLTP yielded proteins with apparent M/sub r/ = 59,000 and 40,000 by SDS-PAGE. PLTP activity was measured by transfer of (/sup 14/C)L-..cap alpha..-dipalmitoyl PC from egg-PC vesicles to HDL. Activity was enhanced at low pH (4.5) upon addition of ..beta..-mercaptoethanol while Ca/sup +2/ and Na/sup +/ had no effect. E/sub act/ for facilitated PC transfer was 18.2 +/- 2 kcal/mol. The donor specificity of PLTP was examined using vesicles containing egg-PC plus cholesterol or sphingomyelin. The fluidity of the donor membrane (measured by fluorescence polarization of diphenylhexatriene) correlated strongly with a decrease in PLTP activity. Phosphatidic acid did not affect activity. Increase in vesicle size reduced activity. The acceptor specificity of PLTP was examined using chemically modified HDL. PLTP activity increased up to 1.7-fold with an initial increase in negative charge and then decreased upon extensive modification. A mechanism is proposed where PLTP binds to vesicls and enhances the diffusion of PC into the medium where it is adsorbed by HDL.

  7. Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

    PubMed Central

    Vrins, Carlos L. J.; Out, Ruud; van Santbrink, Peter; van der Zee, André; Mahmoudi, Tokameh; Groenendijk, Martine; Havekes, Louis M.; van Berkel, Theo J. C.; van Dijk, Ko Willems; Biessen, Erik A. L.

    2013-01-01

    Background The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr−/− mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl−/− mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels. PMID:23469003

  8. APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema

    PubMed Central

    Burkart, Kristin M; Manichaikul, Ani; Wilk, Jemma B; Ahmed, Firas S; Burke, Gregory L; Enright, Paul; Hansel, Nadia N; Haynes, Demondes; Heckbert, Susan R; Hoffman, Eric A; Kaufman, Joel D; Kurai, Jun; Loehr, Laura; London, Stephanie J; Meng, Yang; O’Connor, George T; Oelsner, Elizabeth; Petrini, Marcy; Pottinger, Tess D; Powell, Charles A; Redline, Susan; Rotter, Jerome I; Smith, Lewis J; Artigas, María Soler; Tobin, Martin D; Tsai, Michael Y; Watson, Karol; White, Wendy; Young, Taylor R; Rich, Stephen S; Barr, R Graham

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second ge