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Sample records for plasma hdl cholesterol

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2009-05-01

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

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

    SciTech Connect

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

    1990-11-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2007-05-01

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

  6. Raising HDL cholesterol in women

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    1994-01-01

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

  9. HDL Function, Dysfunction, and Reverse Cholesterol Transport

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2014-08-01

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

  11. Intestinal nuclear receptors in HDL cholesterol metabolism

    PubMed Central

    Degirolamo, Chiara; Sabbà, Carlo; Moschetta, Antonio

    2015-01-01

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

  12. Intestinal nuclear receptors in HDL cholesterol metabolism.

    PubMed

    Degirolamo, Chiara; Sabbà, Carlo; Moschetta, Antonio

    2015-07-01

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

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

    PubMed

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

    2015-02-01

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

  14. [The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy].

    PubMed

    Dobiásová, M; Frohlich, J

    2000-03-01

    The new atherogenic plasma index (AIP) is a logarithmic transformation of the ratio of the molar triglyceride (TG) concentration and high density lipoprotein cholesterol (HDL-C). AIP correlates closely with the size of LDL particles (r = 0.8) and esterification rate of plasma cholesterol devoid of apo B lipoproteins (FERHDL), r = 0.9 which are considered at present the most sensitive indicators of the atherogenic plasma profile. AIP was recommended by the authors, based on analysis of results of 11 previous studies (1156 subjects) where FERHDL and plasma lipid parameters were investigated in different groups of people who differed as to the atherogenic risk. The AIP index was moreover used for evaluation of a clinical study comprising 609 patients with hyperlipidaemia, who were treated for three months with ciprofibrate (Lipanor). The mean AIP values of non-risk groups (plasma from umbilical blood, children, healthy women etc.) equalled zero or were lower, while with an increasing atherogenic risk (men, women after the menopause) AIP reached positive values, incl. high positive values in risk groups (plasma of diabetic subjects, patients with HLP, patients with positive angiography, myocardial infarction etc.). In all groups women had lower AIP values as compared with males. In patients after Lipanor therapy the AIP declined (from 0.58 +/- 0.17 to 0.33_0.18 in men, from 0.50 +/- 0.18 to 0.21 +/- 0.19 in women). If we consider AIP values from negative ones to 0.15 as "safe" from the aspect of atherogenicity, before Lipanor treatment these "safe" levels were recorded in 1.5% men and in 5.2% women and after treatment in 32% men and 48% women. The results indicate, that AIP which reflects the plasma lipoprotein profile quantifies the relations between TG and HDL-C and thus can be an objective indicator of the atherogenic risk and effectiveness of treatment and it is useful because it can be assessed in any surgery. PMID:11048517

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

    PubMed

    Brea Hernando, Ángel Julián

    2014-07-01

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2013-10-01

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

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

    PubMed

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

    2013-12-15

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

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

    PubMed Central

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

    2011-01-01

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

  1. HDL-Mediated Cellular Cholesterol Efflux Assay Method.

    PubMed

    Hafiane, Anouar; Genest, Jacques

    2015-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

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

    2015-08-01

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

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

    PubMed

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

    1992-01-01

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

  5. Synbiotic food consumption reduces levels of triacylglycerols and VLDL, but not cholesterol, LDL, or HDL in plasma from pregnant women.

    PubMed

    Taghizadeh, Mohsen; Hashemi, Teibeh; Shakeri, Hossein; Abedi, Fatemeh; Sabihi, Sima-Sadat; Alizadeh, Sabihe-Alsadat; Asemi, Zatolla

    2014-02-01

    To our knowledge, no reports are available indicating the effects of synbiotic food consumption on blood lipid profiles and biomarkers of oxidative stress among pregnant women. This study was conducted to evaluate the effects of daily consumption of a synbiotic food on blood lipid profiles and biomarkers of oxidative stress in pregnant women. This randomized, double-blind, controlled clinical trial was performed among 52 primigravida pregnant women, aged 18 to 35-year-old at their third trimester. After a 2-week run-in period, subjects were randomly assigned to consume either a synbiotic (n = 26) or control food (n = 26) for 9 weeks. The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes (1 × 10⁷ CFU) and 0.04 g inulin (HPX)/g as the prebiotic. Patients were asked to consume the synbiotic and control foods two times a day. Biochemical measurements including blood lipid profiles, plasma total antioxidant capacity (TAC) and total glutathione (GSH) were conducted before and after 9 weeks of intervention. Consumption of a synbiotic food for 9 weeks resulted in a significant reduction in serum TAG (P = 0.04), VLDL (P = 0.04) and a significant rise in plasma GSH levels (P = 0.004) compared to the control food. No significant effects of the synbiotic food consumption on serum TC, LDL, HDL and plasma TAC levels (P > 0.05) were observed. Trial registry code: http://www.irct.ir . IRCT201212105623N3. PMID:24271261

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

    PubMed Central

    Mani, Preethi; Rohatgi, Anand

    2016-01-01

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

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

    PubMed

    Yamamoto, Suguru; Narita, Ichiei; Kotani, Kazuhiko

    2016-06-01

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

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

    PubMed

    Alfonso, John Edwin Feliciano; Ariza, Iván Darío Sierra

    2008-01-01

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

  9. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs...

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

    PubMed

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

    2016-03-11

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

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

    PubMed Central

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

    2001-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed

    Wang, Jing; Bie, Jinghua; Ghosh, Shobha

    2016-09-01

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

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  2. 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

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2013-11-01

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

  5. 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

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

    PubMed Central

    2012-01-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  9. Metabolism of low-density lipoprotein free cholesterol by human plasma lecithin-cholesterol acyltransferase

    SciTech Connect

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

    1991-09-03

    The metabolism of cholesterol derived from ({sup 3}H) cholesterol-labeled low-density lipoprotein (LDL) was determined in human blood plasma. LDL-derived free cholesterol first appeared in large {alpha}-migrating HDL (HDL{sub 2}) and was then transferred to small {alpha}-HDL (HDL{sub 3}) for esterification. The major part of such esters was retained within HDL of increasing size in the course of lecithin-cholesterol acyltransferase (LCAT) activity; the balance was recovered in LDL. Transfer of preformed cholesteryl esters within HDL contributed little to the labeled cholesteryl ester accumulating HDL{sub 2}. When cholesterol for esterification was derived instead from cell membranes, a significantly smaller proportion of this cholesteryl ester was subsequently recovered in LDL. These data suggest compartmentation of cholesteryl esters within plasma that have been formed from cell membrane or LDL free cholesterol, and the role for HDL{sub 2} as a relatively unreactive sink for LCAT-derived cholesteryl esters.

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

    PubMed

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

    2014-01-01

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

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

    PubMed

    Tsaoussis, V; Vakirtzi-Lemonias, C

    1994-05-01

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

  12. Gene Therapy Targeting LDL Cholesterol but not HDL Cholesterol Induces Regression of Advanced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia

    PubMed Central

    Li, Rongying; Chao, Hsu; Ko, Kerry W.S.; Cormier, Shelley; Dieker, Carrie; Nour, Elie A.; Wang, Shining; Chan, Lawrence; Oka, Kazuhiro

    2012-01-01

    A reduction in low density lipoprotein (LDL) cholesterol or an increase in high density lipoprotein (HDL) cholesterol can reduce the risk of development of atherosclerosis through overlapping or independent mechanisms. However, the clinical outcome of combined therapy remains in debate. In this study, we first characterized effects of various constructs of helper-dependent adenoviral vector (HDAd) expressing apolipoprotein E3 or LDL receptor (LDLR) in vivo on plasma cholesterol levels. Using this information, we designed experiments and compared the effects of long-term (28 weeks) LDL cholesterol lowering or raising HDL cholesterol, or a combination of both on advanced atherosclerosis in Ldlr−/− mice, a mouse model of familial hypercholesterolemia. Our major findings are: (i) various factors influence in vivo functional activity, which appear to be context dependent; (ii) apolipoprotein AI (APOAI) gene transfer, which raises HDL cholesterol, retards progression of atherosclerosis but does not induce regression; (iii) LDLR or LDLR and APOAI combination gene therapy induces lesion regression; however, LDLR gene transfer accounts for the majority of the effects of combined gene therapy; (iv) LDLR gene therapy reduces interleukin-7, which is a master regulator of T-cell homeostasis, but APOAI gene therapy does not. These results indicate that LDL cholesterol lowering is effective and sufficient in protection against atherosclerosis and induction of regression of pre-existing atherosclerosis. PMID:23106034

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

    PubMed

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

    2012-08-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2012-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2014-11-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed Central

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

    2016-01-01

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

  1. A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens.

    PubMed

    Homkham, Nontiya; Cressey, Tim R; Ingsrisawang, Lily; Bouazza, Naïm; Ngampiyaskul, Chaiwat; Hongsiriwon, Suchat; Srirojana, Sakulrat; Kanjanavanit, Suparat; Bhakeecheep, Sorakij; Coeur, Sophie Le; Salvadori, Nicolas; Treluyer, Jean Marc; Jourdain, Gonzague; Urien, Saik

    2016-09-01

    Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment. PMID:26749102

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

    PubMed Central

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

    2016-01-01

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

  3. Effects of simvastatin on liver and plasma levels of cholesterol, dolichol and ubiquinol in hypercholesterolemic rats.

    PubMed

    Marinari, U M; Pronzato, M A; Dapino, D; Gazzo, P; Traverso, N; Cottalasso, D; Odetti, P

    1995-01-01

    Increased levels of blood cholesterol are considered as a major factor in the development of atherosclerosis. Simvastatin, a drug which blocks hydroxymethylglutaryl coenzyme A reductase (HMGCoAR), reduces plasma cholesterol and increases HDL-cholesterol in rats fed a hypercholesterolemic diet. Moreover, simvastatin produces a significant decrease of ubiquinol and dolichol in plasma and in liver. PMID:7797420

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

    PubMed

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

    2002-01-01

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

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

    PubMed Central

    Ackert-Bicknell, Cheryl L.

    2011-01-01

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

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

    PubMed

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

    2013-05-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    DOE PAGESBeta

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

    2015-07-24

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

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

    PubMed

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

    2016-01-01

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

  10. 9-cis β-Carotene Increased Cholesterol Efflux to HDL in Macrophages

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2013-12-01

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

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

    PubMed

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

    2011-04-01

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

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

    PubMed

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

    2009-05-01

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

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

    PubMed

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

    2012-12-01

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

  16. Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure☆

    PubMed Central

    Asselin, Caroline; Ducharme, Anique; Ntimbane, Thierry; Ruiz, Matthieu; Fortier, Annik; Guertin, Marie-Claude; Lavoie, Joël; Diaz, Ariel; Levy, Émile; Tardif, Jean-Claude; Des Rosiers, Christine

    2013-01-01

    Objective Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA). Methods and results Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R2=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only. Conclusion Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts. PMID:24494189

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

    PubMed

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

    2003-07-01

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

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

    PubMed Central

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

    2003-01-01

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

  19. Reference Ranges for Serum Total Cholesterol, HDL-Cholesterol, LDL-Cholesterol, and VLDL-Cholesterol and Triglycerides in Healthy Iranian Ahvaz Population.

    PubMed

    Jalali, Mohammad Taha; Honomaror, Abdolhosain Mosavi; Rekabi, Abdolkarim; Latifi, Mahmod

    2013-07-01

    Cardiovascular diseases (CVD) are recognized as major mortality causes and imposes tremendously heavy socio-economic burden worldwide. A vast variety of risk factors have been introduced in the literature known to enhance the incidence of CVD, such as hyperlipidemia. Therefore in order to make an accurate clinical decision it is essential to have appropriate reference ranges for lipids and lipoprotein particles in a particular population. Healthy female (n = 601) and male (n = 617) cases were randomly selected according to certain exclusion criteria from individuals visiting the major University hospital clinics situated in different part of Ahvaz city, Iran, from June 2010 to December 2010. Fasting blood samples (10 ml) were collected and analyzed for total cholesterol, total triglyceride and HDL-C employing enzymatic assays of CHOD-PAP, GPO-PAP and homogenous methods respectively. The samples were obtained such to include the ethnic populations of Persian, Arab. Lore leaving in this city. The data were analyzed statistically by SPSS-18 software. The obtained results were analyzed then age ethnic-wise and reference ranges (mean ± 1SD) were calculated. Remarkable differences between the obtained results for our population with other nations were seen. Also ethnic difference for HDL-C among our cases was noted. The observed significant differences among different nations and ethnicities emphasizes the need for nation-specific, local reference ranges for lipids and lipoproteins particles, to be established. PMID:24426224

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2003-09-22

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

  2. THE CONSUMPTION OF RED PUPUNHA (BACTRIS GASIPAES KUNTH) INCREASES HDL CHOLESTEROL AND REDUCES WEIGHT GAIN OF LACTATING AND POST-LACTATING WISTAR RATS

    PubMed Central

    Carvalho, R. Piccolotto; Lemos, J.R. Gonzaga; de Aquino Sales, R. Souza; Martins, M. Gassen; Nascimento, C.H.; Bayona, M.; Marcon, J.L.; Monteiro, J. Barros

    2014-01-01

    Introduction The lactating and post-lactating periods are marked by large metabolic change. Production of milk is 60% lipid dependent. We reported in a recent scientific meeting that Red pupunha palm tree fruit increases HDL cholesterol in lactating rats. This study evaluated if consumption of Red Pupunha by adult female rats has a beneficial impact on the lipid metabolism of lacting and post-lacting adult rats. Objective Evaluate if consumption of red pupunha has a beneficial effect in the lipid metabolism of lacting and post-lacting adult Wistar rats. Research Methods Four groups including two for control; (1) control adult lactating rats, (2) control adults post-lactating rats; and two experimental groups; (3) pupunha adults lactating rats and (4) pupunha adult post-lactating rats were evaluated and compared regarding: weight gain, food consumption, plasma total protein, glucose, total lipid, triglycerides, total cholesterol and HDL-cholesterol levels. The mean difference and its 95% confidence intervals were used for group comparisons. Group comparisons were evaluated by using analysis of variance (one-way ANOVA). The statistical significance of the pairwise differences among groups was assessed by using the two-sided Tukey test. Results There were no important differences in food consumption, plasma glucose, total lipids and triglycerides among groups. The red pupunha lactating group gain less weight showing lower body mass index (BMI) than controls (p < 0.05). Total cholesterol was lower in red pupunha lactating than in controls but not in the red pupunha post-lactating group as compared to controls. Triglycerides were lower in the post-lactating red pupunha group as compared to the control group (p = 0.039) but not for the lactating groups. Red pupunha lactating and post-lactating groups had higher HDL-cholesterol than their corresponding control groups (p ≤ 0.01). Conclusion Original findings include the beneficial effect of red pupunha in post

  3. 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

  4. Effect of cigarette smoke and dietary cholesterol on plasma lipoprotein composition

    SciTech Connect

    Hojnacki, J.L.; Mulligan, J.J.; Cluette, J.E.; Kew, R.R.; Stack, D.J.; Huber, G.L.

    1981-01-01

    Pigeons were assigned to four treatment groups: 1) Controls fed a chow diet ad libitum and retained in their cages; 2) Sham pigeons fed a cholesterol-saturated fat diet and exposed to fresh air by the Lorillard smoking machine; 3) Low nicotine-low carbon monoxide (LoLo) animals also fed the cholesterol diet and exposed to low concentrations of cigarette smoke; and 4) High nicotine-high carbon monoxide (HiHi) birds fed the cholesterol diet and subjected to high concentrations of inhalants. Plasma very low density (VLDL), low density (LDL), and high density (HDL) lipoproteins were isolated by density gradient ultracentrifugation. Smoke-related differences appeared in HiHi HDL which contained relatively more free and esterified cholesterol and total lipid, but less total protein than HDL from Sham-smoked pigeons. VLDL from birds exposed to cigarette smoke (LoLo and HiHi) contained relatively more total lipid, but less total protein than VLDL from Sham pigeons. Inhalation smoke produced a marked depression in the HDL2/HDL3 ratio resulting from an increased proportion of the HDL3 subfraction relative to HDL2. Pigeons fed the cholesterol-saturated fat diet circulated HDL with greater free and esterified cholesterol mass than Controls. Diet also altered the type of cholesteryl ester present in HDL with cholesteryl linoleate representing the predominant form in Control pigeons and cholesteryl oleate in cholesterol-fed birds. These results demonstrate that cigarette smoking can mediate alterations in lipoprotein composition independent of changes induced by dietary cholesterol and saturated fat.

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

    PubMed

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

    2006-12-14

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

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

    PubMed

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

    2015-04-01

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

  7. Genetic determinants of HDL metabolism.

    PubMed

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

    2014-01-01

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

  8. Increased hepatic cholesterol esterification with essential fatty acid deficiency (EFAD): relationship to plasma lipoprotein (LP) cholesterol content

    SciTech Connect

    Ney, D.M.; Ziboh, V.A.; Schneeman, B.O.

    1986-03-01

    EFAD in the rat is associated with hepatic accumulation of esterified cholesterol and altered distribution of cholesterol between plasma and hepatic tissue. Little is known regarding the impact of EFAD on LP composition. To determine the relationship between hepatic cholesterol esterification and plasma lP composition in control (C) and EFAD male Wistar rats, the authors induced EFAD with continuous intragastric (IG) infusion of EFA-free solutions containing 3.5% of calories as triolein for 7 and 14 days. C animals received IG infusion of solutions containing 3.5% of calories as linoleic acid. Data in the EFAD groups reveal: (i) marked decreases in hepatic EFAs and increases in monoenoic acids; (ii) progressive increases in hepatic content of triglyceride and esterified cholesterol with 7 and 14 days of feeding; (iii) assay of acyl CoA:cholesterol acyltransferase activity in hepatic tissue using /sup 14/C-cholesterol demonstrates an increase in hepatic cholesterol esterification when compared to C animals. Increased hepatic cholesterol esterification correlates with elevated levels of esterified cholesterol in plasma VLDL and HDL particles. These data indicate that the elevated levels of cholesterol esters in LP particles is due, at least in part, to increased hepatic cholesterol esterification with EFAD.

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

    PubMed Central

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

    2012-01-01

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

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

    SciTech Connect

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

    2015-07-24

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

  11. Dietary cholesterol and plasma lipoprotein profiles: Randomized controlled trials

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early work suggested that dietary cholesterol increased plasma total cholesterol concentrations in humans. Given the relationship between elevated plasma cholesterol concentrations and cardiovascular disease risk, dietary guidelines have consistently recommended limiting food sources of cholesterol....

  12. Rapid labeling of lipoproteins in plasma with radioactive cholesterol. Application for measurement of plasma cholesterol esterification

    SciTech Connect

    Yen, F.T.; Nishida, T. )

    1990-02-01

    In order to efficiently and rapidly label lipoproteins in plasma with ({sup 3}H)cholesterol, micelles consisting of lysophosphatidylcholine (lysoPC) and ({sup 3}H)cholesterol (molar ratio, 50:1) were prepared. When trace amounts of these micelles were injected into plasma, ({sup 3}H)cholesterol rapidly equilibrated among the plasma lipoproteins, as compared to ({sup 3}H)cholesterol from an albumin-stabilized emulsion. The distributions of both ({sup 3}H)cholesterol and unlabeled free cholesterol in plasma lipoproteins were similar in labeled plasma samples. This method of labeling can be used for the measurement of cholesterol esterification, or lecithin:cholesterol acyltransferase activity, in small amounts (20-40 microliters) of plasma samples.

  13. Age related changes in the lipoprotein substrates for the esterification of plasma cholesterol in rats.

    PubMed

    Lee, S M; Kudchodkar, B J; Lacko, A G

    1991-11-15

    The activity of the enzyme lecithin:cholesterol acyltransferase (LCAT) and the properties of its lipoprotein substrates have been investigated in 6- and 19-month-old Fischer-344 rats. These studies were carried out to determine the nature of the relationship between the observed hypercholesterolemia and the age-related decrease in the fractional rate of lipoprotein cholesterol esterification. The distribution of LCAT activity of plasma fractions was determined following gel chromatography and ultracentrifugation respectively. LCAT activity was found to be associated with the high density lipoprotein (HDL) fraction when rat plasma was passed through a Bio-Gel A-5 M column. Upon density gradient ultracentrifugation for 24 h it was found associated with HDL fraction; d = 1.125-1.21 g/ml. However, following prolonged ultracentrifugation (40 h), the majority of the LCAT activity was displaced into the lipoprotein-free infranatant (d greater than 1.225 g/ml). The dissociation of LCAT from its complex with HDL occurred to a smaller extent in aged rat plasma than in young rat plasma. Substrate specificity studies indicated that HDL was a considerably better substrate for LCAT than very low density lipoproteins (VLDL) in both young and aged rats. In addition, HDL from young rats was a better substrate for LCAT than the HDL from aged rats. Incubation experiments followed by the isolation of lipoproteins and the subsequent analyses of their cholesterol contents revealed that the age-related hypercholesterolemia was mainly due to an increase in the cholesterol carried by lipoprotein fractions d = 1.025 -1.07 g/ml (LDL + HDL1). These and other low density lipoproteins (d less than 1.025 g/ml) were poor substrates for LCAT. However, these lipoproteins could provide free cholesterol for esterification by first transferring it to HDL (d = 1.07-1.21). The HDL isolated from the plasma of aged rats was enriched with apolipoprotein (apo) E and these lipoprotein particles were found to

  14. Nonesterified phytosterols dissolved and recrystallized in oil reduce plasma cholesterol in gerbils and humans.

    PubMed

    Hayes, K C; Pronczuk, A; Perlman, D

    2004-06-01

    When free phytosterols are adequately heated and then cooled in fat, they recrystallize and are rendered bioavailable for blocking cholesterol absorption. To extend the application of phytosterols to fried foods, the activity of these modified crystals was assessed in 2 experiments with 26 male gerbils fed purified diets containing 0.15 g/100 g cholesterol with or without 0.75 g/100 g free phytosterols. The heat-modified soybean sterols were added directly to the diet (Expt. 1) or as phytosterol-enriched potato chips (Expt. 2). In the gerbil experiments, only the diet containing phytosterols significantly reduced plasma cholesterol (35-48%) and the total cholesterol/HDL cholesterol (HDL-C) ratio (40%), as well as hepatic cholesterol esters (80%). In a subsequent human study, subjects (n = 7) consumed two 28-g servings of tortilla chips fried in oil with or without phytosterols that provided 0 or 1.5 g/d for 4-wk periods in a crossover design (Expt. 3). During consumption of the phytosterol-enriched chips, significant reductions in plasma cholesterol (10%) and LDL cholesterol (15%) were achieved without affecting HDL-C. This novel means of delivering free phytosterols proved to be both functionally efficient and effective. PMID:15173402

  15. Macadamia nut consumption lowers plasma total and LDL cholesterol levels in hypercholesterolemic men.

    PubMed

    Garg, Manohar L; Blake, Robert J; Wills, Ron B H

    2003-04-01

    This study was conducted to assess the cholesterol-lowering potential of macadamia nuts. Seventeen hypercholesterolemic men (mean age 54 y) were given macadamia nuts (40-90 g/d), equivalent to 15% energy intake, for 4 wk. Plasma total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homocysteine concentrations and the fatty acid composition of plasma lipids were determined before and after treatment. Plasma MUFA 16:1(n-7), 18:1(n-7) and 20:1(n-9) were elevated after intervention with macadamia nuts. Plasma (n-6) and (n-3) PUFA concentrations were unaffected by macadamia nut consumption. Plasma total cholesterol and LDL cholesterol concentrations decreased by 3.0 and 5.3%, respectively, and HDL cholesterol levels increased by 7.9% in hypercholesterolemic men after macadamia nut consumption. Plasma triglyceride and homocysteine concentrations were not affected by treatment. Macadamia nut consumption was associated with a significant increase in the relative intake of MUFA and a reduced relative intake of saturated fatty acids and PUFA. This study demonstrates that macadamia nut consumption as part of a healthy diet favorably modifies the plasma lipid profile in hypercholesterolemic men despite their diet being high in fat. PMID:12672919

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

    PubMed Central

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

    2009-01-01

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

  17. 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

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

    PubMed

    Verma, Nitin; Figueredo, Vincent M

    2014-01-01

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

  19. Regulation of Plasma Cholesterol by Lipoprotein Receptors

    NASA Astrophysics Data System (ADS)

    Brown, Michael S.; Kovanen, Petri T.; Goldstein, Joseph L.

    1981-05-01

    The lipoprotein transport system holds the key to understanding the mechanisms by which genes, diet, and hormones interact to regulate the plasma cholesterol level in man. Crucial components of this system are lipoprotein receptors in the liver and extrahepatic tissues that mediate the uptake and degradation of cholesterol-carrying lipoproteins. The number of lipoprotein receptors, and hence the efficiency of disposal of plasma cholesterol, can be increased by cholesterol-lowering drugs. Regulation of lipoprotein receptors can be exploited pharmacologically in the therapy of hypercholesterolemia and atherosclerosis in man.

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

    PubMed

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

    2013-02-01

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

  1. Plasma cholesterol and other cardiac risk factors in adolescent girls.

    PubMed Central

    Bermingham, M A; Jones, E; Steinbeck, K; Brock, K

    1995-01-01

    The aim was to examine the effects of smoking, physical activity, and body mass on total cholesterol and high density lipoprotein cholesterol (HDL-C) in adolescent schoolgirls in Sydney, Australia. Body mass index (BMI) and waist to hip ratio (WHR) were determined in 144 girls aged 15 to 18 years. Total cholesterol (TC) and HDL-C were estimated on fingerprick blood and behavioural variables assessed by questionnaire. Prevalence of overweight (> 90th centile for BMI) was less in Australian adolescents than reported from the USA. Smokers had lower total cholesterol than non-smokers; this was partly explained by a lower HDL-C in the smokers. Physical activity was associated with a less atherogenic TC/HDL-C ratio. Girls with BMI > 90th centile had higher mean TC/HDL-C and apoprotein B than the group as a whole but those > 90th centile for WHR did not. PMID:8554353

  2. Some kinetic properties of plasma lecithin-cholesterol acyltransferase in hyper-alphalipoproteinemia in man

    SciTech Connect

    Nikiforova, A.A.; Alksnis, E.G.; Ivanova, E.M.

    1985-07-01

    The aim of this investigation was to study some kinetic properties of lecithin-cholesterol acyltransferase (LCAT) in the blood plasma of patients with hyper-alpha-lipoproteinemia, enabling the presence of LCAT isozymes in the blood to be detected. The velocity of the LCAT reaction was judged by determining labeled CHE formed from /sup 14/C-nonesterified CH and lecithin of HDL on incubation of the latter with the enzyme. Dependence of the velocity of the LCAT reaction on concentration of substrate (nonesterified HDL cholesterol) in four subjects with hyper-alpha-lipoproteinemia is shown.

  3. Plasma cholesterol efflux capacity from human THP-1 macrophages is reduced in HIV-infected patients: impact of HAART[S

    PubMed Central

    El Khoury, Petra; Ghislain, Mathilde; Villard, Elise F.; Le Goff, Wilfried; Lascoux-Combe, Caroline; Yeni, Patrick; Meyer, Laurence; Vigouroux, Corinne; Goujard, Cécile; Guerin, Maryse

    2015-01-01

    The capacity of HDL to remove cholesterol from macrophages is inversely associated with the severity of angiographic coronary artery disease. The effect of human immunodeficiency virus (HIV) infection or its treatment on the ability of HDL particles to stimulate cholesterol efflux from human macrophages has never been studied. We evaluated the capacity of whole plasma and isolated HDL particles from HIV-infected subjects (n = 231) and uninfected controls (n = 200), as well as in a subset of 41 HIV subjects receiving highly active antiretroviral therapy (HAART) to mediate cholesterol efflux from human macrophages. Plasma cholesterol efflux capacity was reduced (−12%; P = 0.001) in HIV patients as compared with controls. HIV infection reduced by 27% (P < 0.05) the capacity of HDL subfractions to promote cholesterol efflux from macrophages. We observed a reduced ABCA1-dependent efflux capacity of plasma (−27%; P < 0.0001) from HIV-infected subjects as a result of a reduction in the efflux capacity of HDL3 particles. HAART administration restored the capacity of plasma from HIV patients to stimulate cholesterol efflux from human macrophages (9.4%; P = 0.04). During HIV infection, the capacity of whole plasma to remove cholesterol from macrophages is reduced, thus potentially contributing to the increased coronary heart disease in the HIV population. HAART administration restored the removal of cholesterol from macrophages by increasing HDL functionality. PMID:25573889

  4. Effects of extended-release niacin/laropiprant, simvastatin, and the combination on correlations between apolipoprotein B, LDL cholesterol, and non-HDL cholesterol in patients with dyslipidemia

    PubMed Central

    Farnier, Michel; Chen, Erluo; Johnson-Levonas, Amy O; McCrary Sisk, Christine; Mitchel, Yale B

    2014-01-01

    Background Statins modify correlations between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) and apoB and non-high-density lipoprotein cholesterol (non-HDL-C); however, it is not known whether niacin-based therapies have similar effects. Objective To evaluate the effects of extended-release niacin (ERN)/laropiprant (LRPT), simvastatin (SIMVA), and ERN/LRPT + SIMVA (pooled ERN/LRPT + SIMVA) on apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients. Methods This post-hoc analysis of a 12-week study evaluated the apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients randomized equally to double-blind ERN/LRPT 1 g/20 mg, SIMVA 10, 20, or 40 mg, or ERN/LRPT 1 g/20 mg + SIMVA (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled in all groups except SIMVA 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIMVA 40 mg (switched to ERN/LRPT 2 g/40 mg + SIMVA 40 mg). Simple linear regression analyses were used to calculate LDL-C and non-HDL-C levels corresponding to known apoB baseline values (ie, in untreated patients) and following treatment. Results The apoB:LDL-C and apoB:non-HDL-C correlations were higher and the predicted LDL-C and non-HDL-C levels for a known apoB value were considerably lower following treatment with ERN/LRPT, SIMVA and ERN/LRPT + SIMVA compared with untreated patients at baseline. Conclusion Greater dissociation of apoB, LDL-C, and non-HDL-C targets occur following treatment with ERN/LRPT, SIMVA, and ERN/LRPT + SIMVA in patients with dyslipidemia. The achievement of more aggressive LDL-C and non-HDL-C goals in patients receiving lipid-modifying therapy may further reduce coronary risk by normalizing apoB-containing atherogenic lipoproteins. PMID:24855368

  5. 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

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

    PubMed

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

    1991-04-24

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

  7. 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

  8. Cholesterol efflux and reverse cholesterol transport.

    PubMed

    Favari, Elda; Chroni, Angelika; Tietge, Uwe J F; Zanotti, Ilaria; Escolà-Gil, Joan Carles; Bernini, Franco

    2015-01-01

    Both alterations of lipid/lipoprotein metabolism and inflammatory events contribute to the formation of the atherosclerotic plaque, characterized by the accumulation of abnormal amounts of cholesterol and macrophages in the artery wall. Reverse cholesterol transport (RCT) may counteract the pathogenic events leading to the formation and development of atheroma, by promoting the high-density lipoprotein (HDL)-mediated removal of cholesterol from the artery wall. Recent in vivo studies established the inverse relationship between RCT efficiency and atherosclerotic cardiovascular diseases (CVD), thus suggesting that the promotion of this process may represent a novel strategy to reduce atherosclerotic plaque burden and subsequent cardiovascular events. HDL plays a primary role in all stages of RCT: (1) cholesterol efflux, where these lipoproteins remove excess cholesterol from cells; (2) lipoprotein remodeling, where HDL undergo structural modifications with possible impact on their function; and (3) hepatic lipid uptake, where HDL releases cholesterol to the liver, for the final excretion into bile and feces. Although the inverse association between HDL plasma levels and CVD risk has been postulated for years, recently this concept has been challenged by studies reporting that HDL antiatherogenic functions may be independent of their plasma levels. Therefore, assessment of HDL function, evaluated as the capacity to promote cell cholesterol efflux may offer a better prediction of CVD than HDL levels alone. Consistent with this idea, it has been recently demonstrated that the evaluation of serum cholesterol efflux capacity (CEC) is a predictor of atherosclerosis extent in humans. PMID:25522988

  9. Prospective multicentre study of the effect of voluntary plasmapheresis on plasma cholesterol levels in donors

    PubMed Central

    Rosa-Bray, M; Wisdom, C; Wada, S; Johnson, BR; Grifols-Roura, V; Grifols-Lucas, V

    2013-01-01

    Background and Objectives LDL apheresis is used to treat patients with familial hypercholesterolaemia, and low-volume plasmapheresis for plasma donation may similarly lower cholesterol levels in some donors. This study was designed to assess the effect of plasmapheresis on total, LDL and HDL cholesterol levels in a plasma donor population. Materials and Methods This was a prospective, unblinded longitudinal cohort study in which a blood sample was obtained for analysis before each donation. Data from 663 donors were analysed using a multivariable repeated measures regression model with a general estimating equations approach with changes in cholesterol as the primary outcome measure. Results The model predicted a significant decrease in total and LDL cholesterol for both genders and all baseline cholesterol levels (P < 0·01). The greatest total cholesterol decreases (women, −46·8 mg/dL; men, −32·2 mg/dL) were associated with high baseline levels and 2–4 days between donations. Small but statistically significant increases (P ≤ 0·01) in HDL cholesterol were predicted for donors with low baseline levels. Conclusions These results suggest that, in donors with elevated baseline cholesterol levels, total and LDL cholesterol levels may decrease during routine voluntary plasmapheresis. PMID:23517282

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

    PubMed

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

    1982-05-01

    Abnormal lipoproteins accumulate in the plasma of alcoholic hepatitis patients in association with a deficiency of the cholesterol esterifying enzyme, lecithin:cholesterol acyl-transferase. Most of these abnormal lipoproteins are found in the d > 1.006 g/ml density fraction. To investigate the composition and morphology of the lipoproteins at various times during the illness in four patients, we have employed density gradient ultracentrifugation combined with analyses of gradient fractions by polyacrylamide gel electrophoresis, electroimmunoassay, and electron microscopy. At the onset of the illness, plasma cholesteryl esters ranged from 19-34% of total cholesterol; high density lipoprotein (HDL) cholesterol and apoA-I, the major HDL apoprotein, were <10% of normal; and most of the d > 1.006 g/ml triglycerides and phospholipids were found in the LDL density region. A linear correlation (r = 0.964, P < 0.001) was found between the d > 1.006 g/ml apoB concentration and the summation of the triglyceride and esterified cholesterol for that fraction, indicating a constant ratio of apoB to the summation of these two "core lipids". ApoA-I was primarily found in the fraction d > 1.18 g/ml (HDL(3) and VHDL) but not at all in the HDL(2) density range of the gradient. No cholesteryl esters were present in the apoA-I containing fractions. In contrast to normal, large amounts of apoE accumulated in lipoproteins isolated at d 1.055-1.114 g/ml. The apoE-rich fractions contained primarily phospholipids and unesterified cholesterol; they appeared by electron microscopy to be mixtures of spherical particles, vesicular particles, and chains of bilamellar discs. Analyses of the density gradient fractions by SDS polyacrylamide gel electrophoresis under reducing conditions indicated that apoA-II levels and distribution paralleled apoA-I, not apoE, providing evidence against appreciable concentrations of apoE-apoA-II complexes. During partial recovery from alcoholic hepatitis in three

  11. 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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2011-12-01

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

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

    PubMed Central

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

    2011-01-01

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

  15. Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice.

    PubMed

    Thacker, Seth G; Rousset, Xavier; Esmail, Safiya; Zarzour, Abdalrahman; Jin, Xueting; Collins, Heidi L; Sampson, Maureen; Stonik, John; Demosky, Stephen; Malide, Daniela A; Freeman, Lita; Vaisman, Boris L; Kruth, Howard S; Adelman, Steven J; Remaley, Alan T

    2015-07-01

    LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(-/-)] mice, which have a secondary defect in cholesterol esterification. Scarab(-/-)×LCAT-null [Lcat(-/-)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(-/-)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(-/-)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(-/-)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(-/-) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles. PMID:25964513

  16. HDL biogenesis, remodeling, and catabolism.

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  18. Serum amyloid A impairs the antiinflammatory properties of HDL

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

  20. Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma

    PubMed Central

    Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji

    2016-01-01

    Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664

  1. Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

    PubMed

    Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji

    2016-01-01

    Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664

  2. 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

  3. 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

  4. Different palm oil preparations reduce plasma cholesterol concentrations and aortic cholesterol accumulation compared to coconut oil in hypercholesterolemic hamsters.

    PubMed

    Wilson, Thomas A; Nicolosi, Robert J; Kotyla, Timothy; Sundram, Kalyana; Kritchevsky, David

    2005-10-01

    Several studies have reported on the effect of refined, bleached and deodorized palm oil (RBD-PO) incorporation into the diet on blood cholesterol concentrations and on the development of atherosclerosis. However, very little work has been reported on the influence of red palm oil (RPO), which is higher in carotenoid and tocopherol content than RBD-PO. Thus, we studied the influence of RPO, RBD-PO and a RBD-PO plus red palm oil extract (reconstituted RBD-PO) on plasma cholesterol concentrations and aortic accumulation vs. hamsters fed coconut oil. Forty-eight F1B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three/cage) in hanging polystyrene cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks at which time they were bled after an overnight fast and segregated into four groups of 12 with similar plasma cholesterol concentrations. Group 1 continued on the HCD, Group 2 was fed the HCD containing 10% RPO in place of coconut oil, Group 3 was fed the HCD containing 10% RBD-PO in place of coconut oil and Group 4 was fed the HCD with 10% reconstituted RBD-PO for an additional 10 weeks. Plasma total cholesterol (TC) and non-high-density lipoprotein-cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the hamsters fed the RPO (-42% and -48%), RBD-PO (-32% and -36%) and the reconstituted RBD-PO (-37% and -41%) compared to the coconut oil-fed hamsters. Plasma HDL-C concentrations were significantly higher by 14% and 31% in hamsters fed the RBD-PO and RPO compared to the coconut oil-fed hamsters. Plasma triglyceride (TG) concentrations were significantly lower in hamsters fed RBD-PO (-32%) and the reconstituted RBD-PO (-31%) compared to the coconut oil-fed hamsters. The plasma gamma-tocopherol concentrations were higher

  5. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.

    PubMed Central

    Badimon, J J; Badimon, L; Fuster, V

    1990-01-01

    The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration. Images PMID:2318976

  6. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit.

    PubMed

    Badimon, J J; Badimon, L; Fuster, V

    1990-04-01

    The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration. PMID:2318976

  7. Cholesterol Asymmetry in Synaptic Plasma Membranes

    PubMed Central

    Wood, W. Gibson; Igbavboa, Urule; Müller, Walter E.; Eckert, Gunter P.

    2010-01-01

    Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. A common characteristic of these membrane domains is their association with cholesterol. Lipid rafts and caveolae are examples of cholesterol enriched domains, which have attracted keen interest. However, two other important cholesterol domains are the exofacial and cytofacial leaflets of the plasma membrane. The two leaflets that make up the bilayer differ in their fluidity, electrical charge, lipid distribution, and active sites of certain proteins. The synaptic plasma membrane (SPM) cytofacial leaflet contains over 85% of the total SPM cholesterol as compared with the exofacial leaflet. This asymmetric distribution of cholesterol is not fixed or immobile but can be modified by different conditions in vivo: 1) chronic ethanol consumption; 2) statins; 3) aging; and 4) apoE isoform. Several potential candidates have been proposed as mechanisms involved in regulation of SPM cholesterol asymmetry: apoE, low-density-lipoprotein receptor, sterol carrier protein-2, fatty acid binding proteins, polyunsaturated fatty acids, p-glycoprotein and caveolin-1. This review examines cholesterol asymmetry in SPM, potential mechanisms of regulation and impact on membrane structure and function. PMID:21214553

  8. Randomised controlled trial of the effect of long-term selenium supplementation on plasma cholesterol in an elderly Danish population.

    PubMed

    Cold, Frederik; Winther, Kristian H; Pastor-Barriuso, Roberto; Rayman, Margaret P; Guallar, Eliseo; Nybo, Mads; Griffin, Bruce A; Stranges, Saverio; Cold, Søren

    2015-12-14

    Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) μg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose-dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL-cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population. PMID:26420334

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

    PubMed Central

    2013-01-01

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

  10. ABCA1 and nascent HDL biogenesis.

    PubMed

    Wang, Shuhui; Smith, Jonathan D

    2014-01-01

    ABCA1 mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein AI, to form nascent high-density lipoprotein (HDL). Thus, ABCA1 is a key molecule in cholesterol homeostasis. Functional studies of certain Tangier disease mutations demonstrate that ABCA1 has multiple activities, including plasma membrane remodeling and apoAI binding to cell surface, which participate in nascent HDL biogenesis. Recent advances in our understanding of ABCA1 have demonstrated that ABCA1also mediates unfolding the N terminus of apoAI on the cell surface, followed by lipidation of apoAI and release of nascent HDL. Although ABCA1-mediated cholesterol efflux to apoAI can occur on the plasma membrane, the role of apoAI retroendocytosis during cholesterol efflux may play a role in macrophage foam cells that store cholesterol esters in cytoplasmic lipid droplets. PMID:25359426

  11. 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

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

    PubMed Central

    Choi, Eun-Young; Jang, Jin-Young

    2010-01-01

    This study investigated the effect of coffee intake and exercise on the antioxidative activity and plasma cholesterol profile of physically trained rats while they were exercising. Forty eight rats were under either the control diet with water (C) or control diet with coffee (CF) and at the same time they were given physical training for 4 weeks. In terms of physical training, the rats were exercised on a treadmill for 30 minutes everyday. At the end of 4 weeks, animals in each dietary group were subdivided into 3 groups: before-exercise (BE); during-exercise (DE); after-exercise (AE). Animals in the DE group were exercised on a treadmill for one hour, immediately before being sacrificed. Animals in the AE group were allowed to take a rest for one hour after exercise. TG levels were significantly high in coffee intake group than in control group. Also TG level of AE group was significantly higher than that of BE group. Exercise and coffee-exercise interaction effects were significant in total cholesterol (P = 0.0004, 0.0170). The AE of coffee intake group showed highest total cholesterol levels. HDL-cholesterol was significantly lower in coffee intake group than in control group. Coffee, exercise, and coffee-exercise interaction effects were significant in SOD (P = 0.0001, 0.0001, and 0.0001). The AE and BE of coffee intake group showed higher SOD levels than the other four groups. Catalase activities were significantly higher in coffee intake group than control group. No significant main effect was found in GSH/GSSG. Coffee, exercise, and coffee-exercise interaction effects were significant in MDA levels (P = 0.0464, 0.0016, and 0.0353). The DE and AE of coffee intake group and the DE of control group showed higher MDA levels than the BE of control group. Therefore, coffee intake can promote activities of antioxidant enzyme but it also increases MDA and decreases HDL-cholesterol in physically trained rats. PMID:20827343

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    1979-01-01

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

  15. Correlation between high density lipoprotein-cholesterol and remodeling index in patients with coronary artery disease: IDEAS (IVUS diagnostic evaluation of atherosclerosis in Singapore)-HDL study.

    PubMed

    Lee, Chi-Hang; Tai, Bee-Choo; Lim, Gek-Hsiang; Chan, Mark Y; Low, Adrian F; Tan, Kathryn C; Chia, Boon-Lock; Tan, Huay-Cheem

    2012-01-01

    Serum level of high density lipoprotein (HDL)-cholesterol is associated with risk of coronary artery disease. We correlated the serum level of cholesterol with coronary artery remodeling index of patients with coronary artery disease. A total of 120 patients with de novo lesions located in native coronary artery were studied. Remodeling index was based on intravascular ultrasound (IVUS) interrogation of the lesions using the static approach, and was defined as external elastic membrane (EEM) area at lesion/average EEM area at proximal and distal reference segments. The average remodeling index was 0.9 (SD: 0.2). The remodeling index was not associated with any of the demographic and coronary risk factors. Stable angina was associated with a low remodeling index. Remodeling index correlated with white blood cell count and HDL-cholesterol, but not with total cholesterol, LDL-cholesterol and triglyceride. In the multiple linear regression analysis, HDL-cholesterol and procedure indication were the only 2 significant predictors of remodeling index. An increase of 1 mg/dL of HDL-cholesterol resulted in a decrease of 0.003 (95% CI: 0.0001, 0.007; P = 0.046) in remodeling index, after adjusting for procedural indications. When stratified according to diabetic status, the negative correlation persisted in non-diabetic (P = 0.023), but not in diabetic, patients (P = 0.707). We found a negative correlation between HDL-cholesterol level and remodeling index. Diabetic status may have an influence on the observed relationship. PMID:21197580

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

    PubMed

    Fernandez, Maria Luz; Murillo, Ana Gabriela

    2016-01-01

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

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

    PubMed Central

    Fernandez, Maria Luz; Murillo, Ana Gabriela

    2016-01-01

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

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

    PubMed Central

    Kontush, Anatol

    2015-01-01

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

  19. Extra Virgin Olive Oil Polyphenols Promote Cholesterol Efflux and Improve HDL Functionality

    PubMed Central

    Berrougui, Hicham; Ikhlef, Souad; Khalil, Abdelouahed

    2015-01-01

    Results of the present work give evidence from the beneficial role of extra virgin olive of oil (EVOO) consumption towards oxidative stress and cardiovascular diseases. Polyphenols contained in EVOO are responsible for inhibiting lipoproteins oxidative damages and promoting reverse cholesterol transport process via ABCA1 pathway. PMID:26495005

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  3. Presence of unsedimented precipitate in visually non-turbid supernates in the heparin-manganese method for HDL-cholesterol quantitation.

    PubMed

    Kiss, Z; Simo, I E; Ooi, T C; Meuffels, M; Hindmarsh, J T

    1986-08-01

    An inherent problem with the heparin-manganese precipitation procedure for high density lipoprotein-cholesterol (HDL-C) quantitation is the inability to sediment all the precipitated lipoproteins, especially in hypertriglyceridemic samples. This results in overestimation of HDL-C. Thus ultrafiltration has been recommended for turbid supernates. We have investigated 47 non-turbid supernates for possible presence of unsedimented precipitate. Optical turbidity in these samples was found to correlate with the serum triglyceride level. With ultrafiltration of the supernates, there was a significant decrease in cholesterol, optical turbidity and apoprotein A-I. The percent change in turbidity correlated with the percent change in cholesterol. There was also correlation between percent change in cholesterol and the prefiltration supernate turbidity. These results indicate that visually clear supernates may show optical turbidity; the turbidity is likely due to triglyceride-rich particles, which contain cholesterol; the fall in cholesterol with ultrafiltration is due to removal of these floating particles and some adsorbance of HDL particles to the filters. PMID:3093118

  4. Human plasma lecithin-cholesterol acyltransferase

    SciTech Connect

    Jauhiainen, M.; Stevenson, K.J.; Dolphin, P.J.

    1988-05-15

    Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme which catalyzes the transacylation of the fatty acid at the sn-2 position of lecithin to cholesterol forming lysolecithin and cholesteryl ester. The substrates for and products of this reaction are present within the plasma lipoproteins upon which the enzyme acts to form the majority of cholesteryl ester in human plasma. The authors proposed a covalent catalytic mechanism of action for LCAT in which serine and histidine residues mediate lecithin cleavage and two cysteine residues cholesterol esterification. With the aid of sulfhydryl reactive trivalent organoarsenical compounds which are specific for vicinal thiols they have probed the geometry of the catalytic site. They conclude that the two catalytic cysteine residues of LCAT (Cys/sup 31/ and Cys /sup 184/) are vicinal with a calculated distance between their sulfur atoms of 3.50-3.62 A. The additional residue alkylated by teh bifunctional reagent is within the catalytic site and may represent a previously identified catalytic serine or histidine residue.

  5. 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

  6. The Ala54Thr Polymorphism of the Fatty Acid Binding Protein 2 Gene Modulates HDL Cholesterol in Mexican-Americans with Type 2 Diabetes

    PubMed Central

    Salto, Lorena M.; Bu, Liming; Beeson, W. Lawrence; Firek, Anthony; Cordero-MacIntyre, Zaida; De Leon, Marino

    2015-01-01

    The alanine to threonine amino acid substitution at codon 54 (Ala54Thr) of the intestinal fatty acid binding protein (FABP2) has been associated with elevated levels of insulin and blood glucose as well as with dyslipidemia. The aim of this study was to characterize the effect of this FABP2 polymorphism in Mexican-Americans with type 2 diabetes (T2D) in the context of a three-month intervention to determine if the polymorphism differentially modulates selected clinical outcomes. For this study, we genotyped 43 participant samples and performed post-hoc outcome analysis of the profile changes in fasting blood glucose, HbA1c, insulin, lipid panel and body composition, stratified by the Ala54Thr polymorphism. Our results show that the Thr54 allele carriers (those who were heterozygous or homozygous for the threonine-encoding allele) had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes (those who were homozygous for the alanine-encoding allele). Both groups made clinically important improvements in lipid profiles and glycemic control as a response to the intervention. Whereas the Ala54 homozygotes decreased HDL cholesterol in the context of an overall total cholesterol decrease, Thr54 allele carriers increased HDL cholesterol as part of an overall total cholesterol decrease. We conclude that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes. PMID:26703680

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

    SciTech Connect

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

    1987-05-01

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

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

    PubMed Central

    Tomten, Sissel E.; Høstmark, Arne T.

    2007-01-01

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

  9. apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

    PubMed Central

    Huang, L S; Voyiaziakis, E; Markenson, D F; Sokol, K A; Hayek, T; Breslow, J L

    1995-01-01

    apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes. Images PMID:7593600

  10. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion

    PubMed Central

    Martin, Gregory G.; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Storey, Stephen M.; Howles, Philip N.; Kier, Ann B.

    2014-01-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  11. Ablating L-FABP in SCP-2/SCP-x null mice impairs bile acid metabolism and biliary HDL-cholesterol secretion.

    PubMed

    Martin, Gregory G; Atshaves, Barbara P; Landrock, Kerstin K; Landrock, Danilo; Storey, Stephen M; Howles, Philip N; Kier, Ann B; Schroeder, Friedhelm

    2014-12-01

    On the basis of their abilities to bind bile acids and/or cholesterol, the physiological role(s) of liver fatty acid-binding protein (L-FABP) and sterol carrier protein (SCP) 2/SCP-x (SCP-2/SCP-x) gene products in biliary bile acid and cholesterol formation was examined in gene-ablated male mice. L-FABP (LKO) or L-FABP/SCP-2/SCP-x [triple-knockout (TKO)] ablation markedly decreased hepatic bile acid concentration, while SCP-2/SCP-x [double-knockout (DKO)] ablation alone had no effect. In contrast, LKO increased biliary bile acid, while DKO and TKO had no effect on biliary bile acid levels. LKO and DKO also altered biliary bile acid composition to increase bile acid hydrophobicity. Furthermore, LKO and TKO decreased hepatic uptake and biliary secretion of high-density lipoprotein (HDL)-derived 22-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol), while DKO alone had no effect. Finally, LKO and, to a lesser extent, DKO decreased most indexes contributing to cholesterol solubility in biliary bile. These results suggest different, but complementary, roles for L-FABP and SCP-2/SCP-x in biliary bile acid and cholesterol formation. L-FABP appears to function more in hepatic retention of bile acids as well as hepatic uptake and biliary secretion of HDL-cholesterol. Conversely, SCP-2/SCP-x may function more in formation and biliary secretion of bile acid, with less impact on hepatic uptake or biliary secretion of HDL-cholesterol. PMID:25277800

  12. Rice bran oil and oryzanol reduce plasma lipid and lipoprotein cholesterol concentrations and aortic cholesterol ester accumulation to a greater extent than ferulic acid in hypercholesterolemic hamsters.

    PubMed

    Wilson, Thomas A; Nicolosi, Robert J; Woolfrey, Benjamin; Kritchevsky, David

    2007-02-01

    Our laboratory has reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Because RBO has a greater content of the unsaponifiables, which also lower cholesterol compared to most vegetable oils, we wanted to know whether oryzanol or ferulic acid, two major unsaponifiables in RBO, has a greater cholesterol-lowering activity. Forty-eight F(1)B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three per cage) in cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks, at which time they were bled after an overnight fast (16 h) and segregated into 4 groups of 12 with similar plasma cholesterol concentrations. Group 1 (control) continued on the HCD, group 2 was fed the HCD containing 10% RBO in place of coconut oil, group 3 was fed the HCD plus 0.5% ferulic acid and group 4 was fed the HCD plus 0.5% oryzanol for an additional 10 weeks. After 10 weeks on the diets, plasma total cholesterol (TC) and non-high-density lipoprotein cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the RBO (-64% and -70%, respectively), the ferulic acid (-22% and -24%, respectively) and the oryzanol (-70% and -77%, respectively) diets compared to control. Plasma TC and non-HDL-C concentrations were also significantly lower in the RBO (-53% and -61%, respectively) and oryzanol (-61% and -70%, respectively) diets compared to the ferulic acid. Compared to control and ferulic acid, plasma HDL-C concentrations were significantly higher in the RBO (10% and 20%, respectively) and oryzanol (13% and 24%, respectively) diets. The ferulic acid diet had significantly lower plasma HDL-C concentrations compared to the control (-9%). The RBO and oryzanol diets were significantly lower for

  13. Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

    PubMed Central

    Calabresi, Laura; Baldassarre, Damiano; Simonelli, Sara; Gomaraschi, Monica; Amato, Mauro; Castelnuovo, Samuela; Frigerio, Beatrice; Ravani, Alessio; Sansaro, Daniela; Kauhanen, Jussi; Rauramaa, Rainer; de Faire, Ulf; Hamsten, Anders; Smit, Andries J.; Mannarino, Elmo; Humphries, Steve E.; Giral, Philippe; Veglia, Fabrizio; Sirtori, Cesare R.; Franceschini, Guido; Tremoli, Elena

    2011-01-01

    Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis. PMID:21596929

  14. Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice[S

    PubMed Central

    Thacker, Seth G.; Rousset, Xavier; Esmail, Safiya; Zarzour, Abdalrahman; Jin, Xueting; Collins, Heidi L.; Sampson, Maureen; Stonik, John; Demosky, Stephen; Malide, Daniela A.; Freeman, Lita; Vaisman, Boris L.; Kruth, Howard S.; Adelman, Steven J.; Remaley, Alan T.

    2015-01-01

    LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(−/−)] mice, which have a secondary defect in cholesterol esterification. Scarab(−/−)×LCAT-null [Lcat(−/−)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(−/−)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(−/−)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(−/−)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(−/−) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles. PMID:25964513

  15. 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.

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

    PubMed

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

    2000-09-01

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

  17. Relationship between apolipoprotein concentrations and HDL subclasses distribution.

    PubMed

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

    2007-05-01

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

  18. The Type 2 Diabetes and Insulin-Resistance Locus Near IRS1 Is A Determinant of HDL Cholesterol and Triglycerides Levels Among Diabetic Subjects

    PubMed Central

    Sharma, Rajani; Prudente, Sabrina; Andreozzi, Francesco; Powers, Christine; Mannino, Gaia; Bacci, Simonetta; Gervino, Ernest V.; Hauser, Thomas H.; Succurro, Elena; Mercuri, Luana; Goheen, Elizabeth H.; Shah, Hetal; Trischitta, Vincenzo; Sesti, Giorgio; Doria, Alessandro

    2011-01-01

    OBJECTIVE SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. METHODS SNP rs2943641 was typed in 2,133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. RESULTS HDL cholesterol decreased by 1 mg/dl (p=0.0045) and serum triglycerides increased by 6 mg/dl (p=0.018) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR=1.00, 95% CI 0.88–1.13). CONCLUSIONS The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population. PMID:21353221

  19. Relationship of Lifestyle Medical Advice and Non-HDL Cholesterol Control of a Nationally Representative US Sample with Hypercholesterolemia by Race/Ethnicity

    PubMed Central

    Vaccaro, Joan Anne; Huffman, Fatma G.

    2012-01-01

    Objective. The main purpose of this study was to evaluate the associations of lifestyle medical advice and non-HDL cholesterol control of a nationally representative US sample of adults with hypercholesterolemia by race/ethnicity. Methods. Data were collected by appending sociodemographic, anthropometric, and laboratory data from two cycles of the National Health and Nutrition Survey (2007-2008 and 2009-2010). This study acquired data from male and female adults aged ≥ 20 years (N = 11,577), classified as either Mexican American (MA), (n = 2173), other Hispanic (OH) (n = 1298), Black non-Hispanic (BNH) (n = 2349), or White non-Hispanic (WNH) (n = 5737). Results. Minorities were more likely to report having received dietary, weight management, and exercise recommendations by healthcare professionals than WNH, adjusting for confounders. Approximately 80% of those receiving medical advice followed the recommendation, regardless of race/ethnicity. Of those who received medical advice, reporting “currently controlling or losing weight” was associated with lower non-HDL cholesterol. BNH who reported “currently controlling or losing weight” had higher non-HDL cholesterol than WNH who reported following the advice. Conclusion. The results suggest that current methods of communicating lifestyle advice may not be adequate across race/ethnicity and that a change in perspective and delivery of medical recommendations for persons with hypercholesterolemia is needed. PMID:23119150

  20. On the puzzling distribution of cholesterol in the plasma membrane.

    PubMed

    Giang, H; Schick, M

    2016-09-01

    The distribution of cholesterol between the two leaves of the plasma membrane in mammalian cells presents a conundrum; given cholesterol's known affinity for sphingomyelin, which resides predominantly in the exoplasmic leaf, why is it that experiment finds a majority of the cholesterol in the cytoplasmic leaf? This article reviews a recently proposed solution to this puzzle. PMID:26724709

  1. Plasma lipoproteins and lecithin:cholesterol acyltransferase distribution in patients on dialysis.

    PubMed

    McLeod, R; Reeve, C E; Frohlich, J

    1984-04-01

    Plasma lipoproteins and LCAT activity were studied using a single spin density gradient separation and an exogenous substrate enzyme assay in 41 patients on chronic hemodialysis and in 11 normal subjects. The plasma HDL cholesterol was markedly decreased (33 vs. 63 mg/dl, P less than 0.001) while total and LDL-cholesterol were unchanged in the patients. Plasma LCAT activity was significantly lower in the patient group (42 vs. 59 nmoles/4 hr/ml, P less than 0.001), but the distribution of activity (studied in 13 dialysis patients and 12 control subjects) was not different between the two groups: 90% being associated with HDL and VHDL lipoprotein fractions. To examine the possible genetic influence on the development of hypertriglyceridemia in the patient group, we examined the ratio of apolipoproteins E3/E2 and CII/CIII in ten of the patients and another group of 13 control subjects. The frequency of heterozygotes for E3 deficiency was not different between the patient (one of ten) and the control (two of 13) groups. While the patient group had lower CII/CIII ratio, the figures did not reach statistical significance. The low LCAT activity in the face of higher plasma triglycerides and low HDL may contribute to impaired lipolysis previously documented in uremic patients. A follow-up study performed 1 year after the initial study confirmed the decreased HDL (51 vs. 71 mg/dl, P less than 0.01) and LCAT activity (50 vs. 59 nmoles/hr/ml, P less than 0.02) in an exogenous substrate system (N = 20). LCAT measured using the endogenous substrate was not significantly different from the control group (49 vs. 55 nmoles/hr/ml).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6482172

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  3. HDL Cholesterol Test

    MedlinePlus

    Advertisement Proceeds from website advertising help sustain Lab Tests Online. AACC is a not-for-profit organization ... for trustworthy health information. Verify Compliance . Produced by Advertisement

  4. A big role for small RNAs in HDL homeostasis

    PubMed Central

    Ouimet, Mireille; Moore, Kathryn J.

    2013-01-01

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

  5. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates

    PubMed Central

    Frank-Kamenetsky, Maria; Grefhorst, Aldo; Anderson, Norma N.; Racie, Timothy S.; Bramlage, Birgit; Akinc, Akin; Butler, David; Charisse, Klaus; Dorkin, Robert; Fan, Yupeng; Gamba-Vitalo, Christina; Hadwiger, Philipp; Jayaraman, Muthusamy; John, Matthias; Jayaprakash, K. Narayanannair; Maier, Martin; Nechev, Lubomir; Rajeev, Kallanthottathil G.; Read, Timothy; Röhl, Ingo; Soutschek, Jürgen; Tan, Pamela; Wong, Jamie; Wang, Gang; Zimmermann, Tracy; de Fougerolles, Antonin; Vornlocher, Hans-Peter; Langer, Robert; Anderson, Daniel G.; Manoharan, Muthiah; Koteliansky, Victor; Horton, Jay D.; Fitzgerald, Kevin

    2008-01-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50–70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5′-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia. PMID:18695239

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

    PubMed Central

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

    2014-01-01

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

  7. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.

    PubMed

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D; Granados-Silvestre, Ma de Angeles; Montufar-Robles, Isela; Tito-Alvarez, Ana M; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Lisker, Ruben; Moises, Regina S; Menjivar, Marta; Salzano, Francisco M; Knowler, William C; Bortolini, M Cátira; Hayden, Michael R; Baier, Leslie J; Canizales-Quinteros, Samuel

    2010-07-15

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations. PMID:20418488

  8. A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

    PubMed Central

    Acuña-Alonzo, Víctor; Flores-Dorantes, Teresa; Kruit, Janine K.; Villarreal-Molina, Teresa; Arellano-Campos, Olimpia; Hünemeier, Tábita; Moreno-Estrada, Andrés; Ortiz-López, Ma Guadalupe; Villamil-Ramírez, Hugo; León-Mimila, Paola; Villalobos-Comparan, Marisela; Jacobo-Albavera, Leonor; Ramírez-Jiménez, Salvador; Sikora, Martin; Zhang, Lin-Hua; Pape, Terry D.; de Ángeles Granados-Silvestre, Ma; Montufar-Robles, Isela; Tito-Alvarez, Ana M.; Zurita-Salinas, Camilo; Bustos-Arriaga, José; Cedillo-Barrón, Leticia; Gómez-Trejo, Celta; Barquera-Lozano, Rodrigo; Vieira-Filho, Joao P.; Granados, Julio; Romero-Hidalgo, Sandra; Huertas-Vázquez, Adriana; González-Martín, Antonio; Gorostiza, Amaya; Bonatto, Sandro L.; Rodríguez-Cruz, Maricela; Wang, Li; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Lisker, Ruben; Moises, Regina S.; Menjivar, Marta; Salzano, Francisco M.; Knowler, William C.; Bortolini, M. Cátira; Hayden, Michael R.; Baier, Leslie J.; Canizales-Quinteros, Samuel

    2010-01-01

    It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 × 10−11) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations. PMID:20418488

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

    PubMed Central

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

    2013-01-01

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

  10. Effects of gender and gonadectomy on growth and plasma cholesterol levels in pigs

    PubMed Central

    Kim, Nam-Young; Kim, Kyu-Il

    2009-01-01

    We conducted two studies to determine the effect of gender, gonadectomy (GDX) on growth and plasma cholesterol levels in pigs. In experiment 1, five sham-operated and five GDX female Landrace pigs (26 kg) were allowed to have free access to water and feed up to market weight (approximately 100 kg). Body weight and feed consumption were recorded biweekly, and daily body weight gain, daily feed intake and feed efficiency (gain/feed) were calculated during the feeding period. In experiment 2, 10 male (26 kg) and 10 female (26 kg) Landrace pigs were used; five male and five female pigs were assigned to sham-operated or GDX. Pigs were allowed to have free access to water and a diet without added cholesterol (Table 1) until they were 6 months old (male 104 and female 98 kg) and thereafter they were fed a hypercholesterolemic diet (Table 1) containing 0.5% cholesterol and 0.1% cholate for 10 days. GDX of female pigs increased average daily gain (P<0.05), compared with their sham-operated counterparts during the growing-finishing period, but had no effect (P>0.05) on feed efficiency. Plasma cholesterol levels in pigs fed a hypercholesterolemic diet for 10 days were much higher (P<0.05) in females than in males (161 vs 104 mg/100 mL plasma), and were increased by GDX only in male pigs. HDL-cholesterol/LDL+VLDL-cholesterol ratio appeared to be higher in males than in females, and was not influenced by GDX in either sex. Results suggested that the lower growth rate of female pigs than their male counterparts is attributable to the ovarian activity, and the lower plasma cholesterol level in male than in female pigs fed a hypercholesterolemic diet is due to the testicular activity. PMID:20016700

  11. Rapid on-line determination of cholesterol distribution among plasma lipoproteins after high-performance gel filtration chromatography.

    PubMed

    Kieft, K A; Bocan, T M; Krause, B R

    1991-05-01

    A high-performance gel chromatography (HPGC) system has been developed which allows the unattended on-line determination of lipoprotein cholesterol distribution (VLDL-C, LDL-C, HDL-C), within 40 min, in microliter quantities of plasma using a single, relatively inexpensive column (Superose 6HR). The FAST cholesterol reagent (Sclavo) and a knitted PFTE Kratos reaction coil (Applied Biosystems) were found to provide optimal sensitivity, linearity, resolution, and dispersion characteristics. Validation is provided by comparison to target values for human quality control reference sera, and by comparing the values obtained by HPGC to the beta-quant method (LRC). The utility of the system is illustrated by comparing profiles from seven different species with normal or elevated plasma cholesterol concentrations. This technique allows rapid analysis of samples, regardless of species, without the use of precipitating agents or the ultracentrifuge. It could also be applied for the direct clinical determination of LDL-cholesterol. PMID:2072044

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

    PubMed Central

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

    2016-01-01

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

  13. 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

  14. Kinetics of lipids, apolipoproteins, and cholesteryl ester transfer protein in plasma after a bicycle marathon.

    PubMed

    Föger, B; Wohlfarter, T; Ritsch, A; Lechleitner, M; Miller, C H; Dienstl, A; Patsch, J R

    1994-05-01

    The short-term effects of prolonged intense exercise on plasma lipid transport parameters including cholesterol, triglycerides (TGs), low-density lipoprotein (LD) cholesterol, high-density lipoprotein (HDL) cholesterol, and its subfractions HDL2 cholesterol and HDL3 cholesterol, on apolipoproteins (apos) A-I, A-II, and B, and on mass and activity of cholesteryl ester transfer protein (CETP) were studied in eight male endurance-trained athletes over the first week after a bicycle marathon. CETP mass concentration in plasma was quantified by a newly developed immunoradiometric assay (IRMA). Plasma concentrations of cholesterol, TGs, LDL cholesterol, apo B, CETP, and cholesteryl ester transfer activity (CETA) were significantly reduced in the recovery period compared with pre-exercise values (cholesterol by 20%, P < .05; TGs by 63%, P < .05; LDL cholesterol by 32%, P < .05; apo B by 18%, P < .05; CETP mass by 29%, P < .05; and CETA by 14%, P < .05). HDL cholesterol and HDL2 cholesterol, in contrast, were significantly increased in the post-exercise period (HDL cholesterol by 12%, P < .05, and HDL2 cholesterol by 96%, P < .05), whereas HDL3 cholesterol showed a tendency to decrease in the late recovery period (by 8%, NS). Although changes in cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apo B, and CETP mass and activity were already evident in the early recovery period, HDL2 cholesterol showed a delayed response, reaching its maximum 72 hours after initiation of exercise.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8177053

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

    PubMed Central

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

    2015-01-01

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

  16. Low Maternal Vitamin B12 Status Is Associated with Lower Cord Blood HDL Cholesterol in White Caucasians Living in the UK

    PubMed Central

    Adaikalakoteswari, Antonysunil; Vatish, Manu; Lawson, Alexander; Wood, Catherine; Sivakumar, Kavitha; McTernan, Philip G.; Webster, Craig; Anderson, Neil; Yajnik, Chittaranjan S.; Tripathi, Gyanendra; Saravanan, Ponnusamy

    2015-01-01

    Background and Aims: Studies in South Asian population show that low maternal vitamin B12 associates with insulin resistance and small for gestational age in the offspring. Low vitamin B12 status is attributed to vegetarianism in these populations. It is not known whether low B12 status is associated with metabolic risk of the offspring in whites, where the childhood metabolic disorders are increasing rapidly. Here, we studied whether maternal B12 levels associate with metabolic risk of the offspring at birth. Methods: This is a cross-sectional study of 91 mother-infant pairs (n = 182), of white Caucasian origin living in the UK. Blood samples were collected from white pregnant women at delivery and their newborns (cord blood). Serum vitamin B12, folate, homocysteine as well as the relevant metabolic risk factors were measured. Results: The prevalence of low serum vitamin B12 (<191 ng/L) and folate (<4.6 μg/L) were 40% and 11%, respectively. Maternal B12 was inversely associated with offspring’s Homeostasis Model Assessment 2-Insulin Resistance (HOMA-IR), triglycerides, homocysteine and positively with HDL-cholesterol after adjusting for age and BMI. In regression analysis, after adjusting for likely confounders, maternal B12 is independently associated with neonatal HDL-cholesterol and homocysteine but not triglycerides or HOMA-IR. Conclusions: Our study shows that low B12 status is common in white women and is independently associated with adverse cord blood cholesterol. PMID:25849948

  17. High intake of fatty fish, but not of lean fish, affects serum concentrations of TAG and HDL-cholesterol in healthy, normal-weight adults: a randomised trial.

    PubMed

    Hagen, Ingrid V; Helland, Anita; Bratlie, Marianne; Brokstad, Karl A; Rosenlund, Grethe; Sveier, Harald; Mellgren, Gunnar; Gudbrandsen, Oddrun A

    2016-08-01

    The aim of the present study was to examine whether high intake of lean or fatty fish (cod and farmed salmon, respectively) by healthy, normal-weight adults would affect risk factors of type 2 diabetes and CVD when compared with lean meat (chicken). More knowledge is needed concerning the potential health effects of high fish intake (>300 g/week) in normal-weight adults. In this randomised clinical trial, thirty-eight young, healthy, normal-weight participants consumed 750 g/week of lean or fatty fish or lean meat (as control) for 4 weeks at dinner according to provided recipes to ensure similar ways of preparations and choices of side dishes between the groups. Energy and macronutrient intakes at baseline and end point were similar in all groups, and there were no changes in energy and macronutrient intakes within any of the groups during the course of the study. High intake of fatty fish, but not lean fish, significantly reduced TAG and increased HDL-cholesterol concentrations in fasting serum when compared with lean meat intake. When compared with lean fish intake, fatty fish intake increased serum HDL-cholesterol. No differences were observed between lean fish, fatty fish and lean meat groups regarding fasting and postprandial glucose regulation. These findings suggest that high intake of fatty fish, but not of lean fish, could beneficially affect serum concentrations of TAG and HDL-cholesterol, which are CVD risk factors, in healthy, normal-weight adults, when compared with high intake of lean meat. PMID:27363518

  18. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients; a meta-analysis

    PubMed Central

    Boekholdt, S. Matthijs; Arsenault, Benoit J.; Hovingh, G. Kees; Mora, Samia; Pedersen, Terje R.; LaRosa, John C.; Welch, K.M.A.; Amarenco, Pierre; DeMicco, David A.; Tonkin, Andrew M.; Sullivan, David R.; Kirby, Adrienne; Colhoun, Helen M.; Hitman, Graham A.; Betteridge, D. John; Durrington, Paul N.; Clearfield, Michael B.; Downs, John R.; Gotto, Antonio M.; Ridker, Paul M.; Kastelein, John J.P.

    2013-01-01

    Background It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol (LDL-C) on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. Methods and results We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio 0.83, 95%CI 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR 0.79, 95%CI 0.72–0.82). This association was also observed among patients achieving on-statin LDL-C levels < 50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR 0.98, 95%CI 0.94–1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR 0.93, 95%CI 0.90–0.97). Conclusions Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low LDL-C. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction. PMID:23965489

  19. Pancreatic enzyme and plasma cholesterol response to chronic ingestion of a nonabsorbable lipid in rats.

    PubMed

    Hager, M H; Schneeman, B O

    1986-12-01

    Pancreatic enzyme activity and plasma and high density lipoprotein (HDL) cholesterol levels were measured in rats chronically fed a nonabsorbable lipid, sucrose polyester (SPE), to determine if the rat pancreas responds to SPE as a dietary lipid or a nonnutritive ingredient. Adult male rats were fed for 28 d a diet containing either 5% or 20% corn oil, 5% SPE, 16% and 4% hydrogenated palm oil (HPO), or 16% corn oil and 4% HPO. HPO is used to prevent anal leakage of unabsorbed oil when SPE is fed at high dietary levels. Since HPO and SPE are not absorbed, rats fed SPE derive their energy from protein and carbohydrate in the diet. The tissue levels of pancreatic enzymes in rats consuming high levels of SPE in the diet resemble those of rats eating a low fat diet in which energy is derived from carbohydrate and protein. Plasma and HDL cholesterol levels were lowest in the group consuming high levels of SPE, an observation that is consistent with previous reports. These data indicate that the pancreas responds to SPE as a nonnutritive ingredient rather than a digestible dietary lipid. PMID:3806235

  20. HDL and Cognition in Neurodegenerative Disorders

    PubMed Central

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

    2014-01-01

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

  1. 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

  2. Endothelial lipase is a major determinant of HDL level

    SciTech Connect

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

    2003-01-30

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

  3. Synthetic LXR agonist suppresses endogenous cholesterol biosynthesis and efficiently lowers plasma cholesterol.

    PubMed

    Pfeifer, Thomas; Buchebner, Marlene; Chandak, Prakash G; Patankar, Jay; Kratzer, Adelheid; Obrowsky, Sascha; Rechberger, Gerald N; Kadam, Rajendra S; Kompella, Uday B; Kostner, Gerhard M; Kratky, Dagmar; Levak-Frank, Sanja

    2011-02-01

    The liver X receptors (LXRs) are key regulators of genes involved in cholesterol homeostasis. Natural ligands and activators of LXRs are oxysterols. Numerous steroidal and non-steroidal synthetic LXR ligands are under development as potential drugs for individuals suffering from lipid disorders. N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is a steroidal ligand of LXRs that exerts anti-atherogenic effects in apolipoprotein E-deficient mice without causing negative side effects such as liver steatosis or hypertriglyceridemia. In this report, we investigated the consequences of DMHCA treatment on cholesterol homeostasis in vivo and in vitro. Despite its hydrophobicity, DMHCA is readily absorbed by C57BL/6 mice and taken up by intestinal cells, the lung, heart and kidneys, but is undetectable in the brain. DMHCA significantly reduces cholesterol absorption and uptake in duodenum and jejunum of the small intestine and in turn leads to a reduction of plasma cholesterol by 24%. The most striking finding of this study is that DMHCA inhibited the enzyme 3β-hydroxysterol-Δ24-reductase resulting in an accumulation of desmosterol in the plasma and in feces. Thus, the reduction of plasma cholesterol was due to a block in the final step of cholesterol biosynthesis. Taken together, DMHCA is an interesting compound with properties distinct from other LXR ligands and might be used to study desmosterol-mediated effects in cells and tissues. PMID:21190543

  4. Dysfunctional HDL and atherosclerotic cardiovascular disease.

    PubMed

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

    2016-01-01

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

  5. Plasma mevalonate as a measure of cholesterol synthesis in man.

    PubMed Central

    Parker, T S; McNamara, D J; Brown, C D; Kolb, R; Ahrens, E H; Alberts, A W; Tobert, J; Chen, J; De Schepper, P J

    1984-01-01

    Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p less than 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol. The hypothesis that short-term regulation of HMG-CoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dose-dependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant lowering of plasma cholesterol was achieved through administration of mevinolin at doses that only moderately limit MVA production. PMID:6565710

  6. Plasma and hepatic cholesterol levels and fecal neutral sterol excretion are altered in hamsters fed straw mushroom diets.

    PubMed

    Cheung, P C

    1998-09-01

    The effect of the fruiting body and mycelium of Volvariella volvacea (straw mushroom) on the concentrations of plasma lipids, liver cholesterol, fecal neutral sterol and bile acid excretions was investigated in male Golden Syrian hamsters. The hamsters were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 4 wk to elevate plasma lipid concentrations. Twelve hamsters with elevated plasma total cholesterol were randomly assigned to each treatment group: control (5% cellulose), mushroom fruiting body (5%) and mushroom mycelium (5%). After 4 wk of mushroom diet consumption, the plasma total cholesterol, HDL cholesterol, and combined VLDL + LDL cholesterol concentrations (mmol/L) were significantly lower than control in the group fed the fruiting body-diet (40, 38 and 43%, respectively) (P < 0.05). The liver cholesterol levels were significantly lower in both the mushroom fruiting body- and the mycelium-fed groups (28 and 21% in terms of concentration; 39 and 30% in terms of total content, respectively) (P < 0.05) than that in the control group. Fecal neutral sterol excretion in the mushroom fruiting body- and mycelium-fed groups was significantly higher (81 and 74%, respectively) (P < 0.05) than that in the control group. Although no significant differences (P > 0.05) in the excretion of fecal bile acids were observed among groups fed the mushroom diets and the control diet, the mushroom fruiting body diet-fed hamsters apparently had less bacterial degradation of cholic acid as indicated by a significantly greater proportion (P < 0.05) of fecal cholic acid than in controls. They also had a significantly lower proportion of fecal deoxycholic acid (P < 0.05). This study suggests that the fruiting body of the straw mushroom lowers elevated plasma cholesterol in hypercholesterolemic hamsters, whereas the mycelium does not. PMID:9732312

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

    PubMed

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

    2013-04-01

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

  8. 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

  9. A review on lecithin:cholesterol acyltransferase deficiency.

    PubMed

    Saeedi, Ramesh; Li, Min; Frohlich, Jiri

    2015-05-01

    Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme which esterifies cholesterol, and plays a key role in the metabolism of high-density lipoprotein cholesterol (HDL-C). Genetic disorders of LCAT are associated with lipoprotein abnormalities including low levels of HDL-C and presence of lipoprotein X, and clinical features mainly corneal opacities, changes in erythrocyte morphology and renal failure. Recombinant LCAT is being developed for the treatment of patients with LCAT deficiency. PMID:25172171

  10. Common and Rare Gene Variants Affecting Plasma LDL Cholesterol

    PubMed Central

    Burnett, John R; Hooper, Amanda J

    2008-01-01

    The plasma level of LDL cholesterol is clinically important and genetically complex. LDL cholesterol levels are in large part determined by the activity of LDL receptors (LDLR) in the liver. Autosomal dominant familial hypercholesterolaemia (FH) – with its high LDL cholesterol levels, xanthomas, and premature atherosclerosis – is caused by mutations in either the LDLR or in APOB – the protein in LDL recognised by the LDLR. A third, rare form – autosomal recessive hypercholesterolaemia – arises from mutations in the gene encoding an adaptor protein involved in the internalisation of the LDLR. A fourth variant of inherited hypercholesterolaemia was recently found to be associated with missense mutations in PCSK9, which encodes a serine protease that degrades LDLR. Whereas the gain-of-function mutations in PCSK9 are rare, a spectrum of more frequent loss-of-function mutations in PCSK9 associated with low LDL cholesterol levels has been identified in selected populations and could protect against coronary heart disease. Heterozygous familial hypobetalipoproteinaemia (FHBL) – with its low LDL cholesterol levels and resistance to atherosclerosis – is caused by mutations in APOB. In contrast to other inherited forms of severe hypocholesterolaemia such as abetalipoproteinaemia - caused by mutations in MTP - and homozygous FHBL, a deficiency of PCSK9 appears to be benign. Rare variants of NPC1L1, the gene encoding the putative intestinal cholesterol receptor, have shown more modest effects on plasma LDL cholesterol than PCSK9 variants, similar in magnitude to the effect of common APOE variants. Taken together, these findings indicate that heritable variation in plasma LDL cholesterol is conferred by sequence variation in various loci, with a small number of common and multiple rare gene variants contributing to the phenotype. PMID:18566665

  11. 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

  12. [The clinical evaluation of the hypocholesterolemic effects of an inhibitor of cholesterol synthesis: mevalonic acid].

    PubMed

    Del Nero, E; Aloe, N; Augeri, C; Avola, F; Carta, G; Cavagnaro, A; De Grandi, R; Gianfreda, M; Magro, G P; Mazzarello, G P

    1992-07-01

    Twenty eight patients with heterozygous familial hypercholesterolemia were treated with mevalonic acid (an inhibitor of cholesterol synthesis) for 45 days. Patients received a daily dose of 750 to 1500 mg mevalonic acid depending on plasma cholesterol levels. Results showed a significant reduction in cholesterol values whereas no significant difference was observed in HDL cholesterol and triglyceride levels. PMID:1505176

  13. Effect of dietary Maitake (Grifola frondosa) mushrooms on plasma cholesterol and hepatic gene expression in cholesterol-fed mice.

    PubMed

    Sato, Mayumi; Tokuji, Yoshihiko; Yoneyama, Shozo; Fujii-Akiyama, Kyoko; Kinoshita, Mikio; Chiji, Hideyuki; Ohnishi, Masao

    2013-01-01

    To investigate the effects of dietary Grifola frondosa on cholesterol, normal mice were fed a diet containing 1% cholesterol (HC group) or 1% cholesterol and 10% freeze-dried G. frondosa powder (HC+G group) for 4 weeks and hepatic and plasma lipid levels were compared with those of a cholesterol-free diet-fed mice (N group). Hepatic total cholesterol (TC), triacylglycerol contents were considerably increased and plasma TC / phospholipid (PL) was also increased significantly in the HC group compared with the N group. However, plasma TC content decreased in the HC+G group compared with the HC group. To characterize the mechanisms responsible for lowered plasma cholesterol in G. frondosa-supplemented mice, hepatic gene expression was profiled using DNA microarray and gene ontology. Genome analyses revealed that de novo cholesterol synthesis genes were suppressed following cholesterol intake. However, expression of bile acid biosynthesis and low-density lipoprotein receptor genes showed little change. Scarb1, Abcg5, and Abcg8, involved in cholesterol transport and excretion, were slightly upregulated in the HC+G group compared with the HC group. These data indicate the plasma cholesterol-lowering effect of G. frondosa. Moreover, fatty acid (FA) β-oxidation was promoted via adipocytokine signaling pathways, and Saa, encodes serum amyloid A related to arteriosclerosis, was suppressed in the HC+G group. PMID:24292357

  14. Effect of plant sterol-enriched diets on plasma and egg yolk cholesterol concentrations and cholesterol metabolism in laying hens.

    PubMed

    Liu, X; Zhao, H L; Thiessen, S; House, J D; Jones, P J H

    2010-02-01

    Egg exists as a major dietary source of cholesterol in Western diets. In North America, laying hen diets are usually devoid of cholesterol when diets are formulated to exclude animal-based products. Hence, laying hens meet their physiological cholesterol requirement through de novo synthesis. Plant sterols exert a cholesterol-lowering effect in humans by interfering with intestinal sterol absorption. However, it is unknown whether plant sterol supplementation could be effective in reducing intestinal reabsorption of biliary cholesterol in laying hens, thus modulating whole body cholesterol in favor of lower plasma and yolk cholesterol content. The current study was designed to investigate the effect of diets enriched with 0, 0.5, 1, and 2% plant sterols on cholesterol absorption, synthesis, as well as plasma, liver, and egg yolk cholesterol concentrations in laying hens. After 8 wk of plant sterol intervention (first 2 wk were acclimatization), feed intake, BW, egg weight, egg yolk weight, egg production, Haugh units, liver mass, plasma, and hepatic cholesterol concentrations did not differ as a function of plant sterol supplementation. Egg cholesterol concentrations (mg/g) fluctuated during the 6-wk experimental period. At wk 6, a minor reduction in egg yolk cholesterol concentration (mg per g of yolk, P<0.05, vs. control) was observed in hens fed 1 and 2% cholesterol-enriched diets, respectively. However, such result failed to affect total egg cholesterol content. No statistical difference was observed across treatments over 6 wk. Neither cholesterol absorption rates nor synthesis differed as a function of treatment. Results suggested that overall cholesterol content in egg yolk was not affected by feeding hens plant sterol-enriched diets over 6 wk. PMID:20075279

  15. 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

  16. HDL, Atherosclerosis, and Emerging Therapies

    PubMed Central

    Genest, Jacques

    2013-01-01

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

  17. 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

  18. Effect of menhaden fish oil on plasma cholesterol in copper-deficient rats

    SciTech Connect

    Lee, C.C.; Koo, S.I. )

    1989-02-09

    Weanling male rats were divided into 2 groups: one fed a copper-deficient (CuD) diet and the other fed a copper-adequate (CuA) diet. Both contained 5% corn oil. At 8 wk, each of the 2 groups was divided into two subgroups: one fed the above diet supplemented with 1% refined menhaden-fish oil (FO) and the other with 1% corn oil (CO). Time-course effect of FO on plasma cholesterol (CH) were compared in CuD and CuA groups at 14, 33, 77 and 120 days. FO feeding did not affect plasma CH in CuD rats at any time point, but markedly lowered plasma CH in CuA rats at 77 and 120 days, compared with the CO-fed respective controls. The lack of hypolipidemic effect of FO in CuD rats was due to its inability to lower plasma VLDL. Plasma HDL were not affected by FO. The lipoprotein lipase activity in skeletal muscle was lowered by FO in both CuD and CuA rats, compared with CO-fed counterparts, while no such change was noted in adipose tissue. The failure of FO to lower VLDL in CuD rats suggests that the hypercholesterolemia in copper deficiency may be partly linked to a change in the rate of VLDL output and/or catabolism.

  19. 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

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

    PubMed

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

    2015-01-01

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

  1. Plasma cholesterol-raising potency of dietary free cholesterol versus cholesteryl ester and effect of β-sitosterol.

    PubMed

    Liu, Yuwei; Lei, Lin; Wang, Xiaobo; Ma, Ka Ying; Li, Yuk Man; Wang, Lijun; Man, Sun Wa; Huang, Yu; Chen, Zhen-Yu

    2015-02-15

    The present study (i) compared plasma cholesterol-raising activity of free cholesterol (FC) with that of cholesteryl palmitate (CP) and (ii) examined plasma cholesterol-reducing activity of β-sitosterol in FC-induced and CP-induced hypercholesterolemia. Male hamsters were divided into five groups and fed one of the five diets containing no cholesterol (NC), 2.6mmol cholesterol (C), 2.6mmol cholesterol plus 2.6mmol β-sitosterol (C+S), 2.6mmol cholesteryl palmitate (CP), and 2.6mmol CP plus 2.6mmol β-sitosterol (CP+S), respectively, for 8weeks. Hamsters fed diet C had plasma TC of 317.5mg/dl whereas hamsters fed diet CP has plasma TC of 281.3mg/dl. β-Sitosterol reduced plasma TC by 17.4% and 11.6%, respectively, in FC-induced and CP-induced hypercholesterolemia (not significant). It was concluded that plasma cholesterol-raising activity of dietary cholesterol was a function of its chemical forms in diet, and β-sitosterol could similarly suppress the hypercholesterolemia induced by both dietary FC and CP. PMID:25236227

  2. The effect of a novel intergenic polymorphism (rs11774572) on HDL cholesterol concentrations depends on the TaqIB polymorphism in the cholesterol ester transfer protein gene

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Plasma lipid levels have a strong genetic component and many different loci, including those identified by genome-wide association studies, affect lipoprotein metabolism in humans. Hence, the study of gene-gene interactions may be useful to provide additional predictive value as well as ...

  3. Hypercholesterolemic effect of dietary cholesterol in diets enriched in polyunsaturated and saturated fat. Dietary cholesterol, fat saturation, and plasma lipids.

    PubMed

    Lichtenstein, A H; Ausman, L M; Carrasco, W; Jenner, J L; Ordovas, J M; Schaefer, E J

    1994-01-01

    Within the context of reduced-fat diets, the effects of incorporating a fat high in stearic acid and adding moderate amounts of dietary cholesterol were examined in 14 middle-aged and elderly women and men (range, 46 to 78 years) with low-density lipoprotein cholesterol (LDL-C) concentrations > 130 mg/dL (range, 133 to 219 mg/dL) at screening. The subjects consumed each of the five diets, which were as follows: (1) a baseline diet (35% fat with 13% saturated fatty acids [SFAs], 12% monounsaturated fatty acids [MUFAs], and 8% polyunsaturated fatty acids [PUFAs], and 128 mg cholesterol/1000 kcal); (2) a reduced-fat diet, in which two thirds of the fat was provided as corn oil (corn oil-enriched diet: 29% fat with 7% SFAs, 9% MUFAs, and 11% PUFAs and 85 mg cholesterol/1000 kcal), which met the National Cholesterol Education Program (NCEP) Step 2 guidelines; (3) a reduced-fat diet, in which two thirds of the fat was provided as beef tallow (beef tallow-enriched diet: 31% fat with 13% SFAs, 11% MUFAs, and 3% PUFAs and 109 mg cholesterol/1000 kcal); and two reduced-fat diets, one (4) enriched in corn oil and the other (5) enriched in beef tallow, to which moderate amounts of cholesterol in the form of egg yolk were incorporated (197 or 226 mg cholesterol/1000 kcal final cholesterol content in corn oil- or beef tallow-enriched diets, respectively). All diets were isocaloric and all food and drink were provided by the metabolic kitchen. Reducing the fat content of the diet resulted in decreased concentrations of LDL-C and high-density lipoprotein cholesterol (HDL-C).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8274473

  4. 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...

  5. Association between periodontal disease and plasma levels of cholesterol and triglycerides

    PubMed Central

    Lafaurie, Gloria Inés; Millán, Lina Viviana; Ardila, Carlos Martin; Duque, Andrés; Novoa, Camilo; López, Diego; Contreras, Adolfo

    2013-01-01

    Objective: untreated periodontal disease seems to cause low grade systemic inflammation and blood lipid alteration leading to increased cardiovascular disease risk. To start testing this hypothesis in colombian patients, a multicentre study was conducted including the three main state capitals: bogota, medellin and cali. Methods: in this study 192 (28.4%) advanced and 256 (37.8%) moderate periodontitis patients were investigated for socio-demographic variables, city of precedence, periodontal parameters, smoking, red complex periodontopathic bacteria, serum antibodies against porphyromonas gingivalis and aggregatibacter actinomycetemcomitans and blood lipids including total cholesterol, hdl, ldl and triglycerides (tg). Those parameters were compared to 229 (33.8%) controls having periodontal health or gingivitis. Results: advanced periodontitis had worst periodontal indexes, than moderate periodontitis and controls. Interestingly, higher hdl and tg levels were present in periodontitis. Bmi <30 and smoking were associated with increased hdl, hdl-35, ldl and tg, while glycemia >100 mg/dl associated with hdl, hdl-35 and tg. Tannerella forsythia showed a significant association with hdl-35 in bivariate analysis and serum igg1 against p. Gingivalis associated with hdl-35 and serum igg1 against t. Forsythia associated with tg and serum igg2 against a. Actinomycetemcomitans correlated with levels of hdl y hdl-35. In logistic regression the periodontitis patients from cali presented reduced hdl levels as compared to bogota and medellin patients. Presence of igg1 antibodies against p. Gingivalis and a. Actinomycetemcomitans correlated with reduced hdl levels. Conclusion: this study confirmed that untreated periodontitis generates alteration in serum lipid levels and systemic bacterial exposure against important periodontopathic bacteria could be the biological link. PMID:24892452

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

    PubMed

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

    2010-02-01

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

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

    PubMed Central

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

    2013-01-01

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

  8. The role of the lymphatic system in cholesterol transport

    PubMed Central

    Huang, Li-Hao; Elvington, Andrew; Randolph, Gwendalyn J.

    2015-01-01

    Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease. PMID:26388772

  9. 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

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

    PubMed

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

    2015-03-01

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

  11. Protective Effects of HDL Against Ischemia/Reperfusion Injury

    PubMed Central

    Gomaraschi, Monica; Calabresi, Laura; Franceschini, Guido

    2016-01-01

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

  12. Higher breakfast glycaemic load is associated with increased metabolic syndrome risk, including lower HDL-cholesterol concentrations and increased TAG concentrations, in adolescent girls.

    PubMed

    Nicholl, Analise; du Heaume, Mary; Mori, Trevor A; Beilin, Lawrence J; Oddy, Wendy H; Bremner, Alexandra P; O'Sullivan, Therese A

    2014-12-28

    Almost all previous studies examining the associations between glycaemic load (GL) and metabolic syndrome risk have used a daily GL value. The daily value does not distinguish between peaks of GL intake over the day, which may be more closely associated with the risk of the metabolic syndrome. The aim of the present study was to investigate the cross-sectional associations between daily and mealtime measures of GL and metabolic syndrome risk, including metabolic syndrome components, in adolescents. Adolescents participating in the 14-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study completed 3 d food records and metabolic assessments. Breakfast GL, lunch GL, dinner GL and a score representing meal GL peaks over the day were determined in 516 adolescents. Logistic regression models were used to investigate whether GL variables were independent predictors of the metabolic syndrome in this population-based cohort (3.5% prevalence of the metabolic syndrome). Breakfast GL was found to be predictive of the metabolic syndrome in girls (OR 1.15, 95% CI 1.04, 1.27; P <0.01), but not in boys. Other meal GL values and daily GL were found to be not significant predictors of the metabolic syndrome. When breakfast GL was examined in relation to each of the components of the metabolic syndrome in girls, it was found to be negatively associated with fasting HDL-cholesterol concentrations (P= 0.037; β = - 0.004; 95% CI - 0.008, - 0.002) and positively associated with fasting TAG concentrations (P= 0.008; exp(β) = 1.002; 95% CI 1.001, 1.004). he results of the present study suggest that there may be an association between breakfast composition and metabolic syndrome components in adolescent girls. These findings support further investigation into including lower-GL foods as part of a healthy breakfast in adolescence, particularly for girls. PMID:25327283

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

    PubMed Central

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

    2016-01-01

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

  14. Cholesterol testing and results

    MedlinePlus

    ... lipoprotein (LDL cholesterol) High density lipoprotein (HDL cholesterol) Triglycerides (another type of fat in your blood) Very ... made of fat and protein. They carry cholesterol, triglycerides, and other fats, called lipids, in the blood ...

  15. Novel method for reducing plasma cholesterol: a ligand replacement therapy

    PubMed Central

    Anantharamaiah, GM; Goldberg, Dennis

    2015-01-01

    Despite wide use of statins, significant cardiovascular disease risk persists. High-density lipoprotein based therapy has not yielded any positive results in combating this disease. Newer methods to rapidly decrease plasma cholesterol are much needed. While apolipoprotein B is a ligand for low-density lipoprotein receptor, which clears low-density lipoprotein cholesterol in a highly regulated pathway, apolipoprotein E (apoE) is a ligand for clearing other apolipoprotein B containing atherogenic lipoproteins via an alternate receptor pathway, especially the heparin sulfate proteoglycans on the liver cell surface. We describe here a novel method that replaces apoE as a ligand to clear all of the atherogenic lipoproteins via the heparin sulfate proteoglycans pathway. This ligand replacement apoE mimetic peptide therapy, having been designated as an orphan drug by the US FDA, is in clinical trials. PMID:25937835

  16. Quantification of In Vitro Macrophage Cholesterol Efflux and In Vivo Macrophage-Specific Reverse Cholesterol Transport.

    PubMed

    Escolà-Gil, Joan Carles; Lee-Rueckert, Miriam; Santos, David; Cedó, Lídia; Blanco-Vaca, Francisco; Julve, Josep

    2015-01-01

    Promotion of reverse cholesterol transport (RCT) is thought to be a major HDL-mediated mechanism for protecting against atherosclerosis. Preclinical studies support the concept that increasing cholesterol efflux from macrophages may confer atheroprotective benefits independently of the plasma HDL-cholesterol concentration. The application of the macrophage-to-feces RCT method in genetically engineered mice has provided evidence that this major HDL property correlates closely with changes in atherosclerosis susceptibility. This chapter provides details on the methodologies currently used to measure in vitro cholesterol efflux from macrophages or in vivo macrophage-specific RCT. The general principles and techniques described herein may be applied to measure the in vitro cholesterol efflux capacity of human serum in macrophage cultures and to evaluate the effect of different experimental pathophysiological conditions or the efficacy of different therapeutic strategies on the modulation of in vivo macrophage-RCT in mice. PMID:26445792

  17. 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.

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

    PubMed

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

    2000-02-01

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

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

    PubMed

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

    2015-02-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2015-01-01

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

  2. A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio.

    PubMed

    Guevara-Cruz, Martha; Torres, Nimbe; Tovar, Armando R; Tejero, M Elizabeth; Castellanos-Jankiewicz, Ashley; del Bosque-Plata, Laura

    2014-01-01

    Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention. PMID:25238846

  3. Influence of psyllium preparations on plasma and liver lipids of cholesterol-fed rats.

    PubMed

    Kritchevsky, D; Tepper, S A; Klurfeld, D M

    1995-01-01

    Rats were fed a semi purified diet containing 0.5% cholesterol and 10% fiber (cellulose, pectin, psyllium seed and defatted psyllium husk). One additional group of rats was fed cholesterol (0.5%) as part of a fiber-free diet and another was fed the fiber free diet without cholesterol. Cellulose had virtually no effect on serum or liver lipids. Pectin had a lipid lowering effect. Psyllium seed exerted an effect on total serum cholesterol equal to that of pectin but gave higher levels of HDL-cholesterol. The effects of psyllium seed on liver lipids were more pronounced than those of pectin. Defatted psyllium husk feeding virtually normalized liver size and serum triglyceride levels and produced lower serum total cholesterol levels and higher HDL-cholesterol than observed in normal controls. Defatted psyllium husk feeding also yielded liver lipid values which were in the normal range. Fecal wet and dry weights were significantly higher in rats fed either psyllium preparation. PMID:8833230

  4. 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

  5. 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

  6. Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis.

    PubMed

    Chasman, Daniel I; Paré, Guillaume; Mora, Samia; Hopewell, Jemma C; Peloso, Gina; Clarke, Robert; Cupples, L Adrienne; Hamsten, Anders; Kathiresan, Sekar; Mälarstig, Anders; Ordovas, José M; Ripatti, Samuli; Parker, Alex N; Miletich, Joseph P; Ridker, Paul M

    2009-11-01

    While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5x10(-8)) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism-including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles-all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay. PMID:19936222

  7. Effect of melatonin on cholesterol absorption in rats.

    PubMed

    Hussain, Saad Abdul-Rehman

    2007-04-01

    This study evaluated the influence of melatonin on cholesterol absorption in rats fed on high cholesterol diet (HCD). HCD induced a remarkable increase in hepatic and plasma total cholesterol, plasma very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, a decrease in high density lipoprotein (HDL) cholesterol and an elevation in triacylglyceride (TG) levels in plasma and in the liver. Melatonin suspension (10 mg/kg), specially prepared for this purpose, cholestyramine (230 mg/kg) and ezetimibe (145 microg/kg) were administered orally to the rats fed HCD for 30 days. Melatonin significantly reduced cholesterol absorption in rats fed on HCD and caused significant decreases in total cholesterol, TG, VLDL- and LDL-cholesterol in the plasma and contents of cholesterol and TG in the liver. The level of HDL cholesterol was significantly increased after melatonin. These results suggested that inhibition of cholesterol absorption caused by melatonin could be a mechanism contributing to the positive changes in plasma cholesterol, lipoprotein profile and the lipid contents in the liver. PMID:17349025

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

    PubMed

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

    2008-10-01

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

  9. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

    PubMed Central

    Fernández-Suárez, María E.; Escolà-Gil, Joan C.; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A.; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [3H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [3H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  10. Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport.

    PubMed

    Fernández-Suárez, María E; Escolà-Gil, Joan C; Pastor, Oscar; Dávalos, Alberto; Blanco-Vaca, Francisco; Lasunción, Miguel A; Martínez-Botas, Javier; Gómez-Coronado, Diego

    2016-01-01

    Selective estrogen receptor modulators (SERMs) are widely prescribed drugs that alter cellular and whole-body cholesterol homeostasis. Here we evaluate the effect of SERMs on the macrophage-specific reverse cholesterol transport (M-RCT) pathway, which is mediated by HDL. Treatment of human and mouse macrophages with tamoxifen, raloxifene or toremifene induced the accumulation of cytoplasmic vesicles of acetyl-LDL-derived free cholesterol. The SERMs impaired cholesterol efflux to apolipoprotein A-I and HDL, and lowered ABCA1 and ABCG1 expression. These effects were not altered by the antiestrogen ICI 182,780 nor were they reproduced by 17β-estradiol. The treatment of mice with tamoxifen or raloxifene accelerated HDL-cholesteryl ester catabolism, thereby reducing HDL-cholesterol concentrations in serum. When [(3)H]cholesterol-loaded macrophages were injected into mice intraperitoneally, tamoxifen, but not raloxifene, decreased the [(3)H]cholesterol levels in serum, liver and feces. Both SERMs downregulated liver ABCG5 and ABCG8 protein expression, but tamoxifen reduced the capacity of HDL and plasma to promote macrophage cholesterol efflux to a greater extent than raloxifene. We conclude that SERMs interfere with intracellular cholesterol trafficking and efflux from macrophages. Tamoxifen, but not raloxifene, impair M-RCT in vivo. This effect is primarily attributable to the tamoxifen-mediated reduction of the capacity of HDL to promote cholesterol mobilization from macrophages. PMID:27601313

  11. 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.

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

    PubMed

    Shao, Baohai; Heinecke, Jay W

    2011-10-19

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

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

    PubMed

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

    2011-12-01

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

  14. Cholesterol and Statins

    MedlinePlus

    ... the liver makes ldl & hdl In the liver, triglycerides, cholesterol, and proteins form together to make LDL ... This is especially important for individuals with high triglyceride and/or low HDL levels who are overweight ...

  15. Sphingolipid domains in the plasma membranes of fibroblasts are not enriched with cholesterol

    DOE PAGESBeta

    Frisz, Jessica F.; Klitzing, Haley A.; Lou, Kaiyan; Hutcheon, Ian D.; Weber, Peter K.; Zimmerberg, Joshua; Kraft, Mary L.

    2013-04-22

    The plasma membranes of mammalian cells are widely expected to contain domains that are enriched with cholesterol and sphingolipids. In this work, we have used high-resolution secondary ion mass spectrometry to directly map the distributions of isotope-labeled cholesterol and sphingolipids in the plasma membranes of intact fibroblast cells. Although acute cholesterol depletion reduced sphingolipid domain abundance, cholesterol was evenly distributed throughout the plasma membrane and was not enriched within the sphingolipid domains. As a result, we rule out favorable cholesterol-sphingolipid interactions as dictating plasma membrane organization in fibroblast cells. Because the sphingolipid domains are disrupted by drugs that depolymerize themore » cells actin cytoskeleton, cholesterol must instead affect the sphingolipid organization via an indirect mechanism that involves the cytoskeleton.« less

  16. Sphingolipid domains in the plasma membranes of fibroblasts are not enriched with cholesterol

    SciTech Connect

    Frisz, Jessica F.; Klitzing, Haley A.; Lou, Kaiyan; Hutcheon, Ian D.; Weber, Peter K.; Zimmerberg, Joshua; Kraft, Mary L.

    2013-04-22

    The plasma membranes of mammalian cells are widely expected to contain domains that are enriched with cholesterol and sphingolipids. In this work, we have used high-resolution secondary ion mass spectrometry to directly map the distributions of isotope-labeled cholesterol and sphingolipids in the plasma membranes of intact fibroblast cells. Although acute cholesterol depletion reduced sphingolipid domain abundance, cholesterol was evenly distributed throughout the plasma membrane and was not enriched within the sphingolipid domains. As a result, we rule out favorable cholesterol-sphingolipid interactions as dictating plasma membrane organization in fibroblast cells. Because the sphingolipid domains are disrupted by drugs that depolymerize the cells actin cytoskeleton, cholesterol must instead affect the sphingolipid organization via an indirect mechanism that involves the cytoskeleton.

  17. Decreased plasma cholesterol levels during aging in transgenic mouse models of Alzheimer's disease.

    PubMed

    Wirths, Oliver; Thelen, Karin; Breyhan, Henning; Luzón-Toro, Berta; Hoffmann, Karl-Heinz; Falkai, Peter; Lütjohann, Dieter; Bayer, Thomas A

    2006-02-01

    A large number of studies deals with the association of cholesterol and Abeta levels, however, the results are so far controversial. Whereas some studies report on increased cholesterol levels, other authors refer to an association of decreased peripheral cholesterol and the incidence of Alzheimer's disease. It is also questionable whether plasma cholesterol levels could be used as a predictive biomarker for the incidence of Alzheimer's disease. In the present report, we studied the relationship between these two parameters during aging in different transgenic mouse models of Alzheimer's disease, expressing both mutant human amyloid precursor protein and mutant human presenilin-1. Measurements of plasma cholesterol levels revealed a significant reduction in aged APP/PS1 and APP/PS1ki mice, whereas plasma levels in young and aged control mice remained almost unchanged. Furthermore, statistical analysis revealed a significant negative correlation between plasma cholesterol and brain Abeta42 levels during aging in the mice expressing both APP and PS1. PMID:16307858

  18. Sphingolipid Domains in the Plasma Membranes of Fibroblasts Are Not Enriched with Cholesterol*

    PubMed Central

    Frisz, Jessica F.; Klitzing, Haley A.; Lou, Kaiyan; Hutcheon, Ian D.; Weber, Peter K.; Zimmerberg, Joshua; Kraft, Mary L.

    2013-01-01

    The plasma membranes of mammalian cells are widely expected to contain domains that are enriched with cholesterol and sphingolipids. In this work, we have used high-resolution secondary ion mass spectrometry to directly map the distributions of isotope-labeled cholesterol and sphingolipids in the plasma membranes of intact fibroblast cells. Although acute cholesterol depletion reduced sphingolipid domain abundance, cholesterol was evenly distributed throughout the plasma membrane and was not enriched within the sphingolipid domains. Thus, we rule out favorable cholesterol-sphingolipid interactions as dictating plasma membrane organization in fibroblast cells. Because the sphingolipid domains are disrupted by drugs that depolymerize the cells actin cytoskeleton, cholesterol must instead affect the sphingolipid organization via an indirect mechanism that involves the cytoskeleton. PMID:23609440

  19. 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

  20. Age-related changes in the rate of esterification of plasma cholesterol in Fischer-344 rats.

    PubMed

    Carlile, S I; Kudchodkar, B J; Wang, C S; Lacko, A G

    1986-01-01

    Plasma cholesterol and triglyceride levels and selected molecular species of plasma cholesteryl esters and triglycerides were determined in 6-, 12-, 15-, 18-, 21-, and 24-month-old Fischer-344 rats. Lecithin:cholesterol acyltransferase (LCAT) activity was also determined using two independent methods utilizing endogenous and exogenous substrates. Plasma cholesterol levels increased up to 18 months of age and then plateaued. Of the plasma triglyceride molecular species investigated (C50, C52, C54 and C56), only the levels of C52 increased linearly with age. The concentration of other triglyceride molecular species did not change with age. The fractional rate of plasma cholesterol esterification showed a decreasing trend with age, whereas, the net cholesterol esterification rate showed a gradual age related increase. However, this latter parameter remained unchanged with age when the data were normalized for body weight. The cholesterol esterification rates measured using an exogenous substrate (estimating LCAT enzyme levels) showed essentially no change with age. These data indicate that changes in the levels and/or composition of lipoprotein substrate(s) for LCAT are likely causes of the observed age-related changes in the fractional rate of plasma cholesterol esterification. The net esterification rate of plasma cholesterol was significantly correlated with the plasma triglyceride levels when the animals for all age groups were treated as one experimental group. PMID:3959602

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

    PubMed Central

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

    2015-01-01

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

  2. Essentially All Excess Fibroblast Cholesterol Moves from Plasma Membranes to Intracellular Compartments

    PubMed Central

    Lange, Yvonne; Ye, Jin; Steck, Theodore L.

    2014-01-01

    It has been shown that modestly increasing plasma membrane cholesterol beyond its physiological set point greatly increases the endoplasmic reticulum and mitochondrial pools, thereby eliciting manifold feedback responses that return cell cholesterol to its resting state. The question arises whether this homeostatic mechanism reflects the targeting of cell surface cholesterol to specific intracellular sites or its general equilibration among the organelles. We now show that human fibroblast cholesterol can be increased as much as two-fold from 2-hydroxypropyl-β-cyclodextrin without changing the size of the cell surface pool. Rather, essentially all of the added cholesterol disperses rapidly among cytoplasmic membranes, increasing their overall cholesterol content by as much as five-fold. We conclude that the level of plasma membrane cholesterol is normally at capacity and that even small increments above this physiological set point redistribute essentially entirely to intracellular membranes, perhaps down their chemical activity gradients. PMID:25014655

  3. Detection of cholesterol-rich microdomains in the inner leaflet of the plasma membrane

    SciTech Connect

    Hayashi, Masami; Shimada, Yukiko; Inomata, Mitsushi; Ohno-Iwashita, Yoshiko . E-mail: iwashita@tmig.or.jp

    2006-12-22

    The C-terminal domain (D4) of perfringolysin O binds selectively to cholesterol in cholesterol-rich microdomains. To address the issue of whether cholesterol-rich microdomains exist in the inner leaflet of the plasma membrane, we expressed D4 as a fusion protein with EGFP in MEF cells. More than half of the EGFP-D4 expressed in stable cell clones was bound to membranes in raft fractions. Depletion of membrane cholesterol with {beta}-cyclodextrin reduced the amount of EGFP-D4 localized in raft fractions, confirming EGFP-D4 binding to cholesterol-rich microdomains. Subfractionation of the raft fractions showed most of the EGFP-D4 bound to the plasma membrane rather than to intracellular membranes. Taken together, these results strongly suggest the existence of cholesterol-rich microdomains in the inner leaflet of the plasma membrane.

  4. Origins and determinants of HDL populations and their subpopulations

    SciTech Connect

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

    1990-06-01

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

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

    PubMed Central

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

    2016-01-01

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

  6. Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis.

    PubMed Central

    Hoeg, J M; Santamarina-Fojo, S; Bérard, A M; Cornhill, J F; Herderick, E E; Feldman, S H; Haudenschild, C C; Vaisman, B L; Hoyt, R F; Demosky, S J; Kauffman, R D; Hazel, C M; Marcovina, S M; Brewer, H B

    1996-01-01

    Lecithin:cholesterol acyltransferase (LCAT) is a key plasma enzyme in cholesterol and high density lipoprotein (HDL) metabolism. Transgenic rabbits overexpressing human LCAT had 15-fold greater plasma LCAT activity that nontransgenic control rabbits. This degree of overexpression was associated with a 6.7-fold increase in the plasma HDL cholesterol concentration in LCAT transgenic rabbits. On a 0.3% cholesterol diet, the HDL cholesterol concentrations increased from 24 +/- 1 to 39 +/- 3 mg/dl in nontransgenic control rabbits (n = 10; P < 0.05) and increased from 161 +/- 5 to 200 +/- 21 mg/dl (P < 0.001) in the LCAT transgenic rabbits (n = 9). Although the baseline non-HDL concentrations of control (4 +/- 3 mg/dl) and transgenic rabbits (18 +/- 4 mg/dl) were similar, the cholesterol-rich diet raised the non-HDL cholesterol concentrations, reflecting the atherogenic very low density, intermediate density, and low density lipoprotein particles observed by gel filtration chromatography. The non-HDL cholesterol rose to 509 +/- 57 mg/dl in controls compared with only 196 +/- 14 mg/dl in the LCAT transgenic rabbits (P < 0.005). The differences in the plasma lipoprotein response to a cholesterol-rich diet observed in the transgenic rabbits paralleled the susceptibility to developing aortic atherosclerosis. Compared with nontransgenic controls, LCAT transgenic rabbits were protected from diet-induced atherosclerosis with significant reductions determined by both quantitative planimetry (-86%; P < 0.003) and quantitative immunohistochemistry (-93%; P < 0.009). Our results establish the importance of LCAT in the metabolism of both HDL and apolipoprotein B-containing lipoprotein particles with cholesterol feeding and the response to diet-induced atherosclerosis. In addition, these findings identify LCAT as a new target for therapy to prevent atherosclerosis. Images Fig. 2 Fig. 3 Fig. 4 PMID:8876155

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

    PubMed

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

    2014-01-01

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

  8. Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling.

    PubMed

    Corsetti, James P; Salzman, Peter; Ryan, Dan; Moss, Arthur J; Zareba, Wojciech; Sparks, Charles E

    2016-09-01

    Data is presented that was utilized as the basis for Bayesian network modeling of influence pathways focusing on the central role of a polymorphism of plasminogen activator inhibitor-2 (PAI-2) on recurrent cardiovascular disease risk in patients with high levels of HDL cholesterol and C-reactive protein (CRP) as a marker of inflammation, "Influences on Plasminogen Activator Inhibitor-2 Polymorphism-Associated Recurrent Cardiovascular Disease Risk in Patients with High HDL Cholesterol and Inflammation" (Corsetti et al., 2016; [1]). The data consist of occurrence of recurrent coronary events in 166 post myocardial infarction patients along with 1. clinical data on gender, race, age, and body mass index; 2. blood level data on 17 biomarkers; and 3. genotype data on 53 presumptive CVD-related single nucleotide polymorphisms. Additionally, a flow diagram of the Bayesian modeling procedure is presented along with Bayesian network subgraphs (root nodes to outcome events) utilized as the data from which PAI-2 associated influence pathways were derived (Corsetti et al., 2016; [1]). PMID:27284570

  9. Hemagglutinin clusters in the plasma membrane are not enriched with cholesterol and sphingolipids.

    PubMed

    Wilson, Robert L; Frisz, Jessica F; Klitzing, Haley A; Zimmerberg, Joshua; Weber, Peter K; Kraft, Mary L

    2015-04-01

    The clusters of the influenza envelope protein, hemagglutinin, within the plasma membrane are hypothesized to be enriched with cholesterol and sphingolipids. Here, we directly tested this hypothesis by using high-resolution secondary ion mass spectrometry to image the distributions of antibody-labeled hemagglutinin and isotope-labeled cholesterol and sphingolipids in the plasma membranes of fibroblast cells that stably express hemagglutinin. We found that the hemagglutinin clusters were neither enriched with cholesterol nor colocalized with sphingolipid domains. Thus, hemagglutinin clustering and localization in the plasma membrane is not controlled by cohesive interactions between hemagglutinin and liquid-ordered domains enriched with cholesterol and sphingolipids, or from specific binding interactions between hemagglutinin, cholesterol, and/or the majority of sphingolipid species in the plasma membrane. PMID:25863057

  10. Hemagglutinin Clusters in the Plasma Membrane Are Not Enriched with Cholesterol and Sphingolipids

    PubMed Central

    Wilson, Robert L.; Frisz, Jessica F.; Klitzing, Haley A.; Zimmerberg, Joshua; Weber, Peter K.; Kraft, Mary L.

    2015-01-01

    The clusters of the influenza envelope protein, hemagglutinin, within the plasma membrane are hypothesized to be enriched with cholesterol and sphingolipids. Here, we directly tested this hypothesis by using high-resolution secondary ion mass spectrometry to image the distributions of antibody-labeled hemagglutinin and isotope-labeled cholesterol and sphingolipids in the plasma membranes of fibroblast cells that stably express hemagglutinin. We found that the hemagglutinin clusters were neither enriched with cholesterol nor colocalized with sphingolipid domains. Thus, hemagglutinin clustering and localization in the plasma membrane is not controlled by cohesive interactions between hemagglutinin and liquid-ordered domains enriched with cholesterol and sphingolipids, or from specific binding interactions between hemagglutinin, cholesterol, and/or the majority of sphingolipid species in the plasma membrane. PMID:25863057

  11. ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice

    PubMed Central

    Vaisman, Boris L.; Lambert, Gilles; Amar, Marcelo; Joyce, Charles; Ito, Toshimitsu; Shamburek, Robert D.; Cain, William J.; Fruchart-Najib, Jamila; Neufeld, Edward D.; Remaley, Alan T.; Brewer, H. Bryan; Santamarina-Fojo, Silvia

    2001-01-01

    The discovery of the ABCA1 lipid transporter has generated interest in modulating human plasma HDL levels and atherogenic risk by enhancing ABCA1 gene expression. To determine if increased ABCA1 expression modulates HDL metabolism in vivo, we generated transgenic mice that overexpress human ABCA1 (hABCA1-Tg). Hepatic and macrophage expression of hABCA1 enhanced macrophage cholesterol efflux to apoA-I; increased plasma cholesterol, cholesteryl esters (CEs), free cholesterol, phospholipids, HDL cholesterol, and apoA-I and apoB levels; and led to the accumulation of apoE-rich HDL1. ABCA1 transgene expression delayed 125I-apoA-I catabolism in both liver and kidney, leading to increased plasma apoA-I levels, but had no effect on apoB secretion after infusion of Triton WR1339. Although the plasma clearance of HDL-CE was not significantly altered in hABCA1-Tg mice, the net hepatic delivery of exogenous 3H-CEt-HDL, which is dependent on the HDL pool size, was increased 1.5-fold. In addition, the cholesterol and phospholipid concentrations in hABCA1-Tg bile were increased 1.8-fold. These studies show that steady-state overexpression of ABCA1 in vivo (a) raises plasma apoB levels without altering apoB secretion and (b) raises plasma HDL-C and apoA-I levels, facilitating hepatic reverse cholesterol transport and biliary cholesterol excretion. Similar metabolic changes may modify atherogenic risk in humans. PMID:11457883

  12. 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

  13. Stigmasterol reduces plasma cholesterol levels and inhibits hepatic synthesis and intestinal absorption in the rat.

    PubMed

    Batta, Ashok K; Xu, Guorong; Honda, Akira; Miyazaki, Teruo; Salen, Gerald

    2006-03-01

    Plant sterols compete with cholesterol (cholest-5-en-3beta-ol) for intestinal absorption to limit absorption and lower plasma concentrations of cholesterol. Stigmasterol (24-ethyl-cholesta-5,22-dien-3beta-ol; Delta(22) derivative of sitosterol [24-ethyl-cholest-5-en-3beta-ol]), but not campesterol (24-methyl-cholest-5-en-3beta-ol) and sitosterol, is reported to inhibit cholesterol biosynthesis via inhibition of sterol Delta(24)-reductase in human Caco-2 and HL-60 cell lines. We studied the effect of feeding 0.5% stigmasterol on plasma and liver sterols and intestinal cholesterol and sitosterol absorption in 12 wild-type Kyoto (WKY) and 12 Wistar rats. After 3 weeks of feeding, cholesterol and sitosterol absorption was determined in 6 rats from each group by plasma dual-isotope ratio method. After 3 more weeks, plasma and hepatic sterols and hepatic enzyme activities were determined in all rats. After feeding stigmasterol, baseline plasma cholesterol was 1.3 times and plant sterols 3 times greater in WKY compared with Wistar rats. Stigmasterol feeding lowered plasma cholesterol by approximately 11%, whereas plasma campesterol and sitosterol levels were virtually unchanged in both rat strains, and stigmasterol constituted 3.2% of plasma sterols in WKY rats and 1% in Wistar rats. After 6 weeks of feeding, cholesterol and sitosterol absorption decreased 23% and 30%, respectively, in WKY, and 22% and 16%, respectively, in the Wistar rats as compared with untreated rats. The intestinal bacteria in both rat strains metabolized stigmasterol to mainly the 5beta-H stanol (>40%), with only small amounts of 5alpha-H derivative (approximately 1.5%), whereas the C-22 double bond was resistant to bacterial metabolism. Hepatic stigmasterol levels increased from 11 microg/g liver tissue to 104 mug/g in WKY rats and from 5 microg/g liver tissue to 21 microg/g in Wistar rats. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity was suppressed 4-fold in the WKY and almost 1.8-fold

  14. Guar gum effects on plasma low-density lipoprotein and hepatic cholesterol metabolism in guinea pigs fed low- and high-cholesterol diets: a dose-response study.

    PubMed

    Fernandez, M L; Sun, D M; Tosca, M; McNamara, D J

    1995-01-01

    Guinea pigs were fed semipurified diets containing either 0% or 12.5% guar gum (GG) with 0.04% cholesterol or increasing concentrations of GG (0%, 2.5%, 5%, 7.5%, 10%, and 12.5%) with 0.25% cholesterol (by wt). Compared to the 0% GG diet with 0.04% cholesterol, intake of the 12.5% GG diet with 0.04% cholesterol lowered plasma low-density-lipoprotein (LDL) concentrations, the ratio of LDL cholesteryl ester to protein, hepatic cholesterol concentrations, and the activity of acyl-CoA:cholesterol acyltransferase (ACAT), and increased 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and hepatic apo B/E receptor number (P < 0.01). Intake of GG by animals fed 0.25% cholesterol diets resulted in modest effects on hepatic cholesterol pools and plasma LDL concentrations; however, significant negative correlations were found between both plasma LDL cholesterol and hepatic free cholesterol concentrations with the amount of dietary GG (P < 0.05). Hepatic HMG-CoA reductase was suppressed by the 0.25% cholesterol intake, and GG did not reverse this suppression. In contrast, ACAT activity was negatively correlated with the amount of dietary GG (P < 0.05), and GG intake increased the number of hepatic apo B/E receptors at all intakes with the 0.25% cholesterol diets. These results demonstrate that intake of GG significantly alters endogenous cholesterol metabolism by decreasing hepatic cholesterol pools, altering hepatic cholesterol homeostasis, and reducing plasma LDL concentrations. PMID:7825524

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

    SciTech Connect

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

    2007-06-12

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

  16. HDL cholesterol levels and weight are the main determinants of subclinical atherosclerosis in the young with type 1 diabetes and suitable glycaemic control.

    PubMed

    Pinto, Camila S; Lana, Janaina M; Gabbay, Monica A L; de Sa, Joao R; Dib, Sergio A

    2014-03-01

    The aim of this study was to evaluate subclinical atherosclerosis and related factors in young type 1 diabetes (T1D) patients and healthy peers. Carotid intima-media thickness (cIMT) and anthropometric/laboratorial data were obtained for 83 T1D patients (mean age 19.5 ± 4.0 years, disease duration 9.8 ± 4.8 years) and for 36 matched healthy subjects. Considering all the participants as one group, male sex (p = 0.008), weight (p = 0.016) and T1D (p < 0.001) were positively associated with a higher cIMT. High-density lipoprotein (HDL) (p = 0.036) was negatively associated with cIMT in T1D. In the male T1D patients, HDL ≤47.5 mg/dL had a sensitivity of 87.5% and specificity of 57% (p = 0.035) in detecting those belonging to a higher cIMT tercile. In conclusion, weight and T1D were associated with increased cIMT. HDL levels ≤47.5 mg/dL were related to a higher cIMT in male T1D patients. PMID:24553254

  17. Metabolic and functional relevance of HDL subspecies

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  18. Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies

    PubMed Central

    Zidovetzki, Raphael

    2007-01-01

    The physiological importance of cholesterol in the cell plasma membrane has attracted increased attention in recent years. Consequently, the use of methods of controlled manipulation of membrane cholesterol content has also increased sharply, especially as a method of studying putative cholesterol-enriched cell membrane domains (rafts). The most common means of modifying the cholesterol content of cell membranes is the incubation of cells or model membranes with cyclodextrins, a family of compounds, which, due to the presence of relatively hydrophobic cavity, can be used to extract cholesterol from cell membranes. However, the mechanism of this activity of cyclodextrins is not completely established. Moreover, under conditions commonly used for cholesterol extraction, cyclodextrins may remove cholesterol from both raft and non-raft domains of the membrane as well as alter the distribution of cholesterol between plasma and intracellular membranes. In addition, other hydrophobic molecules such as phospholipids may also be extracted from the membranes by cyclodextrins. We review the evidence for the specific and non-specific effects of cyclodextrins and what is known about the mechanisms for cyclodextrin-induced cholesterol and phospholipid extraction. Finally, we discuss useful control strategies that may help to verify that the observed effects are due specifically to cyclodextrin-induced changes in cellular cholesterol. PMID:17493580

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2015-06-01

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

  1. Psyllium husk. I: Effect on plasma lipoproteins, cholesterol metabolism, and atherosclerosis in African green monkeys.

    PubMed

    McCall, M R; Mehta, T; Leathers, C W; Foster, D M

    1992-08-01

    Psyllium's effects on plasma and lipoprotein cholesterol concentrations, cholesterol metabolism, and diet-induced atherosclerosis were studied in adult male African green monkeys (Cercopithecus aethiops). Animals were fed for 3.5 y one of three experimental diets: low-cholesterol cellulose (LCC), high-cholesterol cellulose (HCC), or high-cholesterol psyllium (HCP). The LCC and HCP groups had significantly (P less than 0.05) lower plasma cholesterol concentrations (39% lower) at 1 mo than did the HCC group. These responses persisted throughout the study. Plasma cholesterol changes were due to a reduction in intermediate-density and low-density lipoproteins; very-low and high-density-lipoprotein concentrations were similar among groups. Aortic atherosclerosis, evaluated as percent sudanophilia at 3.5 y, was lowest in the LCC group, intermediate in the HCP group, and highest in the HCC group. Cholesterol absorption, neutral steroid and fat excretion, HMGCoA reductase activity (in intestine and liver), and body weight were unrelated to psyllium's hypocholesterolemic effects. PMID:1322032

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

    PubMed Central

    Banach, Maciej

    2016-01-01

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

  3. 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

  4. A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease

    PubMed Central

    Kallend, D.G.; Reijers, J.A.A.; Bellibas, S.E.; Bobillier, A.; Kempen, H.; Burggraaf, J.; Moerland, M.; Wijngaard, P.L.J.

    2016-01-01

    Aims Apolipoprotein A-1 (ApoA-1), based on epidemiology, is inversely associated with cardiovascular (CV) events. Human carriers of the ApoA-1 Milano variant have a reduced incidence of CV disease. Regression of atherosclerotic plaque burden was previously observed on intravascular ultrasound (IVUS) with ETC-216, a predecessor of MDCO-216. MDCO-216, a complex of dimeric ApoA-1 Milano and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, is being developed to reduce atherosclerotic plaque burden and CV events. We investigated the efficacy and safety of a single infusion of MDCO-216 in healthy volunteers and in patients with coronary artery disease (CAD). Methods and results Twenty-four healthy volunteers and 24 patients with documented CAD received a 2-h infusion of MDCO-216 in a randomized, placebo controlled, single ascending dose study. Five cohorts of healthy volunteers and four cohorts of CAD patients received ApoA-1 Milano doses ranging from 5 to 40 mg/kg. Subjects were followed for 30 days. Dose-dependent increases in ApoA-1, phospholipid, and pre-beta 1 HDL and decreases in ApoE were observed. Prominent and sustained increases in triglyceride, and decreases in HDL-C, endogenous ApoA-1 and ApoA-II occurred at doses >20 mg/kg and profound increases in ABCA1-mediated cholesterol efflux were observed. Other lipid and lipoprotein parameters were generally unchanged. MDCO-216 was well tolerated. Conclusions MDCO-216-modulated lipid parameters profoundly increased ABCA1-mediated cholesterol efflux and was well tolerated. These single-dose data support further development of this agent for reducing atherosclerotic disease and subsequent CV events. PMID:27418968

  5. Plasma cholesterol metabolism in end-stage renal disease. Difference between treatment by hemodialysis or peritoneal dialysis.

    PubMed Central

    Dieplinger, H; Schoenfeld, P Y; Fielding, C J

    1986-01-01

    Plasma cholesterol metabolism was investigated in normotriglyceridemic patients with end-stage renal disease treated by hemo- or continuous ambulatory peritoneal dialysis (CAPD), and compared with that in a control group with normal renal function. A reversed net transport of free cholesterol from plasma to cultured fibroblasts, as well as greatly reduced levels of plasma cholesterol esterification and cholesterol ester transfer rates to low and very low density lipoproteins (LDL and VLDL), was found in the hemodialysis group compared to the controls. The LDL and VLDL contained increased amounts of free cholesterol and inhibited cholesterol ester transfer when recombined with control plasma. The LDL triglyceride content was doubled in the hemodialysis group, whereas cholesterol esters were decreased. Patients treated by CAPD, in marked contrast, had cholesterol metabolic rates that were within the normal range, as well as normal lipoprotein composition. PMID:3082933

  6. Nanoparticle Targeting and Cholesterol Flux Through Scavenger Receptor Type B-1 Inhibits Cellular Exosome Uptake

    PubMed Central

    Plebanek, Michael P.; Mutharasan, R. Kannan; Volpert, Olga; Matov, Alexandre; Gatlin, Jesse C.; Thaxton, C. Shad

    2015-01-01

    Exosomes are nanoscale vesicles that mediate intercellular communication. Cellular exosome uptake mechanisms are not well defined partly due to the lack of specific inhibitors of this complex cellular process. Exosome uptake depends on cholesterol-rich membrane microdomains called lipid rafts, and can be blocked by non-specific depletion of plasma membrane cholesterol. Scavenger receptor type B-1 (SR-B1), found in lipid rafts, is a receptor for cholesterol-rich high-density lipoproteins (HDL). We hypothesized that a synthetic nanoparticle mimic of HDL (HDL NP) that binds SR-B1 and removes cholesterol through this receptor would inhibit cellular exosome uptake. In cell models, our data show that HDL NPs bind SR-B1, activate cholesterol efflux, and attenuate the influx of esterified cholesterol. As a result, HDL NP treatment results in decreased dynamics and clustering of SR-B1 contained in lipid rafts and potently inhibits cellular exosome uptake. Thus, SR-B1 and targeted HDL NPs provide a fundamental advance in studying cholesterol-dependent cellular uptake mechanisms. PMID:26511855

  7. Relationship of drinking water disinfectants to plasma cholesterol and thyroid hormone levels in experimental studies.

    PubMed Central

    Revis, N W; McCauley, P; Bull, R; Holdsworth, G

    1986-01-01

    The effects of drinking water containing 2 or 15 ppm chlorine (pH 6.5 and 8.5), chlorine dioxide, and monochloramine on thyroid function and plasma cholesterol were studied because previous investigators have reported cardiovascular abnormalities in experimental animals exposed to chlorinated water. Plasma thyroxine (T4) levels, as compared to controls, were significantly decreased in pigeons fed a normal or high-cholesterol diet and drinking water containing these drinking water disinfectants at a concentration of 15 ppm (the exception was chlorine at pH 6.5) for 3 months. In most of the treatment groups, T4 levels were significantly lower following the exposure to drinking water containing the 2 ppm dose. Increases in plasma cholesterol were frequently observed in the groups with lower T4 levels. This association was most evident in pigeons fed the high-cholesterol diet and exposed to these disinfectants at a dose of 15 ppm. For example, after 3 months of exposure to deionized water or water containing 15 ppm monochloramine, plasma cholesterol was 1266 +/- 172 and 2049 +/- 212 mg/dl, respectively, a difference of 783 mg/dl. The factor(s) associated with the effect of these disinfectants on plasma T4 and cholesterol is not known. We suggest however that these effects are probably mediated by products formed when these disinfectants react with organic matter in the upper gastrointestinal tract. PMID:3456597

  8. Relationship of drinking water disinfectants to plasma cholesterol and thyroid hormone levels in experimental studies.

    PubMed

    Revis, N W; McCauley, P; Bull, R; Holdsworth, G

    1986-03-01

    The effects of drinking water containing 2 or 15 ppm chlorine (pH 6.5 and 8.5), chlorine dioxide, and monochloramine on thyroid function and plasma cholesterol were studied because previous investigators have reported cardiovascular abnormalities in experimental animals exposed to chlorinated water. Plasma thyroxine (T4) levels, as compared to controls, were significantly decreased in pigeons fed a normal or high-cholesterol diet and drinking water containing these drinking water disinfectants at a concentration of 15 ppm (the exception was chlorine at pH 6.5) for 3 months. In most of the treatment groups, T4 levels were significantly lower following the exposure to drinking water containing the 2 ppm dose. Increases in plasma cholesterol were frequently observed in the groups with lower T4 levels. This association was most evident in pigeons fed the high-cholesterol diet and exposed to these disinfectants at a dose of 15 ppm. For example, after 3 months of exposure to deionized water or water containing 15 ppm monochloramine, plasma cholesterol was 1266 +/- 172 and 2049 +/- 212 mg/dl, respectively, a difference of 783 mg/dl. The factor(s) associated with the effect of these disinfectants on plasma T4 and cholesterol is not known. We suggest however that these effects are probably mediated by products formed when these disinfectants react with organic matter in the upper gastrointestinal tract. PMID:3456597

  9. Red Blood Cells Play a Role in Reverse Cholesterol Transport

    PubMed Central

    Hung, Kimberly T.; Berisha, Stela Z.; Ritchey, Brian M.; Santore, Jennifer; Smith, Jonathan D.

    2012-01-01

    Objective Reverse cholesterol transport (RCT) involves the removal of cholesterol from peripheral tissue for excretion in the feces. Here, we determined whether red blood cells (RBCs) can contribute to RCT. Methods and Results We performed a series of studies in apoAI-deficient mice where the HDL-mediated pathway of RCT is greatly diminished. RBCs carried a higher fraction of whole blood cholesterol than plasma in apoAI-deficient mice, and as least as much of the labeled cholesterol derived from injected foam cells appeared in RBCs compared to plasma. To determine if RBCs mediate RCT to the fecal compartment, we measured RCT in anemic and control apoAI-deficient mice and found that anemia decreased RCT to the feces by over 35% after correcting for fecal mass. Transfusion of [3H]cholesterol labeled RBCs led to robust delivery of the labeled cholesterol to the feces in apoAI-deficient hosts. In wild type mice, the majority of the blood cholesterol mass, as well as [3H]cholesterol derived from the injected foam cells, was found in plasma, and anemia did not significantly alter RCT to the feces after correction for fecal mass. Conclusion The RBC cholesterol pool is dynamic and facilitates RCT of peripheral cholesterol to the feces, particularly in the low HDL state. PMID:22499994

  10. Fast serial analysis of active cholesterol at the plasma membrane in single cells.

    PubMed

    Tian, Chunxiu; Zhou, Junyu; Wu, Zeng-Qiang; Fang, Danjun; Jiang, Dechen

    2014-01-01

    Previously, our group has utilized the luminol electrochemiluminescence to analyze the active cholesterol at the plasma membrane in single cells by the exposure of one cell to a photomultiplier tube (PMT) through a pinhole. In this paper, fast analysis of active cholesterol at the plasma membrane in single cells was achieved by a multimicroelectrode array without the pinhole. Single cells were directly located on the microelectrodes using cell-sized microwell traps. A cycle of voltage was applied on the microelectrodes sequentially to induce a peak of luminescence from each microelectrode for the serial measurement of active membrane cholesterol. A minimal time of 1.60 s was determined for the analysis of one cell. The simulation and the experimental data exhibited a semisteady-state distribution of hydrogen peroxide on the microelectrode after the reaction of cholesterol oxidase with the membrane cholesterol, which supported the relative accuracy of the serial analysis. An eight-microelectrode array was demonstrated to analyze eight single cells in 22 s serially, including the channel switching time. The results from 64 single cells either activated by low ion strength buffer or the inhibition of intracellular acyl-coA/cholesterol acyltransferase (ACAT) revealed that most of the cells analyzed had the similar active membrane cholesterol, while few cells had more active cholesterol resulting in the cellular heterogeneity. The fast single-cell analysis platform developed will be potentially useful for the analysis of more molecules in single cells using proper oxidases. PMID:24328095

  11. Chlordecone Altered Hepatic Disposition of [14C]Cholesterol and Plasma Cholesterol Distribution but not SR-BI or ABCG8 Proteins in Livers of C57BL/6 Mice

    PubMed Central

    Lee, Junga; Scheri, Richard C.; Curtis, Lawrence R.

    2011-01-01

    Organochlorine (OC) insecticides continue to occur in tissues of humans and wildlife throughout the world although they were banned in the United States a few decades ago. Low doses of the OC insecticide chlordecone (CD) alter hepatic disposition of lipophilic xenobiotics and perturb lipid homeostasis in rainbow trout, mice and rats. CD pretreatment altered tissue and hepatic subcellular distribution of exogenous [14C]cholesterol (CH) equivalents 4 and 16 h after a bolus intraperitoneal (ip) injection of 5 ml corn oil/kg that contained 10 mg CH/kg. CD pretreatment altered tissue distribution of exogenously administered [14C]CH by decreased hepatic and renal accumulation, and increased biliary excretion up to 300%. Biliary excretion of polar [14C]CH metabolites was not altered by CD. CD pretreatment decreased subcellular distribution of [14C]CH equivalents in hepatic cytosol and microsomes and lipoprotein-rich fraction-to-homogenate ratio. CD pretreatment increased the ratio of [14C]CH equivalents in high density lipoprotein (HDL) to that in plasma and reduced [14C]CH equivalents in the non-HDL fraction 4 h after a bolus lipid dose. CD pretreatment increased plasma non-HDL total CH by 80% 4 h after a bolus lipid dose. Scavenger receptor class B type I (SR-BI) and ATPbinding cassette transporter G8 (ABCG8) proteins were quantified by western blotting in hepatic membranes from control and CD treated mice. Liver membrane contents of SR-BI and ABCG8 proteins were unchanged by CD pretreatment. The data demonstrated that a single dose of CD altered CH homeostasis and lipoprotein metabolism. PMID:18387646

  12. Luminol electrochemiluminescence for the analysis of active cholesterol at the plasma membrane in single mammalian cells.

    PubMed

    Ma, Guangzhong; Zhou, Junyu; Tian, Chunxiu; Jiang, Dechen; Fang, Danjun; Chen, Hongyuan

    2013-04-16

    A luminol electrochemiluminescence assay was reported to analyze active cholesterol at the plasma membrane in single mammalian cells. The cellular membrane cholesterol was activated by the exposure of the cells to low ionic strength buffer or the inhibition of intracellular acyl-coA/cholesterol acyltransferase (ACAT). The active membrane cholesterol was reacted with cholesterol oxidase in the solution to generate a peak concentration of hydrogen peroxide on the electrode surface, which induced a measurable luminol electrochemiluminescence. Further treatment of the active cells with mevastatin decreased the active membrane cholesterol resulting in a drop in luminance. No change in the intracellular calcium was observed in the presence of luminol and voltage, which indicated that our analysis process might not interrupt the intracellular cholesterol trafficking. Single cell analysis was performed by placing a pinhole below the electrode so that only one cell was exposed to the photomultiplier tube (PMT). Twelve single cells were analyzed individually, and a large deviation on luminance ratio observed exhibited the cell heterogeneity on the active membrane cholesterol. The smaller deviation on ACAT/HMGCoA inhibited cells than ACAT inhibited cells suggested different inhibition efficiency for sandoz 58035 and mevastatin. The new information obtained from single cell analysis might provide a new insight on the study of intracellular cholesterol trafficking. PMID:23527944

  13. 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

  14. 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

  15. 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

  16. Antihyperlipidemic effect of sesame (Sesamum indicum L.) protein isolate in rats fed a normal and high cholesterol diet.

    PubMed

    Biswas, Arundhati; Dhar, Pubali; Ghosh, Santinath

    2010-01-01

    The dietary influence of sesame protein isolate (protein content 91.5%), produced from dehulled, defatted sesame meal, on blood and tissue lipid profile and lipid peroxidation has been assessed in normal and hypercholesterolemic rats. To evaluate their hypocholesterolemic and antioxidative activity in vivo, we fed 18% sesame protein isolate with or without 2% cholesterol in comparison with casein to rats for 28 d. We determined plasma total protein, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triacylglycerol as well as susceptibility of plasma and erythrocyte membrane lipid to oxidation ex vivo. Liver tissue lipid, cholesterol, phospholipids, and lipid peroxidations were also determined. The total cholesterol, LDL-cholesterol and triacylglycerol levels were significantly reduced in the sesame protein isolate and isolate containing cholesterol group than the corresponding control casein groups. HDL-cholesterol level was also increased in sesame protein isolate (41%) and protein isolate containing cholesterol group (38%) than the corresponding control casein and casein containing cholesterol groups. There was 49% and 64% lowering of plasma lipid peroxidation as well as 36% and 56% lowering of lipoprotein oxidation susceptibility (LOS) in the 2 experimental groups (sesame protein isolate and isolate containing cholesterol group) than the corresponding control (casein and casein containing cholesterol) groups. There was significant lowering of erythrocyte membrane lipid peroxidation (68% and 63% lowering in sesame protein isolate and isolate containing cholesterol groups) and liver lipid peroxidation (61% and 76% lowering in the 2 experimental groups than the corresponding control casein groups). Therefore, our results indicate that sesame protein isolate decreases cholesterol concentration in plasma, increases HDL-cholesterol, and also decreases plasma and erythrocyte membrane lipid peroxidation with or

  17. Temperature effect of cholesterol association with synaptosomal plasma membranes of rabbit brain.

    PubMed Central

    Deliconstantinos, G

    1984-01-01

    Association of exogenous cholesterol with rabbit brain synaptosomal plasma membranes follows an exponential path described by the general formula y = a X ebx. The co-operative nature of this association was shown when increasing amounts of unlabelled cholesterol glucoside (up to 0.5 mM) were added to a fixed amount (5 microM) of [14C]cholesterol, when a biphasic curve of the binding of [14C]cholesterol into the membranes was obtained. Arrhenius plots of this association revealed two break points which occur at 25 degrees C and 42 degrees C. The first break apparently corresponds to the transition from the crystalline to the gel phase. The second break may be due to the (continuously) increasing entropy of the system which creates at a certain point difficulties in the binding of cholesterol into the lipid bilayer. PMID:6487274

  18. Cholesteryl ester transfer activity in hamster plasma: increase by fat and cholesterol rich diets.

    PubMed

    Stein, Y; Dabach, Y; Hollander, G; Stein, O

    1990-01-16

    We investigated the presence of cholesteryl ester transfer activity (CETA) in plasma of hamsters kept on various dietary regimens. In hamsters kept on a regular diet, CETA activity was about 5 units/4 mg protein of d greater than 1.21 g/ml fraction of plasma, as compared to about 35 units present in human d greater than 1.21 g/ml fraction. Addition of 15% margarine or butter alone or together with 2% cholesterol resulted in a 2-3-fold increase in plasma CETA. The increase in plasma CETA was correlated with plasma cholesterol levels (r = 0.78; P less than 0.001) and plasma triacylglycerol levels (r = 0.56, P less than 0.001). Hamsters consuming the cholesterol + butter-supplemented diets had the highest plasma CETA, cholesterol and triacylglycerol levels, while CETA in plasma of rats and mice remained nondetectable even after 4 weeks on the diet. The causal relation between hypercholesterolemia, hypertriglyceridemia and evaluation in CETA in hamsters remains to be elucidated. PMID:2297517

  19. Home-Use Tests - Cholesterol

    MedlinePlus

    ... this test does: This is a home-use test kit to measure total cholesterol. What cholesterol is: Cholesterol is a fat (lipid) in your blood. High-density lipoprotein (HDL) ("good" cholesterol) helps protect your heart, but low-density lipoprotein (LDL) ("bad" cholesterol) can clog the arteries of your ...

  20. Dietary fat, carbohydrate and protein: effects on plasma lipoprotein profiles fat, carbohydrate and protein and plasma lipids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In general, under isoweight conditions, different types of dietary protein or individual amino acids have little effect on lipoprotein patterns. Dietary carbohydrate tends to increase plasma triglyceride when it displaces fat, accompanied by a decrease in HDL cholesterol concentrations. Potential ...

  1. Imaging approaches for analysis of cholesterol distribution and dynamics in the plasma membrane.

    PubMed

    Wüstner, Daniel; Modzel, Maciej; Lund, Frederik W; Lomholt, Michael A

    2016-09-01

    Cholesterol is an important lipid component of the plasma membrane (PM) of mammalian cells, where it is involved in control of many physiological processes, such as endocytosis, cell migration, cell signalling and surface ruffling. In an attempt to explain these functions of cholesterol, several models have been put forward about cholesterol's lateral and transbilayer organization in the PM. In this article, we review imaging techniques developed over the last two decades for assessing the distribution and dynamics of cholesterol in the PM of mammalian cells. Particular focus is on fluorescence techniques to study the lateral and inter-leaflet distribution of suitable cholesterol analogues in the PM of living cells. We describe also several methods for determining lateral cholesterol dynamics in the PM including fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), single particle tracking (SPT) and spot variation FCS coupled to stimulated emission depletion (STED) microscopy. For proper interpretation of such measurements, we provide some background in probe photophysics and diffusion phenomena occurring in cell membranes. In particular, we show the equivalence of the reaction-diffusion approach, as used in FRAP and FCS, and continuous time random walk (CTRW) models, as often invoked in SPT studies. We also discuss mass spectrometry (MS) based imaging of cholesterol in the PM of fixed cells and compare this method with fluorescence imaging of sterols. We conclude that evidence from many experimental techniques converges towards a model of a homogeneous distribution of cholesterol with largely free and unhindered diffusion in both leaflets of the PM. PMID:27016337

  2. Lipoprotein products of lecithin: cholesterol acyltransferase and cholesteryl ester transfer.

    PubMed

    Rose, H G; Ellerbe, P

    1982-09-14

    High-density lipoprotein substrates and products of human plasma lecithin: cholesterol acyltransferase have been labelled with radioisotopic cholesteryl esters in order to facilitate identification. [3H]Cholesteryl esters were formed by endogenous HDL3/VHDL enzyme (d greater than 1.125 g/ml) following incubation with mixed vesicles of phosphatidylcholine, unesterified cholesterol and 3H-labelled unesterified cholesterol. Transfer of labelled esters to acceptor lipoproteins (VLDL+LDL, d less than 1.063 g/ml) was employed to distinguish a hypothetical transfer complex. Separation of labelled HDL3/VHDL was by gel-permeation chromatography. The results indicate that a subpopulation of labelled HDL3/VHDL cholesteryl esters (43-61% of total) were removed by VLDL/LDL during a 3 h transfer period and these derive from the smaller lipoproteins of the spectrum. HDL carrying non-transferable [3H]cholesteryl esters localize to the larger HDL3. Transfer rates were proportional to ratios of acceptor to donor lipoproteins. Net transfer of cholesteryl esters from the smaller HDL3 also occurred, but was smaller in magnitude (about 10.5% of total). Acyltransferase assays indicated that enzyme distribution is skewed to larger-sized HDL3, suggesting that the non-transferable components might be lecithin: cholesterol acyltransferase-containing parent complexes, while the smaller transfer products contain little acyltransferase. The results fit the hypothesis that a parent HDL3-lecithin: cholesterol acyltransferase complex generates a smaller-sized lipoprotein product which is active in cholesteryl ester transport. PMID:7126623

  3. Realistic intake of a flavanol-rich soluble cocoa product increases HDL-cholesterol without inducing anthropometric changes in healthy and moderately hypercholesterolemic subjects.

    PubMed

    Martínez-López, Sara; Sarriá, Beatriz; Sierra-Cinos, José Luis; Goya, Luis; Mateos, Raquel; Bravo, Laura

    2014-02-01

    To assess whether antioxidant, anti-inflammatory and other cardio-protective effects attributed to cocoa are achieved when regularly consuming moderate amounts of a flavanol-rich soluble cocoa product, a non-randomized, controlled, crossover, free-living study was carried out in healthy (n = 24; 25.9 ± 5.6 years) and moderately hypercholesterolemic (200-240 mg dL(-1); n = 20; 30.0 ± 10.3 years) volunteers. Participants consumed two servings per day (7.5 g per serving) of a soluble cocoa product (providing 45.3 mg flavanols per day) in milk, which was compared with consuming only milk during a 4 week period. The effects on systolic and diastolic blood pressure and heart rate were determined, as well as on serum lipid and lipoprotein profiles, interleukins (IL)-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), vascular (VCAM-1) and intercellular cell adhesion molecules (ICAM-1), serum malondialdehyde (MDA), carbonyl groups (CG), ferric reducing/antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and free radical scavenging capacity (ABTS). During the study, the volunteers' diets and physical activity were also evaluated, as well as any changes in weight, skin folds, circumferences and related anthropometric parameters. Cocoa and certain polyphenol-rich fruits and vegetables and their derivatives were restricted. After consuming the cocoa product positive effects were observed such as an increase in serum HDL-C (p < 0.001) and dietary fiber intake (p = 0.050), whereas IL-10 decreased (p = 0.022). Other cardiovascular-related biomarkers and anthropometric parameters were unaffected. We have therefore concluded that regular consumption of this cocoa product in a Spanish-Mediterranean diet may protect against cardiovascular disease in healthy and hypercholesterolemic subjects without producing any weight gain or other anthropometric changes. PMID:24394704

  4. Double Potential Pulse Chronocoulometry for Detection of Plasma Membrane Cholesterol Efflux at Disk Platinum Microelectrodes

    PubMed Central

    West, Richard H.; Lu, Hui; Shaw, Kendrick; Chiel, Hillel J.; Kelley, Thomas J.; Burgess, James D.

    2016-01-01

    A double potential pulse scheme is reported for observation of cholesterol efflux from the plasma membrane of a single neuron cell. Capillary Pt disk microelectrodes having a thin glass insulator allow the 10 μm diameter electrode and cell to be viewed under optical magnification. The electrode, covalently functionalized with cholesterol oxidase, is positioned in contact with the cell surface resulting in enzyme catalyzed cholesterol oxidation and efflux of cholesterol from the plasma membrane at the electrode contact site. Enzymatically generated hydrogen peroxide accumulates at the electrode/cell interface during a 5 s hold-time and is oxidized during application of a potential pulse. A second, replicate potential pulse is applied 0.5 s after the first potential pulse to gauge background charge prior to significant accumulation of hydrogen peroxide. The difference in charge passed between the first and second potential pulse provides a measure of hydrogen peroxide generated by the enzyme and is an indication of the cholesterol efflux. Control experiments for bare Pt microelectrodes in contact with the cell plasma membrane show difference charge signals in the range of about 7–10 pC. Enzyme-modified electrodes in contact with the plasma membrane show signals in the range of 16–26 pC. PMID:27330196

  5. Relationship of drinking water disinfectants to plasma cholesterol and thyroid hormone levels in experimental studies

    SciTech Connect

    Revis, N.W.; McCauley, P.; Bull, R.; Holdsworth, G.

    1986-03-01

    The effects of drinking water containing 2 or 15 ppm chlorine (pH 6.5 and 8.5), chlorine dioxide, and monochloramine on thyroid function and plasma cholesterol were studied because previous investigators have reported cardiovascular abnormalities in experimental animals exposed to chlorinated water. Plasma thyroxine (T4) levels, as compared to controls, were significantly decreased in pigeons fed a normal or high-cholesterol diet and drinking water containing these drinking water disinfectants at a concentration of 15 ppm (the exception was chlorine at pH 6.5) for 3 months. In most of the treatment groups, T4 levels were significantly lower following the exposure to drinking water containing the 2 ppm dose. Increase in plasma cholesterol were frequently observed in the groups with lower T4 levels. This association was most evident in pigeons fed the high-cholesterol diet and exposed to these disinfectants at a dose of 15 ppm. The factor(s) associated with the effect of these disinfectants on plasma T4 and cholesterol is not known. The authors suggest however that these effects are probably mediated by products formed when these disinfectants react with organic matter in the upper gastrointestinal tract.

  6. Effects of dietary palmitoleic acid on plasma lipoprotein profile and aortic cholesterol accumulation are similar to those of other unsaturated fatty acids in the F1B golden Syrian hamster.

    PubMed

    Matthan, Nirupa R; Dillard, Alice; Lecker, Jaime L; Ip, Blanche; Lichtenstein, Alice H

    2009-02-01

    The lower susceptibility of palmitoleic acid (16:1) to oxidation compared to PUFA may confer functional advantages with respect to finding acceptable alternatives to partially hydrogenated fats, but limited data are available on its effect on cardiovascular risk factors. This study investigated the effect of diets (10% fat, 0.1% cholesterol, wt:wt) enriched with macadamia [monounsaturated fatty acid (MUFA)16:1], palm (SFA,16:0), canola (MUFA,18:1), or safflower (PUFA,18:2) oils on lipoprotein profiles and aortic cholesterol accumulation in F1B Golden Syrian hamsters (n = 16/group). After 12 wk, 8 hamsters in each group were killed (phase 1). The remaining hamsters fed palm oil were changed to a diet containing coconut oil, while hamsters in the other diet groups continued on their original diets for an additional 6 wk (phase 2). With minor exceptions, the time course and dietary SFA source did not alter the study outcomes. Macadamia oil-fed hamsters had lower non-HDL cholesterol and triglyceride concentrations compared with the palm and coconut oil-fed hamsters and higher HDL-cholesterol compared with the coconut, canola, and safflower oil-fed hamsters. The aortic cholesterol concentration was not affected by dietary fat type. The hepatic cholesterol concentration was higher in the unsaturated compared with the saturated oil-fed hamsters. RBC membrane and aortic cholesteryl ester, triglyceride, and phospholipid fatty acid profiles reflected that of the dietary oil. These data suggest that an oil relatively high in palmitoleic acid does not adversely affect plasma lipoprotein profiles or aortic cholesterol accumulation and was similar to other unsaturated fatty acid-rich oils. PMID:19106316

  7. Perspective on plasma membrane cholesterol efflux and spermatozoal function.

    PubMed

    Sheriff, Dhastagir Sultan; Ali, Elshaari Farag

    2010-05-01

    enhancing fertility, identifying and treating certain forms of male infertility, and preventing conception. One remarkable insight is the importance of membrane cholesterol efflux in initiating transmembrane signaling events that confer fertilization competence. The identity of the physiologically relevant cholesterol acceptors and modulators of cholesterol efflux is therefore of great interest. Still, it is clear that cholesterol efflux represents only a part of this story. The involvement of phospholipid translocation in mediating dynamic changes in the membrane, rendering it conducive to transmembrane signaling, and the modulation of membrane components of signal transduction cascades by cholesterol or phospholipids will yield important insights into the links between environmental sensing and transmembrane signaling in the sperm. Understanding the membrane molecular events will ultimately provide new and exciting areas of investigation for the future. PMID:21209749

  8. Impact of Dietary Fat Type Within the Context of Altered Cholesterol Homeostasis on Cholesterol and Lipoprotein Metabolism in the F1B Hamster

    PubMed Central

    Lecker, Jaime L.; Matthan, Nirupa R.; Billheimer, Jeffrey T.; Rader, Daniel J.; Lichtenstein, Alice H.

    2010-01-01

    Cholesterol status and dietary fat alter several metabolic pathways reflected in lipoprotein profiles. To assess plasma lipoprotein response and mechanisms by which cholesterol and dietary fat type regulate expression of genes involved in lipoprotein metabolism we developed an experimental model system using F1B hamsters fed diets (12 weeks) enriched in 10% (w/w) coconut, olive or safflower oil with either high cholesterol (0.1%; cholesterol-supplemented) or low cholesterol coupled with cholesterol lowering drugs 10-days prior to killing (0.01% cholesterol, 0.15% lovastatin, 2% cholestyramine; cholesterol-depleted). Irrespective of dietary fat, cholesterol-depletion, relative to supplementation, resulted in lower plasma non-high density lipoprotein (HDL) and HDL cholesterol, and triglyceride concentrations (all P<0.05). In the liver, these differences were associated with higher sterol regulatory element binding protein (SREBP)-2, low density lipoprotein (LDL) receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and 7-α hydroxylase mRNA levels; higher scavenger receptor B1 and apolipoprotein (apo) A-I mRNA and protein levels; and lower apo E protein levels and in intestine modestly lower sterol transporters ATP binding cassette (ABC) A1, ABCG5 and ABCG8 mRNA levels. Irrespective of cholesterol status, coconut oil, relative to olive and safflower oils, resulted in higher non-HDL cholesterol and triglyceride concentrations (both P<0.05) and modestly higher SREBP-2 mRNA levels. These data suggest that in F1B hamsters, differences in plasma lipoprotein profiles in response to cholesterol depletion are associated with changes in the expression of genes involved in cholesterol metabolism, whereas the effect of dietary fat type on gene expression was modest which limits the usefulness of the experimental animal model. PMID:20197195

  9. Impact of dietary fat type within the context of altered cholesterol homeostasis on cholesterol and lipoprotein metabolism in the F1B hamster.

    PubMed

    Lecker, Jaime L; Matthan, Nirupa R; Billheimer, Jeffrey T; Rader, Daniel J; Lichtenstein, Alice H

    2010-10-01

    Cholesterol status and dietary fat alter several metabolic pathways reflected in lipoprotein profiles. To assess plasma lipoprotein response and mechanisms by which cholesterol and dietary fat type regulate expression of genes involved in lipoprotein metabolism, we developed an experimental model system using F1B hamsters fed diets (12 weeks) enriched in 10% (wt/wt) coconut, olive, or safflower oil with either high cholesterol (0.1%; cholesterol supplemented) or low cholesterol coupled with cholesterol-lowering drugs 10 days before killing (0.01% cholesterol, 0.15% lovastatin, 2% cholestyramine; cholesterol depleted). Irrespective of dietary fat, cholesterol depletion, relative to supplementation, resulted in lower plasma non-high-density lipoprotein (non-HDL) and HDL cholesterol, and triglyceride concentrations (all Ps < .05). In the liver, these differences were associated with higher sterol regulatory element binding protein-2, low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and 7α-hydroxylase messenger RNA (mRNA) levels; higher scavenger receptor B1 and apolipoprotein A-I mRNA and protein levels; lower apolipoprotein E protein levels; and in intestine, modestly lower sterol transporters adenosine triphosphate-binding cassette (ABC) A1, ABCG5, and ABCG8 mRNA levels. Irrespective of cholesterol status, coconut oil, relative to olive and safflower oils, resulted in higher non-HDL cholesterol and triglyceride concentrations (both Ps < .05) and modestly higher sterol regulatory element binding protein-2 mRNA levels. These data suggest that, in F1B hamsters, differences in plasma lipoprotein profiles in response to cholesterol depletion are associated with changes in the expression of genes involved in cholesterol metabolism, whereas the effect of dietary fat type on gene expression was modest, which limits the usefulness of the experimental animal model. PMID:20197195

  10. How to Get Your Cholesterol Tested

    MedlinePlus

    ... HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides. A small sample of blood will be drawn ... the amount of LDL (bad) cholesterol level and triglycerides can be affected by what you've recently ...

  11. Dietary Conjugated Linoleic Acid Alters Oxidative Stability and Alleviates Plasma Cholesterol Content in Meat of Broiler Chickens

    PubMed Central

    Kumari Ramiah, Suriya; Meng, Goh Yong

    2014-01-01

    This study was conducted to investigate the effects of dietary conjugated linoleic acid (CLA) on fatty acid composition, lipoprotein content, lipid peroxidation, and meat colour of broiler chickens. A total of 180 broiler chickens were allocated to 3 dietary treatments (0, 2.5, and 5% Lutrell) and given a standard broiler starter diet and finisher diet. Body weight of chickens and feed intake were recorded weekly. After slaughter, the breast meat was aged at 4°C for 0, 3, and 6 days. The fatty acid composition was measured in the breast meat. Body weight (BW) and feed efficiency were decreased by dietary CLA level (P < 0.05). Chicken fed with 2.5% Lutrell had the highest feed intake compared to the control (CON) group. The total CLA increased significantly (P < 0.05) in breast meat from birds supplemented with CLA. Propensity for lipid peroxidation was significantly higher after 6 days of meat storage (P < 0.05) and the redness in chicken breast meat was lower in CLA-fed birds (P < 0.05). It is also notable that a 5% Lutrell supplementation decreased the plasma total cholesterol (TC), low density protein (LDL), and HDL (high-density lipoprotein)/LDL ratio in chickens (P < 0.05). PMID:25386625

  12. Dialysis Modalities and HDL Composition and Function.

    PubMed

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

    2015-09-01

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

  13. Structural modifications of HDL and functional consequences.

    PubMed

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

    2006-01-01

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

  14. Dialysis Modalities and HDL Composition and Function

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  16. Anticoagulant activity of tissue factor pathway inhibitor in human plasma is preferentially associated with dense subspecies of LDL and HDL and with Lp(a).

    PubMed

    Lesnik, P; Vonica, A; Guérin, M; Moreau, M; Chapman, M J

    1993-07-01

    Human plasma contains a multivalent, Kunitz-type proteinase inhibitor termed tissue factor pathway inhibitor (TFPI), which specifically inhibits the action of the factor VII(a)-tissue factor complex in coagulation. In the present study, we examined the distribution and anticoagulant activity of TFPI among plasma lipoprotein subspecies separated by isopycnic density gradient ultracentrifugation; this procedure permitted the simultaneous fractionation of the major lipoprotein classes (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], high-density lipoprotein [HDL] 2 and 3, and very-high-density lipoprotein [VHDL]). Studies of eight normolipidemic subjects revealed two major lipoprotein carriers of TFPI activity: dense LDL subspecies (d = 1.039 to 1.063 g/mL) and both dense HDL particles and VHDL (d = 1.133 to 1.190 g/mL), representing 33.8% and 35.9%, respectively, of the total lipoprotein-associated TFPI activity in plasma. TFPI activity was also associated with lipoprotein(a) (Lp[a]), whose density distribution (d = 1.044 to 1.100 g/mL) overlapped that of LDL and HDL2; such association was related to Lp(a)'s particle size and phenotype. VLDL, IDL, and LDL1 through LDL3 (d = 1.019 to 1.039 g/mL), HDL2 (d = 1.063 to 1.100 g/mL), and light subfractions of HDL3 (d = 1.100 to 1.167 g/mL) conveyed only 1.8%, 10%, and 18.5%, respectively, of lipoprotein-associated TFPI activity. Such anticoagulant activity was dependent on the presence of TFPI protein. The dense subspecies of HDL3 (d = 1.133 to 1.167 g/mL) with which TFPI was preferentially associated were small, displayed a cholesteryl ester to protein ratio of approximately 0.2, and were deficient in phospholipid (13.6% to 18.3%). HDL subspecies of d = 1.110 to 1.167 g/mL mainly contained the higher relative molecular mass form of TFPI of 41 kD (a form that is known to be covalently associated with apolipoprotein [apo] A-II) and minor bands of the 35- and 52-k

  17. Protein and cholesterol electrophoresis of plasma samples from captive cownose ray (Rhinoptera bonasus).

    PubMed

    Cray, Carolyn; Rodriguez, Marilyn; Field, Cara; McDermott, Alexa; Leppert, Lynda; Clauss, Tonya; Bossart, Gregory D

    2015-11-01

    Our study was undertaken to assess the application of semiautomated methods available at the reference laboratory level for the evaluation of plasma protein and cholesterol via electrophoresis in samples from cownose rays (Rhinoptera bonasus). Three groups of animals were assessed: clinically normal, clinically abnormal, and parasitized with leeches. As reported previously, the albumin band was negligible; the protein electrophoretograms were dominated by a large beta-globulin fraction. While the group of samples from the leech-parasitized rays did not show any large differences, the abnormal group exhibited significantly elevated total solids and cholesterol levels. The latter was related to a significant increase in very low density lipoprotein levels. The results demonstrate the potential application of these laboratory methods in quantitation of plasma proteins and cholesterol fractions in subclass Elasmobranchii. PMID:26450839

  18. 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

  19. Effect of frequency of dosing of plant sterols on plasma cholesterol levels and synthesis rate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective was to compare the effects of plant sterols (PS) consumed as a single dose (single) at breakfast or as three doses consumed with breakfast, lunch and dinner (divided) on plasma lipoprotien levels and cholesterol endogenous fractional synthesis rate (FSR). A randomized, placebo-controll...

  20. Plasma cholesterol-lowering effect on rats of dietary fiber extracted from immature plants.

    PubMed

    Nishimura, N; Taniguchi, Y; Kiriyama, S

    2000-12-01

    Crude dietary fiber samples were prepared from beet, cabbage, Japanese radish, onion and mung bean sprouts (BF, CF, RF, OF and MF, respectively). These samples contained total dietary fiber at the levels of 814, 699, 760, 693 and 666 g/kg, respectively. To examine the effect of these dietary fiber sources on the plasma cholesterol concentration, male Sprague-Dawley rats were fed on a fiber-free (FF) diet or on an FF diet supplemented with 5% or 10% dietary fiber. Dietary fiber extracted from vegetables, wood cellulose (CL), pectin (PE) and guar gum (GG) were used as the fiber sources. Compared with the rats fed on the FF diet, a significant reduction in the plasma cholesterol concentration was observed in the rats fed on BF, CF, RF, MF, PE or GG after a 21-d feeding period. Cecal acetate, n-butyrate and total short-chain fatty acids were significantly higher in the rats fed on these dietary fibers, except for CF, than in those fed on the FF diet. A negative correlation was apparent between the total dietary fiber content, hemicellulose content and pectin content of each dietary fiber source and the plasma cholesterol concentration. These results suggest that some vegetable fibers exert a plasma cholesterol-lowering effect through cecal fermentation of these fibers. PMID:11210115

  1. FLIM studies of 22- and 25-NBD-cholesterol in living HEK293 cells: plasma membrane change induced by cholesterol depletion.

    PubMed

    Ostašov, Pavel; Sýkora, Jan; Brejchová, Jana; Olżyńska, Agnieszka; Hof, Martin; Svoboda, Petr

    2013-01-01

    HEK293 cells stably expressing δ-opioid receptor were labeled first with fluorescent analog of cholesterol, 22-NBD-cholesterol, exposed to cholesterol-depleting agent β-cyclodextrin (β-CDX) and analyzed by fluorescence lifetime imaging microscopy (FLIM). In accordance with chemical analysis of cholesterol level, the total cellular signal of this probe was decreased to half. Distribution of lifetime (τtot) values of 22-NBD-cholesterol, however, when screened over the whole cell area indicated no significant difference between control (τtot=4.9±0.1 ns) and β-CDX-treated (τtot=4.8±0.1 ns) cells. On the contrary, comparison of control (τtot=5.1±0.1 ns) and β-CDX-treated (τtot=4.4±0.1 ns) cells by analysis of 25-NBD-cholesterol fluorescence implied highly significant decrease of lifetime values of this probe. The observation that 22-NBD-cholesterol appears to be indifferent to the changes in the membrane packing in living cells is in agreement with previous studies in model membranes. However, our data indicate that the alternation of plasma membrane structure induced by decrease of cholesterol level by β-CDX makes the membrane environment of NBD moiety of 25-NBD-cholesterol probe a significantly more hydrated. This finding not only encourages using 25-NBD-cholesterol in living cells, but also demonstrates that previously drawn discouraging conclusions on the use of 25-NBD-cholesterol in model membranes are not valid for living cells. PMID:23466534

  2. Effect of a diet high in monounsaturated fat from almonds on plasma cholesterol and lipoproteins.

    PubMed

    Spiller, G A; Jenkins, D J; Cragen, L N; Gates, J E; Bosello, O; Berra, K; Rudd, C; Stevenson, M; Superko, R

    1992-04-01

    The effect of almonds as part of a low saturated fat, low cholesterol, high-fiber diet was studied in 26 adults (13 men, 13 women). The baseline diet was modified in a similar way for all subjects by limiting meat, fatty fish, high-fat milk products, eggs, and saturated fat. Grains, beans, vegetables, fruit, and low-fat milk products were the foundation of the diet. During the almond diet period, raw almonds (100 mg/day) supplied 34 g/day of monounsaturated fatty acid (MUFA), 12 g/day of polyunsaturated fatty acid, and 6 g/day of saturated fatty acid. Almond oil was the only oil allowed for food preparation. There was a rapid and sustained reduction in low-density lipoprotein cholesterol without changes in high-density lipoprotein cholesterol. This was reflected in a total plasma cholesterol decrease from (means +/- SEM) 235 +/- 5.0 at baseline to 215 +/- 5.0 at 3 weeks, and to 214 +/- 5.0 mg/dl at 9 weeks (p less than 0.001). When the consumption of nuts high in MUFA increases the fat content of the diet, reduction rather than elevation of plasma cholesterol has to be expected, possibly due to the MUFA content of these nuts. PMID:1315812

  3. [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

  4. Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo.

    PubMed

    Gillard, Baiba K; Rodriguez, Perla J; Fields, David W; Raya, Joe L; Lagor, William R; Rosales, Corina; Courtney, Harry S; Gotto, Antonio M; Pownall, Henry J

    2016-03-01

    Plasma high density lipoprotein-cholesterol (HDL-C) concentrations negatively correlate with atherosclerotic cardiovascular disease. HDL is thought to have several atheroprotective functions, which are likely distinct from the epidemiological inverse relationship between HDL-C levels and risk. Specifically, strategies that reduce HDL-C while promoting reverse cholesterol transport (RCT) may have therapeutic value. The major product of the serum opacity factor (SOF) reaction versus HDL is a cholesteryl ester (CE)-rich microemulsion (CERM), which contains apo E and the CE of ~400,000 HDL particles. Huh7 hepatocytes take up CE faster when delivered as CERM than as HDL, in part via the LDL-receptor (LDLR). Here we compared the final RCT step, hepatic uptake and subsequent intracellular processing to cholesterol and bile salts for radiolabeled HDL-, CERM- and LDL-CE by Huh7 cells and in vivo in C57BL/6J mice. In Huh7 cells, uptake from LDL was greater than from CERM (2-4X) and HDL (5-10X). Halftimes for [(14)C]CE hydrolysis were 3.0±0.2, 4.4±0.6 and 5.4±0.7h respectively for HDL, CERM and LDL-CE. The fraction of sterols secreted as bile acids was ~50% by 8h for all three particles. HDL, CERM and LDL-CE metabolism in mice showed efficient plasma clearance of CERM-CE, liver uptake and metabolism, and secretion as bile acids into the gall bladder. This work supports the therapeutic potential of the SOF reaction, which diverts HDL-CE to the LDLR, thereby increasing hepatic CE uptake, and sterol disposal as bile acids. PMID:26709142

  5. Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae.

    PubMed

    Garver, William S; Krishnan, Kumar; Gallagos, Jayme R; Michikawa, Makoto; Francis, Gordon A; Heidenreich, Randall A

    2002-04-01

    The Niemann-Pick C1 (NPC1) protein regulates cholesterol transport from late endosomes-lysosomes to other intracellular compartments. In this article, cholesterol transport to caveolin-1 and caveolin-2 containing compartments, such as the trans-Golgi network (TGN) and plasma membrane caveolae, was examined in normal (NPC+/+), NPC heterozygous (NPC+/-), and NPC homozygous (NPC-/-) human fibroblasts. The expression and distribution of NPC1 in each cell type were similar, and characterized by a finely dispersed, granular staining pattern. The expression of caveolin-1 and caveolin-2 was increased in NPC+/- and NPC-/- fibroblasts, although the distribution in each cell type was similar and characterized by predominant staining of the TGN and plasma membrane. The TGN in NPC+/+ fibroblasts was relatively cholesterol-enriched, whereas the TGN in NPC+/- and NPC-/- fibroblasts was partially or completely cholesterol-deficient, respectively. Consistent with studies demonstrating the transport of cholesterol from the TGN to plasma membrane caveolae, the concentration of cholesterol in plasma membrane caveolae isolated from NPC+/- and NPC-/- fibroblasts was significantly decreased, even though the total concentration of plasma membrane cholesterol in each cell type was similar. These studies demonstrate that NPC1 regulates cholesterol transport to caveolin-1 and caveolin-2 containing compartments such as the TGN and plasma membrane caveolae. PMID:11907140

  6. 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

  7. 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

  8. Plasma lipid, lipoprotein and apolipoprotein profiles in Nigerian university athletes and non-athletes.

    PubMed Central

    Oyelola, O O; Rufai, M A

    1993-01-01

    The fasting plasma lipid, lipoprotein and apolipoprotein profiles were determined in 14 healthy Nigerian male athletes and controls matched for sex and anthropometric parameters. The mean levels of total cholesterol (P < 0.05), low-density lipoprotein (LDL) cholesterol, apolipoprotein (apo) AII and E were significantly lower (P < 0.01) in the athletes than in the controls. However, there were no statistically significant differences (P > 0.05) between the mean values of the plasma triglycerides, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL) cholesterol, apo AI, B, Lp(a), LpA1 and CIII:NonB respectively for the athletes and controls. A priori, the potential effect on cardiovascular disease (CVD) risk was also compared using three predictor ratios - total cholesterol: HDL cholesterol (TC:HDL), LDL cholesterol: HDL cholesterol and apo B:AI. The mean of the three ratios was lower in the athletes than in the controls; however, the differences were not statistically significant (P > 0.05). Based on our data, exercise appears to decrease the TC:HDL ratio in the athletes by lowering LDL-cholesterol, while the HDL-cholesterol is unaffected. We conclude that physical activity has salutary effects on the lipid, lipoprotein and apolipoprotein profiles of healthy Nigerian men. PMID:8130968

  9. The Human ABCG1 Transporter Mobilizes Plasma Membrane and Late Endosomal Non-Sphingomyelin-Associated-Cholesterol for Efflux and Esterification

    PubMed Central

    Neufeld, Edward B.; O’Brien, Katherine; Walts, Avram D.; Stonik, John A.; Malide, Daniela; Combs, Christian A.; Remaley, Alan T.

    2014-01-01

    We have previously shown that GFP-tagged human ABCG1 on the plasma membrane (PM) and in late endosomes (LE) mobilizes sterol on both sides of the membrane lipid bilayer, thereby increasing cellular cholesterol efflux to lipid surfaces. In the present study, we examined ABCG1-induced changes in membrane cholesterol distribution, organization, and mobility. ABCG1-GFP expression increased the amount of mobile, non-sphingomyelin(SM)-associated cholesterol at the PM and LE, but not the amount of SM-associated-cholesterol or SM. ABCG1-mobilized non-SM-associated-cholesterol rapidly cycled between the PM and LE and effluxed from the PM to extracellular acceptors, or, relocated to intracellular sites of esterification. ABCG1 increased detergent-soluble pools of PM and LE cholesterol, generated detergent-resistant, non-SM-associated PM cholesterol, and increased resistance to both amphotericin B-induced (cholesterol-mediated) and lysenin-induced (SM-mediated) cytolysis, consistent with altered organization of both PM cholesterol and SM. ABCG1 itself resided in detergent-soluble membrane domains. We propose that PM and LE ABCG1 residing at the phase boundary between ordered (Lo) and disordered (Ld) membrane lipid domains alters SM and cholesterol organization thereby increasing cholesterol flux between Lo and Ld, and hence, the amount of cholesterol available for removal by acceptors on either side of the membrane bilayer for either efflux or esterification. PMID:25485894

  10. 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

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

    PubMed

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

    2001-04-01

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

  12. Defatted avocado pulp reduces body weight and total hepatic fat but increases plasma cholesterol in male rats fed diets with cholesterol.

    PubMed

    Naveh, Einat; Werman, Moshe J; Sabo, Edmond; Neeman, Ishak

    2002-07-01

    The potential use of avocado as a fiber source was evaluated. The total dietary fiber content of fresh avocado fruit of the Ettinger variety was 5.2 g/100 g. Approximately 75% was insoluble, and 25% soluble. The water-holding capacity of dry defatted avocado pulp was similar to that of cellulose, and trypsin inhibitors were not detected. The dietary and metabolic consequences of the avocado pulp were studied in male rats fed normal and hypercholesterolemic diets. Rats consumed semipurified diets containing either avocado pulp as the dietary fiber source or cellulose (control) with or without 10 g/kg cholesterol and 5 g/kg cholic acid. Food consumption and body weight gain were lower in rats fed avocado compared with those fed cellulose. Relative cecum weight was higher in avocado-fed rats. Plasma and hepatic cholesterol levels did not differ in rats fed diets without cholesterol, but plasma cholesterol was greater in avocado-fed than in cellulose-fed rats that consumed cholesterol. Regardless of dietary cholesterol, hepatic total fat levels, as evaluated histologically, but not directly, were lower in avocado-fed rats. These data suggest the presence of an appetite depressant in avocado and that avocado pulp interferes with hepatic fat metabolism. PMID:12097685

  13. Cholesterol modulates CFTR confinement in the plasma membrane of primary epithelial cells.

    PubMed

    Abu-Arish, Asmahan; Pandzic, Elvis; Goepp, Julie; Matthes, Elizabeth; Hanrahan, John W; Wiseman, Paul W

    2015-07-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma-membrane anion channel that, when mutated, causes the disease cystic fibrosis. Although CFTR has been detected in a detergent-resistant membrane fraction prepared from airway epithelial cells, suggesting that it may partition into cholesterol-rich membrane microdomains (lipid rafts), its compartmentalization has not been demonstrated in intact cells and the influence of microdomains on CFTR lateral mobility is unknown. We used live-cell imaging, spatial image correlation spectroscopy, and k-space image correlation spectroscopy to examine the aggregation state of CFTR and its dynamics both within and outside microdomains in the plasma membrane of primary human bronchial epithelial cells. These studies were also performed during treatments that augment or deplete membrane cholesterol. We found two populations of CFTR molecules that were distinguishable based on their dynamics at the cell surface. One population showed confinement and had slow dynamics that were highly cholesterol dependent. The other, more abundant population was less confined and diffused more rapidly. Treatments that deplete the membrane of cholesterol caused the confined fraction and average number of CFTR molecules per cluster to decrease. Elevating cholesterol had the opposite effect, increasing channel aggregation and the fraction of channels displaying confinement, consistent with CFTR recruitment into cholesterol-rich microdomains with dimensions below the optical resolution limit. Viral infection caused the nanoscale microdomains to fuse into large platforms and reduced CFTR mobility. To our knowledge, these results provide the first biophysical evidence for multiple CFTR populations and have implications for regulation of their surface expression and channel function. PMID:26153705

  14. 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

  15. Seasonal variation in plasma cholesterol distributions: implications for screening and referral.

    PubMed

    Råstam, L; Hannan, P J; Luepker, R V; Mittelmark, M B; Murray, D M; Slater, J S

    1992-01-01

    In 3,377 men and 3,900 women who participated in a community-based plasma cholesterol screening program, we found a significant cyclic time-trend in cholesterol levels, with maximum peak in January. The 95% confidence interval (CI) of the peak to trough distance was 5.8-13.8 mg/dL (0.15-0.36 mmol/L) in men, corresponding to 2.6%-6.3% of the average cholesterol level. Corresponding figures for women were 2.0-9.3 mg/dL (0.05-0.24 mmol/L) or 1.0%-4.6%. Applying the cutoff level for high cholesterol risk proposed by the National Cholesterol Education Program (< or = 240 mg/dL [6.21 mmol/L]) to sex-specific bimonthly distributions, we found a statistically significant variation in prevalence, attributable to seasonal trends, in men (P < .01), but not in women. In men, the age-adjusted prevalence in winter (25.4%) was double that in the summer (13.5%). Seasonal variation is an important determinant of the prevalence of hypercholesterolemia in men and should be considered in patient follow-up and screening. PMID:1482576

  16. Plasma alpha-tocopherol, total lipids and total cholesterol in wild rockhopper, magellanic and gentoo penguins before and after moulting.

    PubMed

    Williams, G; Ghebremeskel, K; Keymer, I F; Horsley, D T

    1989-06-01

    Post moult rockhopper penguins (Eudyptes crestatus) had significantly higher plasma alpha-tocopherol (vitamin E), total lipid and total cholesterol concentrations than their pre-moult counterparts. In the magellanic penguins (Spheniscus magellanicus) there were post moult increases in total lipid, cholesterol and alpha-tocopherol concentrations, but only the increase in alpha-tocopherol was significant. Plasma alpha-tocopherol, total lipid and total cholesterol concentrations in post moult gentoo (Pygoscelis papua) chicks were similar to those in non-moulting adult gentoos. Species differences in the levels of these nutrients in plasma may be due to differences in their dietary habits. PMID:2773196

  17. Antioxidant properties of HDL

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-09-01

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

  19. The Association of Pediatric LDL-cholesterol and HDL-cholesterol Dyslipidemia Classifications and Change in Dyslipidemia Status with Carotid Intima-Media Thickness in Adulthood: Evidence from the Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study, and the Childhood Determinants of Adult Health (CDAH) Study

    PubMed Central

    Magnussen, Costan G.; Venn, Alison; Thomson, Russell; Juonala, Markus; Srinivasan, Sathanur R.; Viikari, Jorma S.A.; Berenson, Gerald S.; Dwyer, Terence; Raitakari, Olli T.

    2009-01-01

    Objectives – To determine which of the National Cholesterol Education Program (NCEP) or National Health and Nutrition Examination Survey (NHANES) LDL-cholesterol and HDL-cholesterol classifications of dyslipidemia status in adolescents is most effective at predicting high common carotid artery intima-media thickness (IMT) in adulthood. Background – Two classifications of pediatric dyslipidemia status have been proposed. No study has assessed which of these is most effective for predicting adolescents who will develop preclinical atherosclerosis in adulthood. Methods – Three population-based, prospective cohort studies that collected lipoprotein measurements on 1711 adolescents aged 12–18 years who were re-measured as young adults aged 29–39 years. Lipoproteins in adolescence were classified according to NCEP and NHANES cut-points, while high IMT in adulthood was defined as those at or above the age, sex, race, and cohort specific 90th percentile of IMT. Results – Independent of the classification employed, adolescents with dyslipidemia were at significantly increased risk of having high IMT in adulthood (relative risks from 1.6 to 2.5). Differences in predictive capacity between both classifications were minimal. Overweight or obese adolescents with dyslipidemia had increased carotid IMT (males, 0.11mm; females, 0.08mm) in adulthood compared with those who did not have both risk factors. Adolescent dyslipidemia status was more strongly associated with high IMT in adulthood than change in dyslipidemia status. Conclusions – Pediatric dyslipidemia classifications perform equally in the prediction of adolescents who are at increased risk of high IMT in young adulthood. Our data suggest that dyslipidemia screening could be limited to overweight or obese adolescents. PMID:19264243

  20. Inflammation modulates human HDL composition and function in vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. 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

  2. Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review.

    PubMed

    White, C Roger; Garber, David W; Anantharamaiah, G M

    2014-10-01

    Reduced levels of HDL cholesterol (HDL-C) are a strong independent predictor of coronary artery disease (CAD) risk. The major anti-atherogenic function of HDL is to mediate reverse cholesterol transport. This response is highly dependent on apoA-I and apoE, protein components of HDL. Randomized clinical trials have assessed effects of several classes of drugs on plasma cholesterol levels in CAD patients. Agents including cholestyramine, fibrates, niacin, and statins significantly lower LDL cholesterol (LDL-C) and induce modest increases in HDL-C, but tolerance issues and undesirable side effects are common. Additionally, residual risk may be present in patients with persistently low HDL-C and other complications despite a reduction in LDL-C. These observations have fueled interest in the development of new pharmacotherapies that positively impact circulating lipoproteins. The goal of this review is to discuss the therapeutic potential of synthetic apolipoprotein mimetic peptides. These include apoA-I mimetic peptides that have undergone initial clinical assessment. We also discuss newer apoE mimetics that mediate the clearance of atherogenic lipids from the circulation and possess anti-inflammatory properties. One of these (AEM-28) has recently been given orphan drug status and is undergoing clinical trials. PMID:25157031

  3. Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

    PubMed Central

    White, C. Roger; Garber, David W.; Anantharamaiah, G. M.

    2014-01-01

    Reduced levels of HDL cholesterol (HDL-C) are a strong independent predictor of coronary artery disease (CAD) risk. The major anti-atherogenic function of HDL is to mediate reverse cholesterol transport. This response is highly dependent on apoA-I and apoE, protein components of HDL. Randomized clinical trials have assessed effects of several classes of drugs on plasma cholesterol levels in CAD patients. Agents including cholestyramine, fibrates, niacin, and statins significantly lower LDL cholesterol (LDL-C) and induce modest increases in HDL-C, but tolerance issues and undesirable side effects are common. Additionally, residual risk may be present in patients with persistently low HDL-C and other complications despite a reduction in LDL-C. These observations have fueled interest in the development of new pharmacotherapies that positively impact circulating lipoproteins. The goal of this review is to discuss the therapeutic potential of synthetic apolipoprotein mimetic peptides. These include apoA-I mimetic peptides that have undergone initial clinical assessment. We also discuss newer apoE mimetics that mediate the clearance of atherogenic lipids from the circulation and possess anti-inflammatory properties. One of these (AEM-28) has recently been given orphan drug status and is undergoing clinical trials. PMID:25157031

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

    PubMed

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

    2014-10-01

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

  5. Cholesterol and Your Child

    MedlinePlus

    ... traveling together are called lipoproteins . Two kinds — low-density lipoprotein (LDL) and high-density lipoprotein (HDL) — are the ones that most of us have heard about. Low-density lipoproteins , or "bad cholesterol," are the primary cholesterol ...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  7. Development and partial metabolic characterization of a dietary cholesterol-resistant colony of rabbits

    SciTech Connect

    Overturf, M.L.; Smith, S.A.; Hewett-Emmett, D.; Loose-Mitchell, D.S.; Soma, M.R.; Gotto, A.M. Jr.; Morrisett, J.D. )

    1989-02-01

    A colony of New Zealand white rabbits has been developed which, when fed a cholesterol-supplemented diet, exhibit unusual resistance to hypercholesterolemia and atherosclerosis, disorders usually observed in normal cholesterol-fed rabbits. When resistant rabbits (RT) were fed a normal low cholesterol diet (ND), their plasma lipoprotein patterns were significantly different from those of normal rabbits (NR) fed the same diet. The low density lipoprotein cholesterol (LDL-c)/high density lipoprotein cholesterol (HDL-c) ratio and LDL-c/very low density lipoprotein cholesterol (VLDL-c) ratio were lower in the resistant rabbits. The hydrated density of HDL of the normal-responsive rabbits was greater than that of the resistant rabbits. LDL from resistant rabbits contained a lower proportion of esterified cholesterol and protein than LDL from normal rabbits. Peripheral mononuclear cells from resistant rabbits bound about 30% more {sup 125}I-labeled rabbit LDL than mononuclear cells from normal rabbits. These results demonstrate that the plasma cholesterol levels of these animals is at least partly under genetic control and that compositional differences exist between the major plasma lipoprotein classes of normal and resistant rabbits even during the ingestion of low-cholesterol diet. The results indicate that at least a part of the difference in the cholesterolemic responses between the two rabbit groups is due to an enhanced LDL uptake by the mononuclear cells, and presumably by other somatic cells of the resistant group.

  8. How Cholesterol Could Be Drawn to the Cytoplasmic Leaf of the Plasma Membrane by Phosphatidylethanolamine

    PubMed Central

    Giang, Ha; Schick, M.

    2014-01-01

    In the mammalian plasma membrane, cholesterol can translocate rapidly between the exoplasmic and cytoplasmic leaves, so that its distribution between them should be given by the equality of its chemical potential in the leaves. Due to its favorable interaction with sphingomyelin, which is almost entirely in the outer leaf, one expects the great majority of cholesterol to be there also. Experimental results do not support this, implying that there is some mechanism attracting cholesterol to the inner leaf. We hypothesize that it is drawn there to reduce the bending free energy of the membrane caused by the presence of PE (phosphatidylethanolamine). It does this in two ways: first by simply diluting the amount of PE in the inner leaf, and second by ordering the tails of the PE to reduce its spontaneous curvature. Incorporating this mechanism into a model free energy for the bilayer, we find that between 50 and 60% of the total cholesterol should be in the inner leaf of human erythrocytes. PMID:25418302

  9. Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux.

    PubMed

    Anthanont, Pimjai; Asztalos, Bela F; Polisecki, Eliana; Zachariah, Benoy; Schaefer, Ernst J

    2015-01-01

    We report a novel heterozygous apolipoprotein A-I (apoA-I) missense mutation (c.517C>A, p.Arg149Ser, designated as apoA-IBoston) in a 67-year-old woman and her 2 sons, who had mean serum high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-I in very large α-1 HDL that were 10%, 35%, and 16% of normal, respectively (all P < .05). The percentage of HDL cholesterol in the esterified form was also significantly (P < .05) reduced to 52% of control values. Cholesteryl ester tranfer protein (CETP) activity was normal. The mean global, adenosine triphosphate (ATP)-binding cassette transporter A1 and scavenger receptor B type I-mediated cellular cholesterol efflux capacity in apoB-depleted serum from affected family members were 41%, 37%, 47%, 54%, and 48% of control values, respectively (all P < .05). lecithin-cholesterol acyltransferase (LCAT) activity in plasma was 71% of controls, whereas in the cell-based assay, it was 73% of control values (P < .05). The data indicate that this novel apoA-I missense is associated with markedly decreased levels of HDL cholesterol and very large α-1 HDL, as well as decreased serum cellular cholesterol efflux and LCAT activity, but not with premature coronary heart disease, similar to other apoA-I mutations that have been associated with decreased LCAT activity. PMID:26073399

  10. Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults

    PubMed Central

    2013-01-01

    Background In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body weight. We used a linear regression model. Selected genes corresponded to folate metabolism, vitamins B-12, A, and E, and cholesterol pathways or lipid metabolism. Methods Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI-TOF mass spectrometry platform. The adjusted phenotype, y, was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7. Results Statistically significant SNP (where P values were adjusted for false discovery rate) included: CETP (rs7499892 and rs5882); SLC46A1 (rs37514694; rs739439); SLC19A1 (rs3788199); CD36 (rs3211956); BCMO1 (rs6564851), APOA5 (rs662799), and ABCA1 (rs4149267). Many prior association trends of the SNP with HDL were replicated in our cross-validation study. Significantly, the association of SNP in folate transporters (SLC46A1 rs37514694 and rs739439; SLC19A1 rs3788199) with HDL was identified in our study. Conclusions Given recent literature on the role of niacin in the biogenesis of HDL, focus on status and metabolism of B-vitamins and metabolites of eccentric cleavage of β-carotene with lipid metabolism is exciting for future study. PMID:23656756

  11. RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes.

    PubMed

    Daffu, Gurdip; Shen, Xiaoping; Senatus, Laura; Thiagarajan, Devi; Abedini, Andisheh; Hurtado Del Pozo, Carmen; Rosario, Rosa; Song, Fei; Friedman, Richard A; Ramasamy, Ravichandran; Schmidt, Ann Marie

    2015-12-01

    Diabetes exacerbates cardiovascular disease, at least in part through suppression of macrophage cholesterol efflux and levels of the cholesterol transporters ATP binding cassette transporter A1 (ABCA1) and ABCG1. The receptor for advanced glycation end products (RAGE) is highly expressed in human and murine diabetic atherosclerotic plaques, particularly in macrophages. We tested the hypothesis that RAGE suppresses macrophage cholesterol efflux and probed the mechanisms by which RAGE downregulates ABCA1 and ABCG1. Macrophage cholesterol efflux to apolipoprotein A1 and HDL and reverse cholesterol transport to plasma, liver, and feces were reduced in diabetic macrophages through RAGE. In vitro, RAGE ligands suppressed ABCG1 and ABCA1 promoter luciferase activity and transcription of ABCG1 and ABCA1 through peroxisome proliferator-activated receptor-γ (PPARG)-responsive promoter elements but not through liver X receptor elements. Plasma levels of HDL were reduced in diabetic mice in a RAGE-dependent manner. Laser capture microdissected CD68(+) macrophages from atherosclerotic plaques of Ldlr(-/-) mice devoid of Ager (RAGE) displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus Ager-expressing Ldlr(-/-) mice independently of glycemia or plasma levels of total cholesterol and triglycerides. Antagonism of RAGE may fill an important therapeutic gap in the treatment of diabetic macrovascular complications. PMID:26253613

  12. Effects of a low cholesterol eating plan on plasma lipids: results of a three-year community study.

    PubMed Central

    Reeves, R S; Foreyt, J P; Scott, L W; Mitchell, R E; Wohlleb, J; Gotto, A M

    1983-01-01

    In an attempt to demonstrate whether individuals with average plasma lipids would accept a diet low in saturated fat and cholesterol, members of a community organization were taught the HELP Your Heart Eating Plan. Results of 282 individuals suggest that reduced dietary cholesterol from selected foods could be sustained for up to 36 months. While both plasma cholesterol and triglycerides fell during a year of instruction, both rose to above initial values by 36 months. Overall, the results suggest that adults may be willing to accept a new style of eating temporarily but are not committed to making permanent dietary changes. PMID:6869641

  13. Zymosan-mediated inflammation impairs in vivo reverse cholesterol transport.

    PubMed

    Malik, Priya; Berisha, Stela Z; Santore, Jennifer; Agatisa-Boyle, Colin; Brubaker, Gregory; Smith, Jonathan D

    2011-05-01

    Inflammation has been proposed to impair HDL function and reverse cholesterol transport (RCT). We investigated the effects of inflammation mediated by zymosan, a yeast glucan, on multiple steps along the RCT pathway in vivo and ex vivo. Acute inflammation with 70 mg/kg zymosan impaired RCT to plasma, liver, and feces similarly by 17-22% (P < 0.05), with no additional block at the liver. Hepatic gene expression further demonstrated no change in ABCG5, ABCB4, and ABCB11 expression but a decline in ABCG8 mRNA (32% P < 0.05). Plasma from zymosan-treated mice had a 21% decrease in cholesterol acceptor ability (P < 0.01) and a 35% decrease in ABCA1-specific efflux capacity (P < 0.01) in vitro. Zymosan treatment also decreased HDL levels and led to HDL remodeling with increased incorporation of serum amyloid A. In addition, cholesterol efflux from cultured macrophages declined with zymosan treatment in a dose dependent manner. Taken together, our results suggest that zymosan impairs in vivo RCT primarily by decreasing macrophage-derived cholesterol entering the plasma, with minimal additional blocks downstream. Our study supports the notion that RCT impairment is one of the mechanisms for the increased atherosclerotic burden observed in inflammatory conditions. PMID:21335620

  14. A comparison of the impact of amaranth flour and squalene on plasma cholesterol in mice with diet-induced dyslipidemia.

    PubMed

    Chmelík, Zdenek; Kotolová, Hana; Piekutowská, Zuzana; Horská, Katerina; Bartosová, Ladislava; Suchý, Pavel; Kollár, Peter

    2013-01-01

    Amaranth was identified as a possible component of an anti-sclerotic diet. To date, particular substances responsible for this effect have not been exactly specified. Squalene, which is contained in amaranth, could be responsible for this effect. However, there are also other potential substances and the hypolipidemic effect of amaranth can be caused by a synergistic effect of several components. This study investigated and compared the impact of amaranth flour and squalene on the total cholesterol (CHOL(TOT)) and LDL cholesterol (CHOL(LDL)) levels in mice with dyslipidemia induced by a cholesterol- and sugar-rich diet. The experiment included 40 inbred mice (C57Bl/6J SPF). After a 7-days acclimatization period, animals were divided into four groups by random. Individual groups were fed different diets for 49 days: control (group C), high energy diet (group HED), high energy diet with amaranth flour (group HED+A) and high energy diet with squalene (group HED+S). The sugar- and cholesterol-rich diet in HED resulted in the significant increase in the levels of CHOL(TOT) by 125% (P < 0.05) and CHOL(LDL) by 304% (P < 0.05), and at the same time in a decrease of HDL cholesterol (CHOL(HDL)) levels by 58% (P < 0.05) compared to group C. To the contrary, amaranth flour enriched diet in group HED+A led to a decrease of CHOL(TOT) levels by 33% (P < 0.05) and CHOL(LDL) by 37% (P < 0.05), compared to HED. Both, amaranth flour and squalene, had a positive impact on CHOL(HDL) levels. Compared to group HED, there was a 47% increase in HED+A and a 60% increase in HED+S. Results proved the favorable impact of amaranth flour on the levels of total cholesterol CHOL(TOT) and also on CHOL(LDL). Furthermore, the results imply that amaranth flour contains besides squalene other substances, which can actively participate in its hypolipidemic effect. PMID:23758041

  15. Creosote Bush (Larrea tridentata) Improves Insulin Sensitivity and Reduces Plasma and Hepatic Lipids in Hamsters Fed a High Fat and Cholesterol Diet

    PubMed Central

    Del Vecchyo-Tenorio, Georgina; Rodríguez-Cruz, Maricela; Andrade-Cetto, Adolfo; Cárdenas-Vázquez, René

    2016-01-01

    Creosote bush, Larrea tridentata (Sesse y Moc. Ex DC, Zygophyllaceae) is a shrub found in the deserts of Northern Mexico and Southwestern United States. In traditional medicine, it is used to treat a variety of illnesses including type 2 diabetes. The present study aims to investigate the effects of creosote bush ethanolic extract on plasma and liver parameters associated with the metabolic syndrome in hamsters fed a high fat and cholesterol diet (HFD), comparing them with those induced by ezetimibe (EZ). Seven groups of six hamsters each were formed. Six groups were fed HFD for 2 weeks. The following 2 weeks, the HFD groups received: (1) only HFD, (2) HFD + 3 mg% EZ, (3) HFD + 0.2% creosote bush ethanolic extract, (4) only standard diet (Std Diet), (5) Std Diet + 3 mg% EZ, (6) Std Diet + 0.2% creosote bush ethanolic extract. The beneficial effects of creosote bush ethanolic extract in the HFD hamster model were a reduction of insulin resistance, associated with lower serum insulin and leptin, lower hepatic lipid peroxidation and higher liver antioxidant capacity. Plasma and liver lipids tended or were reduced to values closer to those of animals fed standard diet. A similar effect on lipids was induced by EZ, although with even lower hepatic cholesterol and total lipids concentrations. In general, the change from HFD to standard diet plus ethanolic extract induced the same but deeper changes, including a reduction in plasma glucose and an increase in the percentage of HDL cholesterol. Unlike creosote bush extract, EZ increased food consumption and neutral fecal steroids, with no significant effect on body weight, epididymal fat pads, liver peroxidation or antioxidant capacity. Also EZ did not modify serum insulin and leptin. However, insulin sensitivity improved to values similar to those induced by the extract. This suggests that the mechanism of action of creosote bush ethanolic extract is different to inhibition of cholesterol absorption or increase excretion

  16. Creosote Bush (Larrea tridentata) Improves Insulin Sensitivity and Reduces Plasma and Hepatic Lipids in Hamsters Fed a High Fat and Cholesterol Diet.

    PubMed

    Del Vecchyo-Tenorio, Georgina; Rodríguez-Cruz, Maricela; Andrade-Cetto, Adolfo; Cárdenas-Vázquez, René

    2016-01-01

    Creosote bush, Larrea tridentata (Sesse y Moc. Ex DC, Zygophyllaceae) is a shrub found in the deserts of Northern Mexico and Southwestern United States. In traditional medicine, it is used to treat a variety of illnesses including type 2 diabetes. The present study aims to investigate the effects of creosote bush ethanolic extract on plasma and liver parameters associated with the metabolic syndrome in hamsters fed a high fat and cholesterol diet (HFD), comparing them with those induced by ezetimibe (EZ). Seven groups of six hamsters each were formed. Six groups were fed HFD for 2 weeks. The following 2 weeks, the HFD groups received: (1) only HFD, (2) HFD + 3 mg% EZ, (3) HFD + 0.2% creosote bush ethanolic extract, (4) only standard diet (Std Diet), (5) Std Diet + 3 mg% EZ, (6) Std Diet + 0.2% creosote bush ethanolic extract. The beneficial effects of creosote bush ethanolic extract in the HFD hamster model were a reduction of insulin resistance, associated with lower serum insulin and leptin, lower hepatic lipid peroxidation and higher liver antioxidant capacity. Plasma and liver lipids tended or were reduced to values closer to those of animals fed standard diet. A similar effect on lipids was induced by EZ, although with even lower hepatic cholesterol and total lipids concentrations. In general, the change from HFD to standard diet plus ethanolic extract induced the same but deeper changes, including a reduction in plasma glucose and an increase in the percentage of HDL cholesterol. Unlike creosote bush extract, EZ increased food consumption and neutral fecal steroids, with no significant effect on body weight, epididymal fat pads, liver peroxidation or antioxidant capacity. Also EZ did not modify serum insulin and leptin. However, insulin sensitivity improved to values similar to those induced by the extract. This suggests that the mechanism of action of creosote bush ethanolic extract is different to inhibition of cholesterol absorption or increase excretion

  17. Separation of the principal HDL subclasses by iodixanol ultracentrifugation

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-11-01

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

  19. The pleiotropic role of HDL in autoimmune diseases.

    PubMed

    Parra, Sandra; Castro, Antoni; Masana, Luis

    2015-01-01

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

  20. Simultaneous Determination of Oxysterols, Cholesterol and 25-Hydroxy-Vitamin D3 in Human Plasma by LC-UV-MS

    PubMed Central

    Narayanaswamy, Rohini; Iyer, Vignesh; Khare, Prachi; Bodziak, Mary Lou; Badgett, Darlene; Zivadinov, Robert; Weinstock-Guttman, Bianca; Rideout, Todd C.; Ramanathan, Murali; Browne, Richard W.

    2015-01-01

    Background Oxysterols are promising biomarkers of neurodegenerative diseases that are linked with cholesterol and vitamin D metabolism. There is an unmet need for methods capable of sensitive, and simultaneous quantitation of multiple oxysterols, vitamin D and cholesterol pathway biomarkers. Methods A method for simultaneous determination of 5 major oxysterols, 25-hydroxy vitamin D3 and cholesterol in human plasma was developed. Total oxysterols were prepared by room temperature saponification followed by solid phase extraction from plasma spiked with deuterated internal standards. Oxysterols were resolved by reverse phase HPLC using a methanol/water/0.1% formic acid gradient. Oxysterols and 25-hydroxy vitamin D3 were detected with atmospheric pressure chemical ionization mass spectrometry in positive ion mode; in-series photodiode array detection at 204nm was used for cholesterol. Method validation studies were performed. Oxysterol levels in 220 plasma samples from healthy control subjects, multiple sclerosis and other neurological disorders patients were quantitated. Results Our method quantitated 5 oxysterols, cholesterol and 25-hydroxy vitamin D3 from 200 μL plasma in 35 minutes. Recoveries were >85% for all analytes and internal standards. The limits of detection were 3-10 ng/mL for oxysterols and 25-hydroxy vitamin D3 and 1 μg/mL for simultaneous detection of cholesterol. Analytical imprecision was <10 %CV for 24(S)-, 25-, 27-, 7α-hydroxycholesterol (HC) and cholesterol and ≤15 % for 7-keto-cholesterol. Multiple Sclerosis and other neurological disorder patients had lower 27-hydroxycholesterol levels compared to controls whereas 7α-hydroxycholesterol was lower specifically in Multiple Sclerosis. Conclusion The method is suitable for measuring plasma oxysterols levels in human health and disease. Analysis of human plasma indicates that the oxysterol, bile acid precursors 7α-hydroxycholesterol and 27-hydroxycholesterol are lower in Multiple Sclerosis and

  1. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  3. Effectiveness of resistant starch, compared to guar gum, in depressing plasma cholesterol and enhancing fecal steroid excretion.

    PubMed

    Levrat, M A; Moundras, C; Younes, H; Morand, C; Demigné, C; Rémésy, C

    1996-10-01

    Amylase-resistant starch (RS) represents a substrate that can be administered in substantial amounts in the diet, in contrast to gel-forming polysaccharides, such as guar gum (GG). The aim of this work was thus to compare the effects of GG and RS on cholesterol metabolism in rats adapted to 0.4% cholesterol diets, using dietary GG or RS levels (8 or 20%, respectively) that led to a similar development of fermentations, as assessed by the degree of enlargement of the cecum. The RS diet elicited a marked rise in the cecal pool of short-chain fatty acids, especially acetic and butyric acid, whereas the GG diet favored high-propionic acid fermentations. Both polysaccharides markedly altered the cholesterol excretion, from 50% of ingested cholesterol in controls, up to about 70% in rats adapted to the RS or GG diets. With these diets, the fecal excretion of bile acids was enhanced (67 and 144% with the RS and GG diets, respectively). RS and GG diets were effective in lowering plasma cholesterol (about -40%) and triglycerides (-36%). There was practically no effect of the diets on cholesterol in d > 1.040 lipoproteins (high density lipoproteins), whereas RS (and to a larger extent, GG) were very effective to depress cholesterol in d < 1.040 lipoproteins (especially in triglyceride-rich lipoproteins). Fermentable polysaccharides counteracted the accumulation of cholesterol in the liver, especially cholesterol esters. In parallel, liver acyl CoA:cholesterol acyltransferase was depressed in rats fed the RS or GG diets, whereas only the GG diet counteracted the downregulation of 3-hydroxy-3-methylglutaryl-CoA by cholesterol. These data suggest that RS may be practically as effective as a gel-forming gum, such as GG, on steroid excretion and on cholesterol metabolism. PMID:8898306

  4. Effect of dietary Schizochytrium microalga oil and fish oil on plasma cholesterol level in rats.

    PubMed

    Komprda, T; Škultéty, O; Křížková, S; Zorníková, G; Rozíková, V; Krobot, R

    2015-04-01

    The purpose of the study was to test the hypothesis that the dietary oils with different content of n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) affect plasma lipid level in rats in a different degree. The diets with 6% of fish oil (FO) and Schizochytrium microalga oil (SchO; EPA+DHA content in the diets 9.5 + 12.3 and 2.6 + 29.5% of the sum of total fatty acids, respectively) were used; the diet with 6% of safflower oil (high content of n-6 PUFA linoleic acid, 65.5%; EPA+DHA content 0.7 + 0.9%) was used as a control. The difference between FO and SchO was established only in the case of plasma triacylglycerol (TAG) level: plasma TAG of the FO-fed rats did not differ from the control rats (p > 0.05), while SchO decreased (p < 0.05) plasma TAG to 46% of the control. On the other hand, FO and SchO decreased (p < 0.05) total plasma cholesterol (TC) in rats in the same extent, to 73% of the control. Regarding the underlying mechanisms for the TC decrease, both SchO and FO up-regulated hepatic Insig-1 gene (181 and 133% of the control; p < 0.05), which tended (p = 0.15 and p = 0.19 respectively) to decrease the amount of hepatic nSREBP-2 protein (61 and 66% of the control). However, neither SchO nor FO influenced hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase gene expression (p > 0.05); SchO (but not FO) increased (p < 0.05) low-density lipoprotein receptor mRNA in the liver. It was concluded that the decrease of total plasma cholesterol might be caused by an increased cholesterol uptake from plasma into the cells (in the case of SchO), but also by other (in the present study not tested) mechanisms. PMID:25040911

  5. Association between Plasma PFOA and PFOS Levels and Total Cholesterol in a Middle-Aged Danish Population

    PubMed Central

    Eriksen, Kirsten T.; Raaschou-Nielsen, Ole; McLaughlin, Joseph K.; Lipworth, Loren; Tjønneland, Anne; Overvad, Kim; Sørensen, Mette

    2013-01-01

    Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are used in a variety of consumer products and have been detected worldwide in human blood. Recent studies mainly of highly exposed populations have indicated that PFOA and PFOS may affect serum cholesterol levels, but the magnitude of the effect may be inconsistent across exposure levels. The aim of the present cross-sectional study was to investigate the association between plasma PFOA and PFOS and total cholesterol in a general, middle-aged Danish population. The study population comprised 753 individuals (663 men and 90 women), 50–65 years of age, nested within a Danish cohort of 57,053 participants. Blood samples were taken from all cohort members at enrolment (1993–1997) and stored in a biobank at -150°C. Plasma levels of PFOA and PFOS and serum levels of total cholesterol were measured. The associations between plasma PFOA and PFOS levels and total cholesterol levels were analysed by generalized linear models, both crude and adjusted for potential confounders. We observed statistically significant positive associations between both perfluorinated compounds and total cholesterol, e.g. a 4.4 [95% CI  =  1.1–7.8] higher concentration of total cholesterol (mg/dL) per interquartile range of PFOA plasma level. Sex and prevalent diabetes appeared to modify the association between PFOA and PFOS, respectively, and cholesterol. In conclusion, this study indicated positive associations between plasma PFOA and PFOS levels and total cholesterol in a middle-aged Danish population, although whether the observed pattern of results reflects a causal association is unclear. PMID:23441227

  6. Capsaicinoids but not their analogue capsinoids lower plasma cholesterol and possess beneficial vascular activity.

    PubMed

    Huang, Weihuan; Cheang, Wai San; Wang, Xiaobo; Lei, Lin; Liu, Yuwei; Ma, Ka Ying; Zheng, Fangrui; Huang, Yu; Chen, Zhen-Yu

    2014-08-20

    Capsaicinoids exist in chili peppers, whereas capsinoids are present in some sweet peppers. The present study investigated the effects of capsaicinoids and capsinoids on plasma lipids, relaxation of the aorta, atherosclerotic plaque development, and fecal sterol excretion in hamsters fed a high-cholesterol diet. Five groups of male hamsters were given the control diet or one of the four experimental diets containing 1.3 mmol of capsaicinoids (NL), 2.6 mmol of capsaicinoids (NH), 1.3 mmol of capsinoids (OL), or 2.6 mmol of capsinoids (OH), respectively. Results showed capsaicinoids but not capsinoids could decrease plasma total cholesterol (TC), reduce the formation of atherosclerotic plaque, and relax the aortic artery. This was accompanied by a 28-175% increase in fecal excretion of acidic sterols in hamsters fed the diets containing capsaicinoids. Similarly, capsaicinoids but not capsinoids could decrease the pad weights of epididymal and prerenal adipose tissues. It was concluded that capsaicinoids but not capsinoids could favorably modulate plasma lipids and possess beneficial vascular activity. PMID:25078570

  7. Plasma cholesterol synthesis using deuterated water in humans: effect of short-term food restriction

    SciTech Connect

    Jones, P.J.; Scanu, A.M.; Schoeller, D.A.

    1988-06-01

    Our purpose was to develop methods in humans to determine the fractional synthetic rate (FSR) of plasma pool free cholesterol using the rate of deuterium incorporation from body water. The sensitivity of this method was examined by measuring FSR after periods of fasting and feeding. Five healthy men with normal lipoprotein levels were given a prepared diet containing 40% of calories as fat and a polyunsaturated/saturated fatty acid ratio of 0.25 for 8 days, except for day 7 when they were given only drinking water. Beginning after the supper meal on day 6, they received no food until 8 AM on day 8 when they consumed meals as normal. Over days 7 and 8 the subjects were given prime and constant deuterium oxide orally to maintain body water deuterium enrichment at about 0.05 atom % excess. Plasma samples were obtained at 0 hours (day 7, 8 AM) and at 12, 24, 36, and 48 hours thereafter. Free cholesterol was extracted, purified by thin-layer chromatography, and combusted to water. The water was reduced to H/sub 2/ and analyzed for deuterium enrichment by isotope ratio mass spectrometry. Analytic precision of this system was determined as 3.5 0/00 (parts per mil) vs Standard Mean Ocean Water. Deuterium enrichment of plasma water for the group during the 48-hour deuterium oxide administration period was 3143 0/00 +/- 310 0/00 (mean +/- SEM). Cholesterol deuterium enrichment for the group during the 12-hour period of fasting (10.9 0/00 +/- 4.1 0/00) was not different from that during feeding (14.2 0/00 +/- 6.2 0/00).

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

    PubMed Central

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

    2015-01-01

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

  9. Phytosterol intake and dietary fat reduction are independent and additive in their ability to reduce plasma LDL cholesterol

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The plasma LDL-cholesterol-lowering effect of plant sterols (PS) appears to be independent of background diet, but definitive proof is lacking. The effect of background diet on plasma concentrations of PS has not been reported. We determined the effects of manipulating dietary contents of PS and f...

  10. Barley and wheat foods: influence on plasma cholesterol concentrations in hypercholesterolemic men.

    PubMed

    McIntosh, G H; Whyte, J; McArthur, R; Nestel, P J

    1991-05-01

    Twenty-one mildly hypercholesterolemic men aged 30-59 y were provided with comparable barley and wheat foods for each of 4 wk in a crossover-designed experiment. The purpose of the study was to examine the influence of two sources of dietary fiber (nonstarch polysaccharides, NSP) on blood lipids and glucose concentrations. Barley contains beta-glucan as a source of soluble dietary fiber (DF) whereas wheat contains the largely insoluble cellulose and hemicellulose fiber. Total dietary fiber increased from a previous intake of 21-38 g/d during the period of study for the two groups. Consumption of barley relative to wheat foods was associated with a significant fall in both plasma total cholesterol (6%, P less than 0.05) and in low-density-lipoprotein cholesterol (7%, P less than 0.02) whereas triglyceride and glucose concentrations did not change significantly. It is concluded that barley dietary fiber is more effective than wheat dietary fiber at lowering blood cholesterol in hypercholesterolemic men. PMID:1850576

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

    PubMed Central

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

    2009-01-01

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

  12. Resveratrol Protects Rabbits Against Cholesterol Diet-Induced Hyperlipidaemia.

    PubMed

    Tanko, Y; Jimoh, A; Ahmed, A; Mohammed, A; Ayo, J O

    2016-01-01

    The excessive consumption of high cholesterol diet has been associated with an increased incidence oflipidaemia. Lipidaemia is enhanced by formation of oxidative stress, lipid peroxidation and hyperglycaemia. The aim ofthese experiments was to investigate the protective effect of resveratrol co-administered with cholesterol diet inducedhyperlipidaemia in rabbits. Thirty rabbits divided into six groups of five animal (group= 5) each: group 1 = normal control,group 2 = cholesterol diet/high fat diet group only (HFD), group 3 = resveratrol 200 mg/kg (R200), group 4 = resveratrol400 mg/kg (R400), group 5 = HFD + R200 and group 6 = HFD + R400. The normal group was fed with standard animalfeeds only; while the HFD groups were fed with standard animal feeds + cholesterol diet (10% Groundnut oil, 20%Groundnut mill and 2% cholesterol). Resveratrol-treated rabbits received resveratrol suspended in 10 g/Lcarboxymethylcellulose (CMC) and the control group received the vehicle only, CMC. The preparations were administeredfor 8 weeks of experimental protocol. At the end of the study period, the animals were sacrificed. Blood and plasma sampleswere collected. Serum evaluation of lipid profile such as total cholesterol (TC), triacylglycerol (Tg), low density lipoproteincholesterol (LDP-c) and high density lipoprotein cholesterol (HDL-c) were also assessed. The results obtained showsignificant (P < 0.05) decrease in total cholesterol (TC), Low density lipoprotein cholesterol (LDP-c), total triacylglyceroland an increase in high density lipoprotein cholesterol (HDL-c) in resveratrol treated groups compared to HFD group only.In conclusion, the findings indicated that Resveratrol may contain polar products able to lower plasma lipid concentrationsand might be beneficial in treatment of hyperlipidemia and atherosclerosis. PMID:27574767

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

    PubMed Central

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

    2013-01-01

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

  14. Regulation of plasma lecithin:cholesterol acyltransferase. II. Activation during alimentary lipemia.

    PubMed

    Rose, H G; Juliano, J

    1977-03-01

    The effect of dietary fat on plasma lecithin:cholesterol acyltransferase (LCAT) activity has been investigated in 14 normal male subjects. After determination of postabsorptive lipid and LCAT levels, a high-fat liquid test meal (1 to 2 gm./kg. body weight) was fed, followed by lipid and LCAT determinations at 2.5 hour intervals. Plasma triglycerides were elevated by 2.5 hours, peaked at 5.0 hours, fell at 7.5 hours, and were normalized by 10 hours. LCAT was unchanged at 2.5 hours but was elevated by 5.0 hours, exhibiting a broad plateau through 10 hours. Most subjects manifested peak responses at 7.5 hours. The mean maximal increase in individual subjects was 37.2 +/- 13.3 (S.D.) percent. LCAT changes similarly followed the elevation and recession of chylomicrons (Sf greater than 400) and very-low-density lipoprotein triglycerides, both of which closely paralleled plasma triglycerides. Enzyme responses were proportional to percentage elevations of plasma triglycerides (r = 0.93, p less than 0.01) and related to quantity of fat in the test diet. Three subjects who ingested the test diet devoid of the fat component showed no significant change in enzyme activity. Enzyme progress curves revealed linearity for 3 hours for both postabsorptive and lipemic (7.5 hour) plasma from the same subjects, supporting the validity of the assay as a measure of enzyme rate. These studies demonstrate an increase in cholesterol esterifying activity temporally related to the clearance of alimentary particles, suggesting a physiologic role in the clearance process. PMID:839110

  15. 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

  16. Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver[S

    PubMed Central

    Nagashima, Shuichi; Yagyu, Hiroaki; Tozawa, Ryuichi; Tazoe, Fumiko; Takahashi, Manabu; Kitamine, Tetsuya; Yamamuro, Daisuke; Sakai, Kent; Sekiya, Motohiro; Okazaki, Hiroaki; Osuga, Jun-ichi; Honda, Akira; Ishibashi, Shun

    2015-01-01

    Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. PMID:25755092

  17. Higher Plasma LDL-Cholesterol is Associated with Preserved Executive and Fine Motor Functions in Parkinson’s Disease

    PubMed Central

    Sterling, Nicholas W.; Lichtenstein, Maya; Lee, Eun-Young; Lewis, Mechelle M.; Evans, Alicia; Eslinger, Paul J.; Du, Guangwei; Gao, Xiang; Chen, Honglei; Kong, Lan; Huang, Xuemei

    2016-01-01

    Plasma low density lipoprotein (LDL) cholesterol has been associated both with risk of Parkinson’s disease (PD) and with age-related changes in cognitive function. This prospective study examined the relationship between baseline plasma LDL-cholesterol and cognitive changes in PD and matched Controls. Fasting plasma LDL-cholesterol levels were obtained at baseline from 64 non-demented PD subjects (62.7 ± 7.9 y) and 64 Controls (61.3 ± 6.8 y). Subjects underwent comprehensive neuropsychological testing at baseline, 18-, and 36-months. Linear mixed-effects modeling was used to assess the relationships between baseline LDL-cholesterol levels and longitudinal cognitive changes. At baseline, PD patients had lower scores of fine motor (p<0.0001), executive set shifting (p=0.018), and mental processing speed (p=0.049) compared to Controls. Longitudinally, Controls demonstrated improved fine motor and memory test scores (p=0.044, and p=0.003), whereas PD patients demonstrated significantly accelerated loss in fine motor skill (p=0.002) compared to Controls. Within the PD group, however, higher LDL-cholesterol levels were associated with improved executive set shifting (β=0.003, p<0.001) and fine motor scores (β=0.002, p=0.030) over time. These associations were absent in Controls (p>0.7). The cholesterol - executive set shifting association differed significantly between PDs and Controls (interaction p=0.005), whereas the cholesterol - fine motor association difference did not reach significance (interaction, p=0.104). In summary, higher plasma LDL-cholesterol levels were associated with better executive function and fine motor performance over time in PD, both of which may reflect an effect on nigrostriatal mediation. Confirmation of these results and elucidation of involved mechanisms are warranted, and might lead to feasible therapeutic strategies. PMID:27330838

  18. Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects.

    PubMed

    Khatun, K; Mahtab, H; Khanam, P A; Sayeed, M A; Khan, K A

    2007-01-01

    It has been postulated that mushroom has beneficial effect of lowering blood glucose and cholesterol in diabetic subjects. The literature so far searched and found that there was no published data in this regard. This study was undertaken to assess the effect of reducing blood glucose, cholesterol and triglycerides in diabetic patients. Additionally, this study addressed whether there was any hepatic and renal toxicity of mushroom. This clinical investigation was conducted in BIRDEM hospital from July 2005 to January 2006. Eighty-nine subjects were recruited. Baseline investigations included height, weight, blood pressure (SBP, DBP), plasma glucose for fasting (FPG) and 2-h after-breakfast (2hPG), total cholesterol (T-chol), triglycerides (TG) and high-density lipoprotein (HDL-c). Twenty- four days' study constitutes 7-days mushroom, 7-days no mushroom and then 7-days mushroom. Investigations were done at the start and each after every 7-days. Thirty subjects (M / F = 17 / 13) followed to ensure full compliance with the designed protocol for 24 days. The mean (SD) age of the participants was 46.3 (10) years. Mushroom significantly reduced systolic and diastolic blood pressure (SBP, p<0.01; DBP, p<0.05). It also lowered both plasma glucose significantly (FPG & 2-hPG, p<0.001). Mushroom also lowered total cholesterol and TG significantly; whereas, there was no significant change in weight and HDL-c. When mushroom was withdrawn, there were significant increases of DBP, FPG, 2hPG, T-cholesterol and TG, whereas, no significant change was observed in weight, SBP and HDL-c. Restarting mushroom there was again significant reduction of blood glucose, TG and cholesterol. We conclude that mushroom significantly reduced blood glucose, blood pressure, TG and cholesterol of diabetic subjects without any deleterious effect on liver and kidney. The effect of mushroom may be investigated in a large sample for a longer duration to evaluate its efficacy and toxicity. PMID:17344789

  19. Plasma proteomic analysis of stable coronary artery disease indicates impairment of reverse cholesterol pathway

    PubMed Central

    Basak, Trayambak; Tanwar, Vinay Singh; Bhardwaj, Gourav; Bhardwaj, Nitin; Ahmad, Shadab; Garg, Gaurav; V, Sreenivas; Karthikeyan, Ganesan; Seth, Sandeep; Sengupta, Shantanu

    2016-01-01

    Coronary artery disease (CAD) is one of the largest causes of death worldwide yet the traditional risk factors, although useful in identifying people at high risk, lack the desired predictive accuracy. Techniques like quantitative plasma proteomics holds immense potential to identify newer markers and this study (conducted in three phases) was aimed to identify differentially expressed proteins in stable CAD patients. In the first (discovery) phase, plasma from CAD cases (angiographically proven) and controls were subjected to iTRAQ based proteomic analysis. Proteins found to be differentially expressed were then validated in the second and third (verification and validation) phases in larger number of (n = 546) samples. After multivariate logistic regression adjusting for confounding factors (age, diet, etc.), four proteins involved in the reverse cholesterol pathway (Apo A1, ApoA4, Apo C1 and albumin) along with diabetes and hypertension were found to be significantly associated with CAD and could account for approximately 88% of the cases as revealed by ROC analysis. The maximum odds ratio was found to be 6.70 for albumin (p < 0.0001), followed by Apo AI (5.07, p < 0.0001), Apo CI (4.03, p = 0.001), and Apo AIV (2.63, p = 0.003). Down-regulation of apolipoproteins and albumin implicates the impairment of reverse cholesterol pathway in CAD. PMID:27350024

  20. Plasma proteomic analysis of stable coronary artery disease indicates impairment of reverse cholesterol pathway.

    PubMed

    Basak, Trayambak; Tanwar, Vinay Singh; Bhardwaj, Gourav; Bhardwaj, Nitin; Ahmad, Shadab; Garg, Gaurav; V, Sreenivas; Karthikeyan, Ganesan; Seth, Sandeep; Sengupta, Shantanu

    2016-01-01

    Coronary artery disease (CAD) is one of the largest causes of death worldwide yet the traditional risk factors, although useful in identifying people at high risk, lack the desired predictive accuracy. Techniques like quantitative plasma proteomics holds immense potential to identify newer markers and this study (conducted in three phases) was aimed to identify differentially expressed proteins in stable CAD patients. In the first (discovery) phase, plasma from CAD cases (angiographically proven) and controls were subjected to iTRAQ based proteomic analysis. Proteins found to be differentially expressed were then validated in the second and third (verification and validation) phases in larger number of (n = 546) samples. After multivariate logistic regression adjusting for confounding factors (age, diet, etc.), four proteins involved in the reverse cholesterol pathway (Apo A1, ApoA4, Apo C1 and albumin) along with diabetes and hypertension were found to be significantly associated with CAD and could account for approximately 88% of the cases as revealed by ROC analysis. The maximum odds ratio was found to be 6.70 for albumin (p < 0.0001), followed by Apo AI (5.07, p < 0.0001), Apo CI (4.03, p = 0.001), and Apo AIV (2.63, p = 0.003). Down-regulation of apolipoproteins and albumin implicates the impairment of reverse cholesterol pathway in CAD. PMID:27350024

  1. Glucomannan and glucomannan plus spirulina added to pork significantly block dietary cholesterol effects on lipoproteinemia, arylesterase activity, and CYP7A1 expression in Zucker fa/fa rats.

    PubMed

    González-Torres, Laura; Vázquez-Velasco, Miguel; Olivero-David, Raúl; Bastida, Sara; Benedí, Juana; González, Rafaela Raposo; González-Muñoz, Ma José; Sánchez-Muniz, Francisco J

    2015-12-01

    Zucker fa/fa rats easily develop dyslipidemia and obesity. Restructured pork (RP) is a suitable matrix for including functional ingredients. The effects of glucomannan- RP or glucomannan plus spirulina-enriched RP on plasma lipid/lipoprotein levels, cytochrome P450 7A1 (CYP7A1) expression, and arylesterase activity in growing fa/fa rats fed high-energy, high-fat cholesterol-enriched diets were tested. Groups of six rats each received diet containing 15% control-RP (C), 15% glucomannan-RP diet (G), 15% glucomannan + spirulina-RP diet (GS), and same diets enriched with 2.4% cholesterol and 0.49% cholic acid (cholesterol-enriched control (HC), cholesterol-enriched glucomannan (HG), and cholesterol-enriched glucomannan + spirulina (HGS) diets) over a 7-week period. C diet induced obesity, severe hyperglycemia, moderate hypercholesterolemia, and hypertriglyceridemia. Those facts were not significantly modified by G or GS diets. G diet increased CYP7A1 expression but decreased the total cholesterol/high density lipoproteins (HDL)-cholesterol ratio (p < 0.05) vs. C diet. GS vs. G diet increased (p < 0.05) CYP7A1 expression. HC vs. C diet reduced food intake, body weight gain, and plasma glucose (p < 0.01) but increased cholesterolemia (p < 0.01), lipidemia (plasma cholesterol plus triglycerides) (p < 0.001), cholesterol/triglyceride ratio in very low density lipoproteins (VLDL), and HDL (p < 0.05), cholesterol transported by VLDL and intermediate density lipoproteins (IDL) + low density lipoproteins (LDL), total cholesterol/HDL-cholesterol ratio and CYP7A1 expression (at least p < 0.05). HG and HGS diets vs. HC noticeably reduced lipidemia (p < 0.001), normalized VLDL and IDL + LDL lipid composition, and increased CYP7A1 expression (p < 0.01) but did not modify the cholesterol/HDL-cholesterol ratio. HGS vs. HG decreased triglyceridemia, the triglyceride-glucose (TyG) index and increased arylesterase/HDL-cholesterol activity (p < 0

  2. 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

  3. Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length.

    PubMed Central

    Woollett, L A; Spady, D K; Dietschy, J M

    1989-01-01

    These studies were designed to elucidate how shorter (MCT) and longer (HCO) chain-length saturated triacylglycerols and cholesterol interact to alter steady-state plasma LDL-cholesterol levels. When either MCT or HCO was fed in the absence of cholesterol, there was little effect on receptor-dependent LDL transport but a 36-43% increase in LDL-cholesterol production. Cholesterol feeding in the absence of triacylglycerol led to significant suppression of receptor-dependent LDL transport and a 26-31% increase in LDL-cholesterol production. However, when the longer chain-length saturated triacylglycerol was fed together with cholesterol there was a marked increase in the suppression of receptor-dependent LDL transport and an 82% increase in production rate. Together, these two alterations accounted for the observed eightfold increase in plasma LDL-cholesterol concentration. In contrast, feeding the shorter chain-length saturated triacylglycerol with cholesterol actually enhanced receptor-dependent LDL transport while also causing a smaller increase (52%) in the LDL-cholesterol production rate. As a result of these two opposing events, MCT feeding had essentially no net effect on plasma LDL-cholesterol levels beyond that induced by cholesterol feeding alone. PMID:2738148

  4. 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

  5. Rapid turn-over of plasma membrane sphingomyelin and cholesterol in baby hamster kidney cells after exposure to sphingomyelinase.

    PubMed

    Slotte, J P; Härmälä, A S; Jansson, C; Pörn, M I

    1990-12-14

    Plasma membrane sphingomyelin in baby hamster kidney (BHK-21) cells was hydrolyzed with sphingomyelinase (Staphylococcus aureus) and the effects on membrane cholesterol translocation and the properties of membrane bound adenylate cyclase and Na+/K(+)-ATPase were determined. Exposure of confluent BHK-21 cells to 0.1 U/ml of sphingomyelinase led to the degradation (at 37 degrees C) of about 60% of cell sphingomyelin. No simultaneous hydrolysis of phosphatidylcholine occurred. The hydrolysis of sphingomyelin subsequently led to the translocation (within 40 min) of about 50-60% of cell [3H]cholesterol from a cholesterol oxidase susceptible pool to an oxidase resistant compartment. The translocation of [3H]cholesterol from the cell surface to intracellular membranes was accompanied by a paralleled increase in [3H]cholesterol ester formation. When cells were first exposed to sphingomyelinase (to degrade sphingomyelin) and then incubated without the enzyme in serum-free media, the mass of cell sphingomyelin decreased initially (by 60%), but then began to increase and reached control levels within 3-4 h. The rapid re-synthesis of sphingomyelin was accompanied by an equally rapid normalization of cell [3H]cholesterol distribution. The re-formation of cell sphingomyelin also led to a decreased content of cellular [3H]cholesterol esters, indicating that unesterified [3H]cholesterol was pulled out of the cholesterol ester cycle and transported to the cell surface. Exposure of BHK-21 cells to sphingomyelinase further led to a dramatically decreased activity of ouabain-sensitive Na+/K(+)-ATPase, whereas forskolin-stimulated adenylate cyclase activity was not affected. The activity of Na+/K(+)-ATPase returned to normal in parallel with the normalization of cell sphingomyelin mass and cholesterol distribution. We conclude that sphingomyelin has profound effects on the steady-state distribution of cell cholesterol, and that manipulations of cell sphingomyelin levels directly and

  6. Ultrafast Diffusion of a Fluorescent Cholesterol Analog in Compartmentalized Plasma Membranes

    PubMed Central

    Hiramoto-Yamaki, Nao; Tanaka, Kenji A K; Suzuki, Kenichi G N; Hirosawa, Koichiro M; Miyahara, Manami S H; Kalay, Ziya; Tanaka, Koichiro; Kasai, Rinshi S; Kusumi, Akihiro; Fujiwara, Takahiro K

    2014-01-01

    Cholesterol distribution and dynamics in the plasma membrane (PM) are poorly understood. The recent development of Bodipy488-conjugated cholesterol molecule (Bdp-Chol) allowed us to study cholesterol behavior in the PM, using single fluorescent-molecule imaging. Surprisingly, in the intact PM, Bdp-Chol diffused at the fastest rate ever found for any molecules in the PM, with a median diffusion coefficient (D) of 3.4 µm2/second, which was ∼10 times greater than that of non-raft phospholipid molecules (0.33 µm2/second), despite Bdp-Chol's probable association with raft domains. Furthermore, Bdp-Chol exhibited no sign of entrapment in time scales longer than 0.5 milliseconds. In the blebbed PM, where actin filaments were largely depleted, Bdp-Chol and Cy3-conjugated dioleoylphosphatidylethanolamine (Cy3-DOPE) diffused at comparable Ds (medians = 5.8 and 6.2 µm2/second, respectively), indicating that the actin-based membrane skeleton reduces the D of Bdp-Chol only by a factor of ∼2 from that in the blebbed PM, whereas it reduces the D of Cy3-DOPE by a factor of ∼20. These results are consistent with the previously proposed model, in which the PM is compartmentalized by the actin-based membrane-skeleton fence and its associated transmembrane picket proteins for the macroscopic diffusion of all of the membrane molecules, and suggest that the probability of Bdp-Chol passing through the compartment boundaries, once it enters the boundary, is ∼10× greater than that of Cy3-DOPE. Since the compartment sizes are greater than those of the putative raft domains, we conclude that raft domains coexist with membrane-skeleton-induced compartments and are contained within them. PMID:24506328

  7. Apolipoprotein B but not LDL Cholesterol Is Associated With Coronary Artery Calcification in Type 2 Diabetic Whites

    PubMed Central

    Martin, Seth S.; Qasim, Atif N.; Mehta, Nehal N.; Wolfe, Megan; Terembula, Karen; Schwartz, Stanley; Iqbal, Nayyar; Schutta, Mark; Bagheri, Roshanak; Reilly, Muredach P.

    2009-01-01

    OBJECTIVE Evidence favors apolipoprotein B (apoB) over LDL cholesterol as a predictor of cardiovascular events, but data are lacking on coronary artery calcification (CAC), especially in type 2 diabetes, where LDL cholesterol may underestimate atherosclerotic burden. We investigated the hypothesis that apoB is a superior marker of CAC relative to LDL cholesterol. RESEARCH DESIGN AND METHODS We performed cross-sectional analyses of white subjects in two community-based studies: the Penn Diabetes Heart Study (N = 611 type 2 diabetic subjects, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (N = 803 nondiabetic subjects, 52.8% men) using multivariate analysis of apoB and LDL cholesterol stratified by diabetes status. RESULTS In type 2 diabetes, apoB was associated with CAC after adjusting for age, sex, and medications [Tobit regression ratio of increased CAC for 1-SD increase in apoB; 1.36 (95% CI 1.06–1.75), P = 0.016] whereas LDL cholesterol was not [1.09 (0.85–1.41)]. In nondiabetic subjects, both were associated with CAC [apoB 1.65 (1.38–1.96), P < 0.001; LDL cholesterol 1.56 (1.30–1.86), P < 0.001]. In combined analysis of diabetic and nondiabetic subjects, apoB provided value in predicting CAC scores beyond LDL cholesterol, total cholesterol, the total cholesterol/HDL cholesterol and triglyceride/HDL cholesterol ratios, and marginally beyond non-HDL cholesterol. CONCLUSIONS Plasma apoB, but not LDL cholesterol, levels were associated with CAC scores in type 2 diabetic whites. ApoB levels may be particularly useful in assessing atherosclerotic burden and cardiovascular risk in type 2 diabetes. PMID:19491209

  8. Effects of cholesterol on plasma membrane lipid order in MCF-7 cells by two-photon microscopy

    NASA Astrophysics Data System (ADS)

    Zeng, Yixiu; Chen, Jianling; Yang, Hongqin; Wang, Yuhua; Li, Hui; Xie, Shusen

    2014-09-01

    Lipid rafts are cholesterol- and glycosphingolipids- enriched microdomains on plasma membrane surface of mammal cells, involved in a variety of cellular processes. Depleting cholesterol from the plasma membrane by drugs influences the trafficking of lipid raft markers. Optical imaging techniques are powerful tools to study lipid rafts in live cells due to its noninvasive feature. In this study, breast cancer cells MCF-7 were treated with different concentrations of MβCD to deplete cholesterol and an environmentally sensitive fluorescence probe, Laurdan was loaded to image lipid order by two-photon microscopy. The generalized polarization (GP) values were calculated to distinguish the lipid order and disorder phase. GP images and GP distributions of native and cholesterol-depleted MCF-7 cells were obtained. Our results suggest that even at low concentration (0.5 mM) of MβCD, the morphology of the MCF-7 cells changes. Small high GP areas (lipid order phase) decrease more rapidly than low GP areas (lipid disorder phase), indicating that lipid raft structure was altered more severely than nonraft domains. The data demonstrates that cholesterol dramatically affect raft coverage and plasma membrane fluidity in living cells.

  9. Modulation of ileal bile acid transporter (ASBT) activity by depletion of plasma membrane cholesterol: association with lipid rafts

    PubMed Central

    Annaba, Fadi; Sarwar, Zaheer; Kumar, Pradeep; Saksena, Seema; Turner, Jerrold R.; Dudeja, Pradeep K.; Gill, Ravinder K.; Alrefai, Waddah A.

    2016-01-01

    Apical sodium-dependent bile acid transporter (ASBT) represents a highly efficient conservation mechanism of bile acids via mediation of their active transport across the luminal membrane of terminal ileum. To gain insight into the cellular regulation of ASBT, we investigated the association of ASBT with cholesterol and sphingolipid-enriched specialized plasma membrane microdomains known as lipid rafts and examined the role of membrane cholesterol in maintaining ASBT function. Human embryonic kidney (HEK)-293 cells stably transfected with human ASBT, human ileal brush-border membrane vesicles, and human intestinal epithelial Caco-2 cells were utilized for these studies. Floatation experiments on Optiprep density gradients demonstrated the association of ASBT protein with lipid rafts. Disruption of lipid rafts by depletion of membrane cholesterol with methyl-β-cyclodextrin (MβCD) significantly reduced the association of ASBT with lipid rafts, which was paralleled by a decrease in ASBT activity in Caco-2 and HEK-293 cells treated with MβCD. The inhibition in ASBT activity by MβCD was blocked in the cells treated with MβCD-cholesterol complexes. Kinetic analysis revealed that MβCD treatment decreased the Vmax of the transporter, which was not associated with alteration in the plasma membrane expression of ASBT. Our study illustrates that cholesterol content of lipid rafts is essential for the optimal activity of ASBT and support the association of ASBT with lipid rafts. These findings suggest a novel mechanism by which ASBT activity may be rapidly modulated by alterations in cholesterol content of plasma membrane and thus have important implications in processes related to maintenance of bile acid and cholesterol homeostasis. PMID:18063707

  10. The amount of dietary cholesterol changes the mode of effects of (n-3) polyunsaturated fatty acid on lipoprotein cholesterol in hamsters.

    PubMed

    Lin, Mei-Huei; Lu, Shao-Chun; Huang, Po-Chao; Liu, Young-Chau; Liu, Shyun-Yeu

    2004-01-01

    This study was designed to investigate the effects of the interaction between dietary (n-3) polyunsaturated fatty acids (PUFA) and different dietary cholesterol content on plasma and liver cholesterol in hamsters. Male Syrian hamsters consumed diets containing an incremental increase in dietary cholesterol content (0, 0.025, 0.05, 0.1 and 0.2%, w/w) with either (n-3) PUFA (21 g/100 g fatty acids) or (n-6) PUFA (37.4 g/100 g fatty acids) fat for 6 weeks. In hamsters fed the nonatherogenic diet (0 or 0.025% dietary cholesterol), very low density lipoprotein (VLDL)-cholesterol levels in the (n-3) PUFA group were not significantly different from those in the (n-6) PUFA group, and low density lipoprotein (LDL)-cholesterol levels in the (n-3) PUFA group were significantly lower than those in the (n-6) PUFA group. In contrast, in hamsters fed the atherogenic diet (0.1 or 0.2% dietary cholesterol), VLDL- and LDL-cholesterol levels in the (n-3) PUFA group were significantly higher than those in the (n-6) PUFA group, in a dose-dependent manner. When the hamsters were fed with 0, 0.025, 0.05, 0.1 or 0.2% (w/w) dietary cholesterol, high density lipoprotein (HDL) cholesterol concentration was significantly lower in the (n-3) PUFA group than those in the (n-6) PUFA group. Hepatic cholesteryl esters were significantly lower, while hepatic microsomal acyl-coenzyme A:cholesterol acyltransferase activity and VLDL-cholesteryl esters were significantly higher in hamsters fed (n-3) PUFA with the atherogenic diet (0.1 or 0.2% dietary cholesterol) than in those fed (n-6) PUFA with the atherogenic diet. Our results demonstrate that the amount of dietary cholesterol is an important factor in determining the mode and extent of effects of dietary (n-3) PUFA, especially on VLDL- and LDL-cholesterol levels. When dietary cholesterol intake was above 0.1% (w/w), the plasma cholesterol-lowering effect of (n-3) PUFA disappeared, and instead, it showed a cholesterol-increasing effect. However, the

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

    PubMed Central

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

    2013-01-01

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

  12. Phospholipid liposomes acquire apolipoprotein E in atherogenic plasma and block cholesterol loading of cultured macrophages.

    PubMed Central

    Williams, K J; Tall, A R; Bisgaier, C; Brocia, R

    1987-01-01

    A single infusion of phospholipid liposomes promptly and persistently abolished the ability of hypercholesterolemic rabbit plasma to cause cholesteryl ester loading in cultured macrophages. This phospholipid enrichment of plasma caused moderate stimulation of cellular cholesterol efflux and, unexpectedly, almost complete inhibition of cellular uptake of beta-very low density lipoprotein (beta-VLDL), the major cholesteryl ester-rich particle in hypercholesterolemic rabbit plasma. Cell viability and LDL receptor activity were unaffected. Incubation of liposomes with beta-VLDL resulted in transfer of apolipoprotein-E (apoE) to the liposomes; reisolated apoE-phospholipid liposomes then competed efficiently for cellular apoprotein receptors. Thus, a major mechanism by which phospholipid infusions result in diminished accumulation of cholesteryl ester in cultured macrophages is by blocking cellular uptake of beta-VLDL. The liposomes deplete beta-VLDL of apoE, then compete for receptor-mediated uptake. These results suggest a novel mechanism contributing to the known antiatherogenic effect of phospholipid infusions: infused liposomes acquire apoE, then block uptake of atherogenic lipoproteins by arterial wall macrophages. Images PMID:3571495

  13. Diet rich in high glucoraphanin broccoli reduces plasma LDL cholesterol: Evidence from randomised controlled trials

    PubMed Central

    Armah, Charlotte N; Derdemezis, Christos; Traka, Maria H; Dainty, Jack R; Doleman, Joanne F; Saha, Shikha; Leung, Wing; Potter, John F; Lovegrove, Julie A; Mithen, Richard F

    2015-01-01

    Scope Cruciferous-rich diets have been associated with reduction in plasma LDL-cholesterol (LDL-C), which may be due to the action of isothiocyanates derived from glucosinolates that accumulate in these vegetables. This study tests the hypothesis that a diet rich in high glucoraphanin (HG) broccoli will reduce plasma LDL-C. Methods and results One hundred and thirty volunteers were recruited to two independent double-blind, randomly allocated parallel dietary intervention studies, and were assigned to consume either 400 g standard broccoli or 400 g HG broccoli per week for 12 weeks. Plasma lipids were quantified before and after the intervention. In study 1 (37 volunteers), the HG broccoli diet reduced plasma LDL-C by 7.1% (95% CI: –1.8%, –12.3%, p = 0.011), whereas standard broccoli reduced LDL-C by 1.8% (95% CI +3.9%, –7.5%, ns). In study 2 (93 volunteers), the HG broccoli diet resulted in a reduction of 5.1% (95% CI: –2.1%, –8.1%, p = 0.001), whereas standard broccoli reduced LDL-C by 2.5% (95% CI: +0.8%, –5.7%, ns). When data from the two studies were combined the reduction in LDL-C by the HG broccoli was significantly greater than standard broccoli (p = 0.031). Conclusion Evidence from two independent human studies indicates that consumption of high glucoraphanin broccoli significantly reduces plasma LDL-C. PMID:25851421

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

    PubMed

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

    2016-04-01

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

  15. 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

  16. 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

  17. Hepatic Gene Expression Related to Lower Plasma Cholesterol in Hamsters Fed High Fat Diets Supplemented with Blueberry Pomace and Extract

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We analyzed plasma lipid profiles, and genes related to cholesterol and bile acid metabolism, and inflammation in livers as well as adipose tissue from Syrian Golden hamsters fed high-fat diets supplemented with blueberry (BB) pomace byproducts including 8% dried whole blueberry peels (BBPWHL), 2% d...

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

    PubMed

    Rai, Himanshu; Dhaneshwar, Suneela S

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  1. Citrulline increases cholesterol efflux from macrophages in vitro and ex vivo via ATP-binding cassette transporters

    PubMed Central

    Uto-Kondo, Harumi; Ayaori, Makoto; Nakaya, Kazuhiro; Takiguchi, Shunichi; Yakushiji, Emi; Ogura, Masatsune; Terao, Yoshio; Ozasa, Hideki; Sasaki, Makoto; Komatsu, Tomohiro; Sotherden, Grace Megumi; Hosoai, Tamaki; Sakurada, Masami; Ikewaki, Katsunori

    2014-01-01

    Reverse cholesterol transport (RCT) is a mechanism critical to the anti-atherogenic property of HDL. Although citrulline contributes to the amelioration of atherosclerosis via endothelial nitric oxide production, it remains unclear whether it affects RCT. This study was undertaken to clarify the effects of citrulline on expressions of specific transporters such as ATP binding cassette transporters (ABC)A1 and ABCG1, and the cholesterol efflux from macrophages to apolipoprotein (apo) A-I or HDL in vitro and ex vivo. Citrulline increased ABCA1 and ABCG1 mRNA and protein levels in THP-1 macrophages, translating into enhanced apoA-I- and HDL-mediated cholesterol efflux. In the human crossover study, 8 healthy male volunteers (age 30–49 years) consumed either 3.2 g/day citrulline or placebo for 1 week. Citrulline consumption brought about significant increases in plasma levels of citrulline and arginine. Supporting the in vitro data, monocyte-derived macrophages (MDM) differentiated under autologous post-citrulline sera demonstrated enhancement of both apoA-I- and HDL-mediated cholesterol efflux through increased ABCA1 and ABCG1 expressions, compared to MDM differentiated under pre-citrulline sera. However, the placebo did not modulate these parameters. Therefore, in addition to improving endothelium function, citrulline might have an anti-atherogenic property by increasing RCT of HDL. PMID:25120277

  2. 2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

    PubMed Central

    Andersen, Charlotte; Schjoldager, Janne G.; Tortzen, Christian G.; Vegge, Andreas; Hufeldt, Majbritt R.; Skaanild, Mette T.; Vogensen, Finn K.; Kristiansen, Karsten; Hansen, Axel K.; Nielsen, John

    2013-01-01

    Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice. PMID:23738334

  3. Plasma cholesterol-lowering activity of gingerol- and shogaol-enriched extract is mediated by increasing sterol excretion.

    PubMed

    Lei, Lin; Liu, Yuwei; Wang, Xiaobo; Jiao, Rui; Ma, Ka Ying; Li, Yuk Man; Wang, Lijun; Man, Sun Wa; Sang, Shengmin; Huang, Yu; Chen, Zhen-Yu

    2014-10-29

    The present study investigated the cholesterol-lowering activity of gingerol- and shogaol-enriched ginger extract (GSE). Thirty hamsters were divided into three groups and fed the control diet or one of the two experimental diets containing 0.5 and 1.0% GSE. Plasma total cholesterol, liver cholesterol, and aorta atherosclerotic plaque were dose-dependently decreased with increasing amounts of GSE added into diets. The fecal sterol analysis showed dietary GSE increased the excretion of both neutral and acidic sterols in a dose-dependent manner. GSE down-regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5), whereas it up-regulated hepatic cholesterol-7α-hydroxylase (CYP7A1). It was concluded that beneficial modification of the lipoprotein profile by dietary GSE was mediated by enhancing excretion of fecal cholesterol and bile acids via up-regulation of hepatic CYP7A1 and down-regulation of mRNA of intestinal NPC1L1, ACAT2, and MTP. PMID:25290252

  4. Peptides identified in soybean protein increase plasma cholesterol in mice on hypercholesterolemic diets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The in vitro micellar cholesterol displacement assay has been used to identify peptides that may potentially reduce cholesterol in vivo. We tested two of these peptides, LPYPR and WGAPSI, derived from soybean protein (SP) that have been reported to displace cholesterol from micelles by feeding them...

  5. Aronia melanocarpa (chokeberry) polyphenol-rich extract improves antioxidant function and reduces total plasma cholesterol in apolipoprotein E knockout mice.

    PubMed

    Kim, Bohkyung; Ku, Chai Siah; Pham, Tho X; Park, Youngki; Martin, Derek A; Xie, Liyang; Taheri, Rod; Lee, Jiyoung; Bolling, Bradley W

    2013-05-01

    We hypothesized that a polyphenol-rich chokeberry extract (CBE) would modulate hepatic lipid metabolism and improve antioxidant function in apolipoprotein E knockout (apoE(-/-)) mice. ApoE(-/-) mice were fed diets containing 15% fat with 0.2% cholesterol alone or supplemented with 0.005% or 0.05% CBE for 4 weeks. CBE polyphenol content was determined by the total phenols, 4-dimethylaminocinnamaldehyde, and ultra high-performance liquid chromatography-mass spectrometry methods. The 0.05% CBE diet provided mice with mean daily doses of 1.2 mg gallic acid equivalents of total phenols, 0.19 mg anthocyanins, 0.17 mg phenolic acids, 0.06 mg proanthocyanidins (as catechin-equivalents), and 0.02 mg flavonols. The 0.05% CBE group had 12% less plasma total cholesterol concentrations than the control. Despite the hypocholesterolemic effect of CBE, hepatic mRNA levels of low-density lipoprotein receptor, hydroxyl-3-methylglutaryl coenzyme A reductase and cholesterol 7α-hydroxylase in CBE-fed mice were not significantly different from controls. Dietary CBE did not alter hepatic lipid content or the hepatic expression of genes involved in lipogenesis and fatty acid β-oxidation such as fatty acid synthase, carnitine palmitoyltransferase 1 and acyl-CoA oxidase. Plasma paraoxonase and catalase activities were significantly increased in mice fed 0.05% CBE. Both CBE diets increased hepatic glutathione peroxidase (GPx) activity but the 0.05% CBE group had 24% less proximal intestine GPx activity relative to controls. Thus, dietary CBE lowered total cholesterol and improved plasma and hepatic antioxidant function at nutritionally-relevant doses in apoE(-/-) mice. Furthermore, the CBE cholesterol-lowering mechanism in apoE(-/-) mice was independent of hepatic expression of genes involved in cholesterol metabolism. PMID:23684442

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

    PubMed

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

    2013-04-01

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

  7. 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

  8. Zymosan-mediated inflammation impairs in vivo reverse cholesterol transport[S

    PubMed Central

    Malik, Priya; Berisha, Stela Z.; Santore, Jennifer; Agatisa-Boyle, Colin; Brubaker, Gregory; Smith, Jonathan D.

    2011-01-01

    Inflammation has been proposed to impair HDL function and reverse cholesterol transport (RCT). We investigated the effects of inflammation mediated by zymosan, a yeast glucan, on multiple steps along the RCT pathway in vivo and ex vivo. Acute inflammation with 70 mg/kg zymosan impaired RCT to plasma, liver, and feces similarly by 17–22% (P < 0.05), with no additional block at the liver. Hepatic gene expression further demonstrated no change in ABCG5, ABCB4, and ABCB11 expression but a decline in ABCG8 mRNA (32% P < 0.05). Plasma from zymosan-treated mice had a 21% decrease in cholesterol acceptor ability (P < 0.01) and a 35% decrease in ABCA1-specfic efflux capacity (P < 0.01) in vitro. Zymosan treatment also decreased HDL levels and led to HDL remodeling with increased incorporation of serum amyloid A. In addition, cholesterol efflux from cultured macrophages declined with zymosan treatment in a dose dependant manner. Taken together, our results suggest that zymosan impairs in vivo RCT primarily by decreasing macrophage-derived cholesterol entering the plasma, with minimal additional blocks downstream. Our study supports the notion that RCT impairment is one of the mechanisms for the increased atherosclerotic burden observed in inflammatory conditions. PMID:21335620

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

    PubMed Central

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

    2015-01-01

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

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

    DOE PAGESBeta

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

    2015-03-04

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

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

    SciTech Connect

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

    2015-03-04

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

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

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

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  15. Inhibition of cholesterol ester transfer protein CGS 25159 and changes in lipoproteins in hamsters.

    PubMed

    Kothari, H V; Poirier, K J; Lee, W H; Satoh, Y

    1997-01-01

    As a result of screening, several isoflavans were identified to be antagonists of cholesterol ester transfer protein (CETP) activity. The present study evaluates CGS 25159, a synthetic isoflavan, as a putative inhibitor of CETP activity of human and hamster plasma. Determined by [3]CE transfer from HDL to VLDL + LDL fraction or by fluorescent-CE transfer assay, CGS 25159 inhibited CETP in both human plasma bottom fraction (d = 1.21 g/ml) and in plasma from Golden Syrian Hamsters with an IC50 < 10 microM. The compound also inhibited (IC 50 approximately equal to 15 microM) the reciprocal transfer of triglycerides in the incubated whole plasma from normal and hyperlipidemic hamsters. When orally administered to normolipidemic hamsters, CGS 25159 (10 mg/kg, 4 days) reduced plasma transfer activity by 35-60%. Treatment with CGS 25159 (10 and 30 mg/kg, p.o.) resulted in dose dependent and time dependent changes in CETP activity. After two weeks of treatment at 10 mg/kg, the changes in VLDL + LDL cholesterol, total triglycerides and HDL cholesterol were -22 +/- 4.6*, -23 +/- 7.5 and +10 +/- 2.8%, respectively. The corresponding changes at 30 mg/kg were -28 +/- 5.5*, -38 +/- 6.8* and +29 +/-4.4.*%, (*, P, 0.05; mean +/- S.E.M., n = 6). A single spin gradient density ultracentrifugation of plasma lipoproteins and treated animals showed an increase in HDL cholesterol and a redistribution to larger HDL particles. These data support the contention that pharmacological down regulation of CETP activity could result in favorable changes in lipoprotein profile. PMID:9051198

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

    PubMed Central

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

    2015-01-01

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

  17. Perfluoroalkyl substances and lipid concentrations in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study

    PubMed Central

    Starling, Anne P.; Engel, Stephanie M.; Whitworth, Kristina W.; Richardson, David B.; Stuebe, Alison M.; Daniels, Julie L.; Haug, Line Småstuen; Eggesbø, Merete; Becher, Georg; Sabaredzovic, Azemira; Thomsen, Cathrine; Wilson, Ralph E.; Travlos, Gregory S.; Hoppin, Jane A.; Baird, Donna D.; Longnecker, Matthew P.

    2013-01-01

    Background Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia. Methods This cross-sectional analysis included 891 pregnant women enrolled in the Norwegian Mother and Child (MoBa) Cohort Study in 2003–2004. Non-fasting plasma samples were obtained at mid-pregnancy and analyzed for nineteen PFASs. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in plasma. Linear regression was used to quantify associations between each PFAS exposure and each lipid outcome. A multiple PFAS model was also fitted. Results Seven PFASs were quantifiable in >50% of samples. Perfluorooctane sulfonate (PFOS) concentration was associated with total cholesterol, which increased 4.2 mg/dL per interquartile shift (95% CI=0.8, 7.7) in adjusted models. Five of the seven PFASs studied were positively associated with HDL cholesterol, and all seven had elevated HDL associated with the highest quartile of exposure. Perfluoroundecanoic acid showed the strongest association with HDL: HDL increased 3.7 mg/dL per interquartile shift (95% CI=2.5, 4.9). Conclusion Plasma concentrations of PFASs were positively associated with HDL cholesterol, and PFOS was positively associated with total cholesterol in this sample of pregnant Norwegian women. While elevated HDL is not an adverse outcome per se, elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal. PMID:24189199

  18. 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

  19. 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

  20. A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane.

    PubMed

    Smart, E J; Ying, Y s; Donzell, W C; Anderson, R G

    1996-11-15

    Caveolin is a 22-kDa membrane protein found associated with a coat material decorating the inner membrane surface of caveolae. A remarkable feature of this protein is its ability to migrate from caveolae directly to the endoplasmic reticulum (ER) when membrane cholesterol is oxidized. We now present evidence caveolin is involved in transporting newly synthesized cholesterol from the ER directly to caveolae. MA104 cells and normal human fibroblasts transported new cholesterol to caveolae with a half-time of approximately 10 min. The cholesterol then rapidly flowed from caveolae to non-caveolae membrane. Cholesterol moved out of caveolae even when the supply of fresh cholesterol from the ER was interrupted. Treatment of cells with 10 microg/ml progesterone blocked cholesterol movement from ER to caveolae. Simultaneously, caveolin accumulated in the lumen of the ER, suggesting cholesterol transport is linked to caveolin movement. Caveolae fractions from cells expressing caveolin were enriched in cholesterol 3-4-fold, while the same fractions from cells lacking caveolin were not enriched. Cholesterol transport to the cell surface was nearly 4 times more rapid in cells expressing caveolin than in matched cells lacking caveolin. PMID:8910609

  1. Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation.

    PubMed

    Evans, Malkanthi; Rumberger, John A; Azumano, Isao; Napolitano, Joseph J; Citrolo, Danielle; Kamiya, Toshikazu

    2014-01-01

    High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to 16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines. PMID:24600231

  2. Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation

    PubMed Central

    Evans, Malkanthi; Rumberger, John A; Azumano, Isao; Napolitano, Joseph J; Citrolo, Danielle; Kamiya, Toshikazu

    2014-01-01

    High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines. PMID:24600231

  3. 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

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

    PubMed

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

    2007-12-01

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

  6. 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

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

    PubMed Central

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

    2015-01-01

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

  8. Lipid-lowering effects of methanolic extract of Vernonia amygdalina leaves in rats fed on high cholesterol diet.

    PubMed

    Adaramoye, Oluwatosin A; Akintayo, Olajumoke; Achem, Jonah; Fafunso, Michael A

    2008-01-01

    We investigated the lipid-lowering effects of methanolic extract of Vernonia amygdalina (VA) leaves in rats fed an high cholesterol diet, and compared with a standard hypolipidemic drug, Questran (Qu). The effects of VA on the lipid profile were assessed by measuring the levels of total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, lipid peroxidation (LPO), phospholipid, and glutathione (GSH) in the plasma and liver of the rats. Administration of cholesterol at a dose of 30 mg/0.3 ml, five times in a week for nine consecutive weeks resulted in a significant increase (p < 0.05) in plasma and post mitochondrial fraction (PMF) cholesterol levels by 33% and 55%, respectively. However, treatment with extract of VA at doses of 100 and 200 mg/kg caused a dose dependent reduction in the plasma and PMF cholesterol by 20%, 23% and 23%, 29%, respectively. Similar reduction in cholesterol levels was obtained in Qu-treated rats. Furthermore, VA at 200 mg/kg decreased the plasma and PMF LDL-cholesterol levels by 23% and 49%, and also decreased plasma and PMF triglyceride levels by 29% and 28%, respectively. Also, VA at 100 and 200 mg/kg caused a dose-dependent increase in plasma HDL-cholesterol levels by 41% and 59%, respectively. However, there were no significant differences (p > 0.05) in the PMF HDL-cholesterol and phospholipid levels of the treated rats when compared to hypercholesterolemic rats. There were significant decreases (p < 0.05) in the LPO levels of extract-treated rats. Precisely, VA at 100 and 200 mg/kg decreased the levels of plasma and PMF LPO by 38%, 42% and 35%, 45%, respectively. In addition, VA augmented the cholesterol-induced decrease in PMF glutathione levels of the rats. Taken together, these results suggest the lipid-lowering effects of VA and, probably serve as a new potential natural product for the treatment of hyperlipidemia. PMID:18629374

  9. Free cholesterol is a potent regulator of lipid transfer protein function

    SciTech Connect

    Morton, R.E.

    1988-09-05

    This study investigates the effect of altered lipoprotein free cholesterol (FC) content on the transfer of cholesteryl ester (CE) and triglyceride (TG) from very low- (VLDL), low- (LDL), and high-(HDL) density lipoproteins by the plasma-derived lipid transfer protein (LTP). The FC content of VLDL and HDL was selectively altered by incubating these lipoproteins with FC/phospholipid dispersions of varying composition. FC-modified lipoproteins were then equilibrated with (3H) TG, (14C)CE-labeled lipoproteins of another class to facilitate the subsequent modification of the radiolabeled donor lipoproteins. LTP was added and the extent of radiolabeled TG and CE transfer determined after 1 h. With either LDL or VLDL as lipid donor, an increase in the FC content of these lipoproteins caused a concentration-dependent inhibition (up to 50%) of CE transfer from these particles, without any significant effect on TG transfer. In contrast, with HDL as donor, increasing the HDL FC content had little effect on CE transfer from HDL, but markedly stimulated (up to 2.5-fold) the transfer of TG. This differential effect of FC on the unidirectional transfer of radiolabeled lipids from VLDL and HDL led to marked effects on LTP-facilitated net mass transfer of lipids. During long-term incubation of a constant amount of LTP with FC-modified VLDL and HDL, the extent of net mass transfer was linearly related to lipoprotein FC content; a 4-fold increase in FC content resulted in a 3-fold stimulation of the CE mass transferred to VLDL, which was coupled to an equimolar, reciprocal transfer of TG mass to HDL. Since lipid transfer between lipoproteins is integral to the process of reverse cholesterol transport, we conclude that lipoprotein FC levels are a potent, positive regulator of the pathways involved in sterol clearance. FC may modulate lipid transfer by altering the availability of CE and TG to LTP at the lipoprotein surface.

  10. Polysaccharide gel coating of the leaves of Brasenia schreberi lowers plasma cholesterol in hamsters.

    PubMed

    Kim, Hyunsook; Wang, Qian; Shoemaker, Charles F; Zhong, Fang; Bartley, Glenn E; Yokoyama, Wallace H

    2015-01-01

    Brasenia schreberi ( chún cài) is an invasive aquatic weed found in the USA, but the plant has economic value in Asia where it is cultivated for food. The young leaves of B. schreberi are coated with gelatinous water-insoluble mucilage. This mucilage is a polysaccharide composed of galactose, mannose, fucose, and other monosaccharides. Because some carbohydrate gels are hypocholesterolemic, we evaluated their cholesterol-lowering properties in male hamsters fed hypercholesterolemic diets containing 2% gel coat from B. schreberi (GEL), or 1% cholestyramine (CA), or 5% hydroxypropyl methylcellulose (HPMC), and compared them to 5% microcrystalline cellulose (control) for 3 weeks. We found that very-low-density lipoprotein-, low-density lipoprotein-, and total-cholesterol concentrations in plasma were significantly lowered by GEL, CA, and HPMC compared to control. High-density lipoprotein-cholesterol concentration was lowered by CA and HPMC. Body weights and abdominal adipose tissue weight of GEL and control group animals were greater than those of the CA and HPMC groups. Fecal lipid excretion was greater in the CA and HPMC groups than in the control group. Expression of hepatic CYP51 and CYP7A1 mRNA was upregulated by CA, HPMC, and GEL, indicating increased hepatic cholesterol and bile acid synthesis. Expression of low-density lipoprotein receptor mRNA was upregulated by all treatments. These results suggest that modulation of hepatic expression of cholesterol and bile acid metabolism-regulated genes contributes to the cholesterol-lowering effects of GEL. PMID:26151010

  11. Cholesterol transport from plasma membranes to intracellular membranes is inhibited by 3 beta-[2-(diethylamino)ethoxy]androst-5-en-17-one.

    PubMed

    Härmälä, A S; Pörn, M I; Mattjus, P; Slotte, J P

    1994-03-24

    The compound U1866A (3 beta-[2-(diethylamino)ethoxy]androst-5-en-17-one) has been shown to inhibit the cellular transfer of low-density lipoprotein-derived cholesterol from lysosomes to plasma membranes (Liscum and Faust (1989) J. Biol. Chem. 264, 11796-806). We have in this study examined the effects of U18666A on cholesterol translocation from plasma membranes to intracellular membranes. Translocation of plasma membrane cholesterol was induced by degradation of plasma membrane sphingomyelin. The sphingomyelinase-induced activation of the acyl-CoA cholesterol acyl transferase (ACAT) reaction was completely inhibited in a dose-dependent manner by U18666A, both in cultured human skin fibroblasts and baby hamster kidney cells. Half-maximal inhibition (within 60 min) was obtained with 0.5-1 microgram/ml of U18666A. A time-course study indicated that the onset of inhibition was rapid (within 10-15 min), and reversible if U18666A was removed from the incubation mixture. Using a cholesterol oxidase assay, we observed that the extent of plasma membrane cholesterol translocation in sphingomyelinase-treated HSF cells was significantly lowered in the presence of U18666A (at 3 micrograms/ml). The effect of U18666A on cholesterol translocation was also fully reversible when the drug was withdrawn. In mouse Leydig tumor cells, labeled to constant specific activity with [3H]cholesterol, the compound U18666A inhibited in a dose-dependent manner the cyclic AMP-stimulated secretion of [3H]steroid hormones. The effects seen with compound U18666A appeared to be specific for this molecule, since another hydrophobic amine, imipramine, did not in our experiments affect cholesterol translocation or ACAT activation. Since different cell types display sensitivity to U18666A in various intracellular cholesterol transfer processes, they appear to have a common U18666A-sensitive regulatory mechanism. PMID:8130265

  12. Atorvastatin and fenofibrate combination induces the predominance of the large HDL subclasses and increased apo AI fractional catabolic rates in New Zealand white rabbits with exogenous hypercholesterolemia.

    PubMed

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

    2015-08-01

    The anti-atherogenic properties of high-density lipoproteins (HDLs) may be related to their structure and metabolism. The HDL physicochemical characteristics that determine their plasma clearance during treatment with statins and fibrates are not well understood. In this study, we analyzed HDL-apo AI fractional catabolic rates (FCRs), size distributions, and the lipid composition of the HDL subclasses in New Zealand white rabbits with exogenous dyslipidemia that received low doses of atorvastatin and fenofibrate. Hypercholesterolemia decreased only partially with the combination of both drugs. HDL size distribution shifted toward larger particles among the groups of rabbits that received atorvastatin, fenofibrate, or their combination, compared with both the control group and the dyslipidemic group. The HDL subclasses were significantly rich in cholesterol in each of the groups compared with controls. The structural changes noted in the HDL subclasses were not associated with impaired plasma paraoxonase-1 (PON1) activity. The groups receiving monotherapy and the drug combination group were all associated with a higher apo AI FCR value compared with both the dyslipidemic rabbits and the control group. In conclusion, the combination of atorvastatin and fenofibrate induced a more favorable HDL subclass profile than did the individual use of these drugs. Similarly, the apo AI FCR values were augmented in every group receiving drug treatment (either monotherapy or combination therapy) in the setting of hypercholesterolemia. The anti-atherogenic properties of HDLs, excluding their capacity to bind PON1, may be enhanced by the structural and metabolic modifications induced by the combination of atorvastatin and fenofibrate. PMID:25982284

  13. The effects of genotype and infant weight on adult plasma levels of fibrinogen, factor VII, and LDL cholesterol are additive.

    PubMed Central

    Henry, J A; Bolla, M; Osmond, C; Fall, C; Barker, D J; Humphries, S E

    1997-01-01

    High circulating levels of cholesterol, particularly low density lipoprotein (LDL) cholesterol and the clotting factors fibrinogen and factor VII, are associated with increased risk of myocardial infarction. Variations in the plasma levels of these factors are determined in part by polymorphisms in the genes concerned and also by weight at 1 year (infant weight). We have looked at the possibility of interactions between these genetic factors and infant weight in a sample of 290 men and 192 women from Hertfordshire using the beta-fibrinogen G/A-455, factor VII R353Q, and ApoE polymorphisms. The rare allele frequencies of the three polymorphisms were 0.19 for beta-fibrinogen, 0.10 for factor VII, and 0.07 and 0.13 for the 2 and 4 alleles of ApoE, and these frequencies were not different in subjects of different infant weight. In this sample, the polymorphisms showed the expected effects on plasma levels of fibrinogen, factor VII, and LDL cholesterol. The A-455 allele was associated with higher fibrinogen levels but the effect was only statistically significant in women (p = 0.003). The R353 allele was associated with higher factor VII activity in both men and women (p < 0.0001 for both). The ApoE2 allele was associated with lower levels of LDL cholesterol (p = 0.03 in men, p = 0.006 in women), while the ApoE4 allele was associated with higher levels (p < 0.001 in men, not significant in women). In this sample of men and women the effect of low infant weight was only associated with significant effects on fibrinogen and LDL cholesterol in the group of men (p = 0.005 and p = 0.008 respectively). Compared with the E3E3 subjects, the LDL lowering effect of the E2 allele and the raising effect of the E4 allele was greater in those with low infant weight compared with those with high infant weight (low v high infant weight for E2: 12.7% v 9.4%; for E4 12.7% v 8.5%). Although in this sample the interactive effect did not reach statistical significance, the additive effect

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

    PubMed

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

    2014-11-01

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

  15. Three-week psyllium-husk supplementation: effect on plasma cholesterol concentrations, fecal steroid excretion, and carbohydrate absorption in men.

    PubMed

    Abraham, Z D; Mehta, T

    1988-01-01

    This study was conducted to determine the effect of psyllium husk on plasma total and lipoprotein cholesterol in healthy human subjects and to elucidate possible hypocholesterolemic mechanisms. Seven males were given a nutritionally controlled diet based on their usual intake for x = 3 wk followed by 3 wk in which 21 g/d per person psyllium husk was added to the basal diet. After 10 d and after 3 wk of psyllium supplementation, total, low-density, and high-density cholesterol were reduced (p less than 0.002, p less than 0.01, and p less than 0.03, respectively). Fecal steroid excretion, determined from 5-d collections, was not affected by psyllium supplementation. Although psyllium tended to delay lipid absorption, plasma triglycerides, retinyl esters, glucose, insulin, and glucagon quantitated during meal tolerance tests given on the last day of each diet period were not different (p greater than 0.05). Thus the cholesterol-lowering mechanism of psyllium may not involve increased bile acid excretion or decreases in nutrient absorption. PMID:2827455

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

    PubMed

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

    2015-06-01

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

  17. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the ut...

  18. New horizons for cholesterol ester transfer protein inhibitors.

    PubMed

    Schwartz, Gregory G

    2012-02-01

    High-density lipoprotein (HDL) cholesterol levels bear an inverse relationship to cardiovascular risk. To date, however, no intervention specifically targeting HDL has been demonstrated to reduce cardiovascular risk. Cholesterol ester transfer protein (CETP) mediates transfer of cholesterol ester from HDL to apolipoprotein B-containing particles. Most, but not all observational cohort studies indicate that genetic polymorphisms of CETP associated with reduced activity and higher HDL cholesterol levels are also associated with reduced cardiovascular risk. Some, but not all studies indicate that CETP inhibition in rabbits retards atherosclerosis, whereas transgenic CETP expression in mice promotes atherosclerosis. Torcetrapib, the first CETP inhibitor to reach phase III clinical development, was abandoned due to excess mortality associated with increases in aldosterone and blood pressure. Two other CETP inhibitors have entered phase III clinical development. Anacetrapib is a potent inhibitor of CETP that produces very large increases in HDL cholesterol and large reductions in low-density lipoprotein (LDL) cholesterol, beyond those achieved with statins. Dalcetrapib is a less potent CETP inhibitor that produces smaller increases in HDL cholesterol with minimal effect on LDL cholesterol. Both agents appear to allow efflux of cholesterol from macrophages to HDL in vitro, and neither agent affects blood pressure or aldosterone in vivo. Two large cardiovascular outcomes trials, one with anacetrapib and one with dalcetrapib, should provide a conclusive test of the hypothesis that inhibition of CETP decreases cardiovascular risk. PMID:22083134

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

    PubMed Central

    Levkau, Bodo

    2015-01-01

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

  20. Bis(monoacylglycero)phosphate accumulation in macrophages induces intracellular cholesterol redistribution, attenuates liver-X receptor/ATP-Binding cassette transporter A1/ATP-binding cassette transporter G1 pathway, and impairs cholesterol efflux

    PubMed Central

    Luquain-Costaz, Céline; Lefai, Etienne; Arnal-Levron, Maud; Markina, Daria; Sakaï, Shota; Euthine, Vanessa; Makino, Asami; Guichardant, Michel; Yamashita, Shizuya; Kobayashi, Toshihide; Lagarde, Michel; Moulin, Philippe; Delton-Vandenbroucke, Isabelle

    2013-01-01

    Objective Endosomal signature phospholipid bis(monoacylglycero)phosphate (BMP) has been involved in the regulation of cellular cholesterol homeostasis. Accumulation of BMP is a hallmark of lipid storage disorders and was recently reported as a noticeable feature of oxidized LDL-laden macrophages. This study was designed to delineate the consequences of macrophage BMP accumulation on intracellular cholesterol distribution, metabolism and efflux and to unravel the underlying molecular mechanisms. Methods and results We have developed an experimental design to specifically increase BMP content in RAW macrophages. Following BMP accumulation, cell cholesterol distribution was markedly altered despite no change in LDL uptake and hydrolysis, cholesterol esterification, or total cell cholesterol content. The expression of cholesterol regulated genes SREBP2 and HMGCoAR was decreased by 40%, indicative of an increase of endoplasmic reticulum associated-cholesterol. Cholesterol delivery to plasma membrane was reduced as evidenced by the 20% decrease of efflux by cyclodextrin. Functionally, BMP accumulation reduced cholesterol efflux to both apoA1 and HDL by 40%, correlated with a 40% decrease in mRNA contents of ABCA1 and ABCG1 transporters and LXR α and β. Foam cell formation induced by oxidized LDL exposure was exacerbated in BMP enriched cells. Conclusion The present work shows for the first time a strong functional link between BMP and cholesterol regulating genes involved in both intracellular metabolism and efflux. We propose that accumulation of cellular BMP might contribute to the deregulation of cholesterol homeostasis in atheromatous macrophages. PMID:23788762

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

    PubMed Central

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

    2013-01-01

    To evaluate the impact of low levels of high density lipoprotein cholesterol (HDL-c) on patients with LDL-c average levels, focusing on oxidative, lipidic, and inflammatory profiles. Patients with cardiovascular risk factors (n = 169) and control subjects (n = 73) wer